Nicotinamide riboside and its derivatives in intravenous preparations and methods of use thereof

Abstract

A stable intravenous (IV) composition comprises, in the intravenous form, nicotinamide riboside (NR) as described, or another nicotinyl riboside compound that is an NAD+ precursor. NR chloride may be provided in an intravenous (IV) formulation for administration to human subjects.

Description

[Technical Field]

[0001] Technical field The present invention relates to a process for providing nicotinamide riboside (NR) or salts or solvates thereof, or other nicotinyl riboside compounds that are NAD+ precursors, in the intravenous form, for intravenous administration. NR chlorides may be provided in intravenous (IV) formulations for administration to mammals, including human subjects. [Background technology]

[0002] background Nicotinamide riboside (NR) is a beneficial physiologically active intermediate. This compound is associated with NAD+-related processing and metabolic pathways (J. Preiss and P. Handler, J. Biol. Chem. (1958) 233:488-492). Nicotinic acid and nicotinamide, collectively known as niacin, are the vitamin form of nicotinamide adenine dinucleotide (NAD+). Eukaryotes can de novo synthesize NAD+ from tryptophan via the kynurenine pathway (Krehl, et al. Science (1945) 101:489-490; Schutz and Feigelson, J. Biol. Chem. (1972) 247:5327-5332), and niacin supplementation can prevent pellagra, which can occur in populations with a tryptophan-deficient diet. Thus, it is well established that nicotinic acid is phosphoribosylated to nicotinic acid mononucleotide (NaMN), then adenylated to form nicotinic acid adenine dinucleotide (NaAD), and subsequently amidated to form NAD+ (Preiss and Handler (1958) 233:488-492; Ibid., 493-50).

[0003] Nicotinamide adenine dinucleotide ("NAD") +Nicotinamide is an enzyme cofactor essential for the function of several enzymes associated with reduction-oxidation reactions and energy metabolism (Katrina L. Bogan & Charles Brenner, Nicotinic Acid, Nicotinamide, and Nicotinamide Riboside: A Molecular Evaluation of NAD). + Precursor Vitamins in Human Nutrition,28 Annual Review of Nutrition 115(2008)). N.A.D. + It functions as an electron carrier in the cellular metabolism of amino acids, fatty acids, and carbohydrates. (Bogan & Brenner 2008). NAD + It acts as an activator and substrate for sirtuins, a family of protein deacetylases associated with metabolic function and life extension in lower organisms. (Laurent Mouchiroud et al., The NAD) + / Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling, 154 Cell 430(2013)). N.A.D. + Through its coenzyme activity, along with the strict regulation of its biosynthesis and bioavailability, it plays a crucial role in the metabolic monitoring system that is clearly involved in the aging process.

[0004] NAD(P) +When converted intracellularly, vitamin B3 is used as a co-substrate in two types of intracellular regulation (adenosine diphosphate ribosylation and deacetylation) that control many essential signaling events, is a cofactor for over 400 redox enzymes, and thus controls metabolism. This is revealed by a series of metabolic endpoints including the deacetylation of important regulatory proteins, increased mitochondrial activity, and oxygen consumption. Critically, the NAD(P)(H)-cofactor family can promote mitochondrial dysfunction and cellular malfunction when present at suboptimal intracellular concentrations. Vitamin B3 deficiency results in cell inactivity manifest through NAD + depletion, and further NAD + bioavailability beneficial effects are mainly observed in cells and tissues with impaired metabolism and mitochondrial function. Interestingly, supplementation with nicotinic acid ("NA") and nicotinamide ("Nam") is important in acute vitamin B3 deficiency, while all three metabolites contribute to NAD + biosynthesis at the cellular level, but do not show the same physiological results compared to nicotinamide riboside ("NR") supplementation. This emphasizes the complexity of the pharmacokinetics and biodistribution of B3-vitamin components.

[0005] De novo NAD + is obtained from tryptophan, while the majority of intracellular NAD + is thought to be recycled through the efficient reuse of nicotinamide ("Nam"). (Anthony Rongvaux et al., Reconstructing eukaryotic NAD metabolism, 25 BioEssays 683 (2003)). Importantly, these recycling and de novo pathways clearly depend on the functional forms of vitamins B1, B2 and B6 to generate NAD + via phosphoriboside pyrophosphate intermediates. Nicotinamide riboside ("NR") is independent of vitamins B1, B2 and B6 for NAD+ NAD is the only form of vitamin B3 that can be produced. + The reuse pathway using nicotinamide riboside ("NR") for production is expressed in most eukaryotes.

[0006] Major NADs to replenish the reuse pathway + The precursors are nicotinamide ("Nam") and nicotinamide riboside ("NR") (Bogan & Brenner 2008). From the tests, nicotinamide riboside ("NR") is found to be involved in the formation of nicotinamide mononucleotide ("NMN"), which is linked to NAD. + It has been shown to be used in a conserved reuse pathway that leads to synthesis. Upon entry into cells, nicotinamide riboside ("NR") is phosphorylated by NR kinase ("NRK"), which produces NMN, and this is then converted to NAD by nicotinamide mononucleotide adenylyltransferase ("NMNAT"). + It is converted to NAD in mitochondria. (Bogan & Brenner 2008). NMN is converted to NAD in mitochondria. + Since nicotinamide ("Nam") and nicotinamide riboside ("NR") are the only metabolites that can be converted to NAD, nicotinamide ("Nam") and nicotinamide riboside ("NR") are NAD. + Two candidate NADs that can replenish and thus improve the oxidation of mitochondrial fuel + It is a precursor. The key difference is that nicotinamide riboside ("NR") bypasses the rate-limiting step of the reuse pathway, nicotinamide phosphoribosyltransferase ("NAMPT"), and NAD + It has a direct two-step pathway for synthesis. Nicotinamide ("Nam") is NAD + NAMPT activity is required to produce it. This is because nicotinamide riboside ("NR") is very effective against NAD + This reinforces the fact that it is a precursor. Conversely, dietary NAD + Deficiency of precursors and / or tryptophan leads to pellagra, a disease characterized by dermatitis, diarrhea, and dementia (Bogan & Brenner 2008). In summary, NAD +NAD is necessary for normal mitochondrial function, and since mitochondria are the powerhouses of cells, NAD is essential for energy production within cells. + NAD+ is required. NAD+ was initially characterized as a coenzyme for oxidoreductases. Despite the fact that the conversion between NAD+, NADH, NADP, and NADPH is not accompanied by a comprehensive coenzyme deficiency, it has been discovered that NAD+ also undergoes metabolic turnover in cells for unknown purposes (Maayan, Nature (1964) 204:1169-1170). Sirtuin enzymes such as Sir2 of S. cerevisiae and their homologs deacetylate lysine residues by consuming the NAD+ equivalent, and this activity is required for Sir2's function as a transcriptional silencer (Imai, et al., Cold Spring Harb. Symp. Quant. Biol. (2000) 65:297-302). NAD+-dependent deacetylation is required not only for altering gene expression but also for suppressing ribosomal DNA recombination and extending lifespan in response to calorie restriction (Lin, et al., Science (2000) 289:2126-2128; Lin, et al., Nature (2002) 418:344-348). NAD+ is consumed by Sir2 to produce a mixture of 2'- and 3'O-acetylated ADP-ribose + nicotinamide and deacetylated polypeptides (Sauve, et al., Biochemistry (2001) 40:15456-15463). Further enzymes, including poly(ADP-ribose) polymerase and cADP-ribose synthase, are also NAD+-dependent and produce nicotinamide and ADP-ribosyl products (Ziegler, Eur.J.Biochem.(2000)267:1550-1564; Burkle, Bioessays(2001)23:795-806).

[0007] Due to the non - coenzyme properties of NAD⁺, new interest has been focused on NAD⁺ biosynthesis. Figure 1 depicts how NAR, NR, and other metabolic intermediates are converted into NAD⁺. Briefly, the biosynthetic pathway for NAR proceeds directly to NaMN, then to NaAD, and finally forms NAD⁺.

[0008] Certain drug therapies produce the characteristic sensation of pain associated with their intravenous (I.V.) administration. This includes potassium, which can cause a burning or painful sensation via I.V. when administered (Heng SY, Yap RT, Tie J, McGrouther DA (April 2020). “Peripheral Vein Thrombophlebitis in the Upper Extremity: A Systematic Review of a Frequent and Important Problem”. The American Journal of Medicine. 133(4):473 - 484). The occurrence of side effects specific to the dosing can be affected by the type of access (peripheral vs. central), the administration rate, or the quality of the drug being administered. If the administration of a pharmaceutical through an I.V. line is too rapid, a series of nonspecific symptoms such as erythema or rash, fever, etc. can occur; this is called the “drip reaction” and is often prevented by reducing the administration rate of the pharmaceutical.

[0009] If NR or its derivatives, salts or prodrugs as described herein can be developed in a stable intravenous (I.V.) formulation or a reconstitutable formulation for use in intravenous administration, for example, to enhance NAD⁺ levels in cells, and can be administered with minimal pain or unpleasant side effects or symptoms, this would represent a useful contribution to the art. Summary of the Invention Means for Solving the Problems

[0010] Summary The composition comprises NR or a salt or solvate thereof in a stable aqueous-based intravenous (IV) formulation. In one embodiment, the IV formulation contains a stable crystalline powder form of NR that can be reconstituted in an aqueous-based formulation for IV administration.

[0011] In one embodiment, the composition comprises NR in a stable, solid-reconstituteable form for use in aqueous-based intravenous (IV) formulations, or a salt or solvate thereof.

[0012] Another embodiment describes a method for preparing a composition comprising an aqueous intravenous (IV) formulation containing a compound selected from nicotinamide riboside, its salt or solvate or derivative thereof (including the reduced 1-4-dihydropyridine form), the method comprising (a) providing nicotinamide riboside (NR), its salt or solvate in crystalline or amorphous form; and (b) adding water or an aqueous-based liquid to dissolve the NR, its salt or solvate. Optionally, a solid or liquid inert carrier, such as a stabilizer and / or buffer, may be used.

[0013] In one embodiment, NR is prepared by a stabilization step. The NR structure and stability are maintained through the stabilization step. The stabilization step is performed on dried NR-Cl powder using e-beam or gamma irradiation. Sterile water added and mixed in a vial is prepared by several methods, including distillation and / or chemical treatment. In one embodiment, sterilization includes, but is not limited to, freeze-drying, gamma irradiation, e-beam irradiation, and heat sterilization. In one embodiment, a sterile filtrate of pre-mixed water and NR is prepared.

[0014] In further embodiments, a method for intravenous administration of NR, its salt, or its solvate to a human subject comprises: (a) providing an aqueous-based intravenous formulation containing NR, its salt, or its solvate; (b) intravenously administering an effective amount of the intravenous formulation to the human subject such that pain response or systemic discomfort (or other adverse effects causing discomfort) is minimized and / or comfort is maintained; and (c) continuously measuring and monitoring the pain response and / or comfort level of the human subject during intravenous administration of the intravenous formulation to ensure that pain response is minimized. Pain response measurement may include numerical variable analog scale (VAS) pain scale levels.

[0015] In other embodiments, derivatives of NR may be used in stable aqueous-based IV formulations, including but not limited to 1-(2',3',5'-triacetyl-beta-D-ribofuranosyl)-nicotinamide ("NR triacetate" or "NRTA"), nicotinic acid riboside (NAR), 1,4-dihydropyridyl reduced nicotinamide riboside ("NRH"), or 1,4-dihydropyridyl reduced nicotinic acid riboside ("NARH"). [Brief explanation of the drawing]

[0016] Brief explanation of the drawing [Figure 1] Figure 1 shows the NAD+ biosynthesis pathway. Nicotinic acid riboside (NAR) and nicotinamide riboside (NR) are shown. [Figure 2A] Figure 2A shows the infusion duration for NAD+IV, NR IV, and saline IV in Test 1. The infusion duration for Test 1 is shown in minutes, with a line drawn at the median and whiskers at the minimum and maximum values. Analysis by ANOVA; ns - no significant difference *p<0.05, **p<0.01, ****p<0.0001. [Figure 2B] Figure 2B shows the infusion duration for NAD+IV and NR IV in Study 2. The infusion duration for Study 2 is shown in minutes, with a line drawn at the median and whiskers at the minimum and maximum values. Analysis by ANOVA; ***p<0.001. [Figure 3] Figure 3 shows the time-course NAD measurements when evaluated using dried blood spots (DBS). Dried blood spots were collected at various time points to observe the dynamics of changes in NAD+ after intervention with NAD+IV, NR IV, saline, or oral NR. NAD levels are reported as mean with standard deviation. Analysis by ANOVA; *, ** = NR IV vs. saline (*p<0.05, **p<0.01); †, †† = NAD+IV vs. NR IV (†p<0.05, ††p<0.01); ‡, ‡‡ = NR IV vs. oral (‡p<0.05, ‡‡p<0.01). [Figure 4] Figure 4 shows the hematological measurements of neutrophils (%) over time in the test group. Analysis by ANOVA; * = NR IV vs. physiological saline (*p<0.05); † = NAD+ IV vs. NR IV (†p<0.05); ‡ = NR IV vs. oral (‡p<0.05). [Figure 5] Figure 5 shows the hematological measurements of lymphocytes (%) over time in the test group. Analysis by ANOVA; † = NAD+IV vs. NR IV (†p<0.05). [Figure 6] Figure 6 shows hematological measurements of white blood cell count (1000 units / microliter) over time in the test group. Analysis by ANOVA; * = NR IV vs. normal saline (*p<0.05); † = NAD+ IV vs. NR IV (†p<0.05). [Figure 7] Figure 7 shows the hematological measurements of absolute neutrophils (cell count / microliter) over time in the test group. Analysis by ANOVA; * = NR IV vs. physiological saline (*p<0.05); † = NAD+IV vs. NR IV (†p<0.05); ‡ = NR IV vs. oral (‡p<0.05). [Figure 8] Figure 8 shows the time course of IL-6 inflammatory marker (femtogram / mL) measurements in the test group. Levels were measured using a custom-made Mesoscale discovery S-PLEX Proinflammatory kit. [Figure 9]Figure 9 shows the time course of TNF-alpha inflammatory marker (femtogram / mL) measurements in the test group. Levels were measured using a custom-made Mesoscale discovery S-PLEX Proinflammatory kit. [Figure 10] Figure 10 shows the frequency of adverse reactions reported in the NAD+IV, NR IV, and saline treatment groups during administration. Adverse reactions include chest tightness, nausea, gastrointestinal disorders, stinging pain, myalgia, cold arm, burning / cooling sensation, head pressure, burning of the tongue / jaw, headache, hot flashes, fatigue, chills, nasal congestion, and dizziness. [Modes for carrying out the invention]

[0017] Detailed explanation Nicotinamide riboside ("NR") is given by formula (I): [ka] It is a pyridinium compound having [a specific characteristic].

[0018] In formula (I), NR may include a salt or a solvate. The salt may include a counterion (indicated as "X-") selected from chlorides, bromides, iodides, etc. For example, one useful salt is the chloride salt of NR ("NR-Cl"). Further salts may include, but are not limited to, fluoride, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbatate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate, succinate, sulfate, tartrate, hydrogen tartrate, malate, hydrogen malate, maleate, fumarate, citrate, steartrate, palmitate, myristate, laurate, caprate, caprilate, caproate, oleate, linoleate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, trichloroacetate, tribromoacetate, and trifluoroacetate. For NAR, NAMN, and NMN, if X- is absent, the counterion is optionally the internal salt and / or zwitterion.

[0019] NR requires a pharmaceutically acceptable and stable formulation for use in humans. For example, stable aqueous-based formulations containing NR, its salts, or its solvates suitable for use in humans in an IV formulation are provided herein.

[0020] In one embodiment, NR is available in an IV formulation as Niagen®+IV (also known as "NR IV"). Furthermore, Niagen®, which is nicotinamide riboside chloride, is the only active ingredient in the Tru Niagen® consumer product available from ChromaDex, Inc. (Los Angeles, California).

[0021] In a further embodiment, a derivative of NR is given by formula (Ia): [ka] (In the formula, R 6 The substituent is selected from the group consisting of hydrogen, C(O)R', C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, and preferred substituents include, but are not limited to, alkyl, alkylaryl, aryl, heteroaryl, halide, hydroxyl, carboxylate, carbonyl (including alkylcarbonyl and arylcarbonyl), phosphate, amino (including alkylamino, dialkylamino, hydroxylamino, dihydroxylamino, alkylhydroxylamino, arylamino, diarylamino, and alkylarylamino), thiol (including alkylthiol, arylthiol, and thiocarboxylate), sulfate, nitro, cyano, and azide; R' is hydrogen, -(C1-C 24 Selected from the group consisting of alkyl, -(C1-C8)cycloalkyl, aryl, heteroaryl, heterocyclic, aryl(C1-C4)alkyl, and heterocyclic(C1-C4)alkyl; R7 and R8 are independently hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C 24 The salt is intended to have a counterion selected from the group consisting of alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl (C1-C4) alkyl and substituted or unsubstituted heterocyclic (C1-C4) alkyl, or a salt, solvate or prodrac thereof. The salt is intended to have a counterion selected from the above, such as chloride, bromide, iodide ("X - This may include (defined as ").

[0022] This disclosure also includes, but is not limited to, other NAD+ precursors and their salts, solvates, mixtures, or derivatives thereof, such as one or more nicotinyl riboside compounds selected from nicotinic acid riboside (NAR, II), nicotinamide mononucleotide (NMN, III), reduced nicotinamide mononucleotide (NMNH), nicotinic acid mononucleotide (NaMN, IV), reduced nicotinic acid mononucleotide (NaMNH), reduced nicotinamide riboside (NRH, V), reduced nicotinic acid riboside (NARH, VI), NR triacetate (NRTA, VII, which is a type of Ia), NAR triacetate (NARTA, VIII), NRH triacetate (NRH-TA, IX), or NARH triacetate (NARH-TA, X). Examples of salts for NMNH and NAMNH include, but are not limited to, one or more sodium, potassium, lithium, magnesium, calcium, strontium, barium, or nitrogen-containing cations. In one embodiment, examples of nitrogen-containing cations include substituted or unsubstituted ammonium, substituted or unsubstituted pyridinium, substituted or unsubstituted pyrrolidinium, and substituted or unsubstituted imidazolium.

[0023] Riboside nicotinate (NAR) is given by formula (II): [ka] It is a pyridinium nicotinyl compound having [a specific characteristic].

[0024] Furthermore, X - If none is present, NAR is an internal salt (zwitterion). Further salts may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, strontium, barium, or nitrogen-containing cations.

[0025] Nicotinamide mononucleotide (NMN) is given by formula (III): [ka] It is a pyridinium nicotinyl compound having [a specific characteristic].

[0026] Furthermore, X - If none is present, NMN is an internal salt (zwitterion). Furthermore, the phosphate addition salt may or may not be limited to one or more sodium, potassium, lithium, magnesium, calcium, strontium, barium, or nitrogen-containing cations.

[0027] Nicotinic acid mononucleotide (NaMN) is given by formula (IV): [ka] It is a pyridinium nicotinyl compound having [a specific characteristic].

[0028] Furthermore, X - If none is present, NAMN is an internal salt (zwitterion). Furthermore, the phosphate addition salt may or may not be limited to one or more of sodium, potassium, lithium, magnesium, calcium, strontium, barium, or nitrogen-containing cations.

[0029] Reduced nicotinamide riboside ("NRH") is given by formula (V): [ka] It is a 1,4-dihydropyridyl reduced nicotinyl compound having [a specific characteristic].

[0030] Reduced nicotinic acid riboside ("NARH") is given by formula (VI): [ka] It is a 1,4-dihydropyridyl reduced nicotinyl compound having [a specific characteristic].

[0031] Furthermore, possible but not limited to sodium, potassium, lithium, magnesium, calcium, strontium, barium, or nitrogen-containing cations may be added as addition salts.

[0032] In the species of compound (Ia), the free hydrogen of the hydroxyl group on the ribose moiety of nicotinamide riboside (NR, I) is substituted by an acetyl group (CH3-C(=O)-), resulting in formula (VII): [ka] This can form 1-(2',3',5'-triacetyl-beta-D-ribofuranosyl)-nicotinamide ("NR triacetate" or "NRTA") having the following properties.

[0033] The free hydrogens of the hydroxyl group on the ribose moiety of nicotinic acid riboside (NAR, II) are substituted with acetyl groups (CH3-C(=O)-), resulting in formula (VIII): [ka] This can form 1-(2',3',5'-triacetyl-beta-D-ribofuranosyl)-nicotinic acid ("NAR triacetate" or "NARTA") having the following properties.

[0034] Furthermore, X - If none is present, NARTA is an internal salt (zwitterion). Furthermore, possible but not limited to sodium, potassium, lithium, magnesium, calcium, strontium, barium, or nitrogen-containing cations may be added as addition salts.

[0035] The free hydrogens of the hydroxyl group on the ribose moiety of reduced nicotinamide riboside (NRH, V) are substituted with acetyl groups (CH3-C(=O)-), resulting in formula (IX): [ka] This can form 1-(2',3',5'-triacetyl-beta-D-ribofuranosyl)-1,4-dihydronicotinamide ("NRH triacetate" or "NRH-TA") having the following properties.

[0036] In reduced nicotinic acid riboside (NARH, VI), the free hydrogen of the hydroxyl group on the ribose moiety is replaced with an acetyl group (CH3-C(=O)-), resulting in formula (X): [ka] This can form 1-(2',3',5'-triacetyl-beta-D-ribofuranosyl)-1,4-dihydronicotinic acid ("NARH triacetate" or "NARH-TA") having the following properties.

[0037] Further addition salts may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, strontium, barium, or nitrogen-containing cations.

[0038] For each of the following nicotinamide ribosides (NR, I), nicotinic acid riboside (NAR, II), nicotinamide mononucleotide (NMN, III), nicotinic acid mononucleotide (NaMN, IV), reduced nicotinamide riboside (NRH, V), reduced nicotinic acid riboside (NARH, VI), nicotinamide riboside triacetate (NRTA, VII), nicotinic acid riboside triacetate (NARTA, VIII), reduced nicotinamide riboside triacetate (NRH-TA, IX), and reduced nicotinic acid riboside triacetate (NARH-TA, X), the counterion X- is either absent or, if X- is present, X- is a bromide, iodide, fluoride, formate, acetate, propionate, butyrate. Selected from the group consisting of lat, glutamate, aspartate, ascorbat, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methyl sulfate, nitrate, phosphat, diphosphat, succinate, sulfate, tartrat, hydrogentartrate, malat, hydrogentmalat, malat, fumarate, citrate, stearat, palmitate, myristate, laurate, caprate, caprilate, caproate, oleate, linoleate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, trichloroacetate, tribromoacetate, and trifluoroacetate; Optionally, if X- is absent, the counterion is optionally an internal salt or a zwitterion; Optionally, X - is an anion of a substituted or unsubstituted carboxylic acid selected from monocarboxylic acids, dicarboxylic acids, or polycarboxylic acids; Optionally, X -is an anion of a substituted monocarboxylic acid, and further optionally, an anion of a substituted propanoic acid (propanoate or propionate), an anion of a substituted acetic acid (acetate), an anion of hydroxyl-propanoic acid, or an anion of 2-hydroxypropanoic acid (which is lactic acid; the anion of lactic acid is lactate), or a trihaloacetate selected from trichloroacetate, tribromoacetate, or trifluoroacetate; Optionally, X - These are anions, formates, acetates, propionates, butyrates, and stearates of unsubstituted monocarboxylic acids selected from formic acid, acetic acid, propanoic acid, or butyric acid, respectively; or C6-C 24 Anions of long-chain fatty acids including saturated, unsaturated and polyunsaturated fatty acids of the carbon chain length (e.g., stearic acid, palmitic acid, myristic acid, lauric acid, capric acid, caprylic acid, caproic acid, oleic acid, linoleic acid, omega-6 fatty acids, omega-3 fatty acids; anions include stearic acid, palmitate, myristic acid, laurate, caprate, caprylate, caproate, oleate, linoleate, etc.); and Optionally, X- is an anion of a substituted or unsubstituted amino acid, i.e., an amino-monocarboxylic acid or amino-dicarboxylic acid, optionally selected from glutamic acid and aspartic acid, which are glutamate and aspartate anions, respectively; or, an anion selected from alanine, beta-alanine, arginine, asparagine, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan or tyrosine, and Optionally, X - It is the anion of ascorbic acid, which is ascorbate; Optionally, X - is a halide selected from fluoride, chloride, bromide, or iodide; Optionally, X -is an anion of a substituted or unsubstituted sulfonic acid, and further optionally selected from trifluoromethanesulfonate, tribromomethanesulfonate, or trichloromethanesulfonate; Optionally, X - This is a substituted or unsubstituted carbonic acid, and optionally a bicarbonate anion. Optionally, X - This is a substituted or unsubstituted sulfuric acid, and optionally a hydrogen sulfate anion. Optionally, X - This is a substituted or unsubstituted phosphate, and optionally a dihydrogen phosphate or monohydrogen phosphate anion.

[0039] For each of the aforementioned structures (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), and (X), their substituted derivatives and / or analogs are intended to be useful for compositions IV as described herein, or for methods of producing compositions IV or formulations comprising one or more of the aforementioned compounds as described herein.

[0040] (In case studies) Direct intravenous administration of NAD+ to human subjects over approximately 4 hours using standard IV infusion techniques has been reported to cause significant pain and / or inflammation in the subjects. Inflammatory markers that may be affected include, but are not limited to, IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, TNF-alpha, TNF-beta, IFN-alpha, IFN-gamma, IFN-gamma, VEGF, PDGF, GSCF, FGF2, CSF, MCP-1, chemokines (including subfamilies CXCL and CCL), C-reactive protein (CRP), serum amyloid A, and erythrocyte sedimentation rate (ESR). Nevertheless, in efforts to reduce or alleviate pain or to resolve problems that may cause further pain, combinations of NR(I) with or without NAD+, or compounds / formula (II-X), NMNH and NAMNH or their salts or solvates are also considered for IV administrations according to the methods described herein.

[0041] Other suitable delivery systems are considered. For example, liposomes in the form of liposome encapsulation may be used. In one embodiment, dispersible lipid nanoparticles are used.

[0042] In particular, IV formulations that do not contain NAD+ are preferred. To mitigate known (or anecdotal) adverse problems associated with NAD+ IV administration (e.g., pain, inflammation, prolonged administration), compound NR(I) or compounds / formulas (II-X), NMNH, and NAMNH or their salts or solvates may be administered as substitutes for NAD+. For example, a specific adverse effect of extracellular NAD+ may be the generation of an inflammatory response. These adverse responses, including pain and inflammation, are expected to be mitigated by NR-containing formulations. Nadlinger, et al., “Influence of reduced nicotinamide adenine dinucleotide on the production of interleukin-6 by peripheral human blood leukocytes,” Neuroimmunomodulation(2001)9(4):203-208; Adriouch, et al., “Extracellular NAD(+): a danger signal hindering regulatory T cells,” Microbes See Infect.(2012,Nov)14(14):1284-1292.

[0043] In other embodiments, preferred IV formulations described herein may be used to improve recovery time from exercise, promote performance enhancement, improve fatigue / exhaustion levels, enhance mental capacity, improve cognitive skills such as memory, reduce stress, or improve sleep or sleep patterns. It is expected that all of these conditions will be improved when using preferred IV formulations without NAD+ compared to NAD+ IV administration alone.

[0044] In this regard, both specific (e.g., phlebitis at injection) and systemic inflammation in situ can be problematic when injecting NAD+ into human subjects. Therefore, it is expected that IV formulations containing NAD+ in combination with NR(I) or compounds / formulas (II-X), NMNH, and NAMNH or their salts or solvates will reduce both systemic and specific inflammation, as well as other inflammatory responses or processes, in human subjects compared to IV administration of NAD+ alone.

[0045] To further modulate or prevent the inflammatory response, formulations IV provided herein may include NR(I) and its salts or solvates, or combinations of NR(I) and at least one nicotinyl compound / formula (II-X), NMNH and NAMNH or their salts or solvates, and / or combinations of the foregoing with NAD+. These formulations may also be combined with, concurrently administered with, or sequentially administered with anti-inflammatory agents. Useful anti-inflammatory agents include aceclofenac, acemetacin, e-acetamidocaproic acid, acetaminophen, acetaminosarol, acetanilide, acetylsalicylic acid, S-adenosylmethionine, alclofenac, alclomethasone, alfentanil, algestone, allylprozine, aluminoprofen, alloxyprine, alphaprozine, bis(acetylsalicylic acid)aluminum, amcinonide, amfenac, and aminoac. Lortenoxazine, 3-amino-4-hydroxybutyrate, 2-amino-4-picoline, aminopropylone, aminopyrine, amixetrin, ammonium salicylate, ampiroxicam, amtormethine guayl, anirelidine, antipyrine, anthraphenine, Apazon, beclomethasone, Bendazac, Benolilate, benoxaprofen, benzpiperilone, benzydamine, benzylmorphine, belmoprofen, betamethasone, betamethasone N-17-valerate, vegitramide, α-bisabolol, bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, bromosaligenin, busetin, bucloxic acid, bucolome, budesonide, bufexamac, bumazisone, buprenorphine, butacetin, butibufen, butorphanol, carbamazepine, carbifen, carbiphen, carprofen, carsalam, chlorobutanol, chloroprednisone, chlortenoxazine, sa Choline lycylate, syncofen, synmethacin, silamadol, clidanac, clobetasol, crocoltrone, clomethacin, clonitazen, clonixin, clopirac, cloprednol, clove, codeine, codeine methyl bromide, codeine phosphate, codeine sulfate, cortisone, cortibazole, clopropamide, clotetamide, cyclazosin, deflazacort, dehydrotestosterone, desomorphine, desonide, desoxymethasone,Dexamethasone, dexamethasone-21-isonicotinate, dexoxadrol, dextromoramide, dextropropoxyfen, deoxycorticosterone, dezosin, diampromide, diamorphone, diclofenac, difenamizole, diphenpyramide, diflorazone, diflucortolone, diflunisal, difluprednate, dihydrocodeine, dihydrocodeinone enolacetate, dihydromorphine, dihydroxyaluminum acetylsalilate, dimenoxadol, dimefeptano Dimethylthiambutene, Dioxafetylbutyrate, Dipipanone, Diprocetyl, Dipyrone, Ditasol, Droxicam, Emorphazone, Enfenamic Acid, Enoxolone, Epirizol, Eptazosine, Etersalate, Ethenzamide, Etoheptadine, Ethoxazene, Ethylmethylthiambutene, Ethylmorphine, Etodolac, Etofenamate, Etonitazene, Eugenol, Felbinac, Fenbufen, Fencrosic Acid, Fendosal, Fenoprofen, Fentanyl, Fenthiazac, Feprazino Fluoropropyl alcohol, feprazon, fluctaphenin, fluazacort, fluchloronide, flufenamic acid, flumethasone, flunisolide, flunixin, flunoxaprofen, fluocinolone acetonide, fluocinonide, fluocinolone acetonide, fluocortin butyl, fluocortone, fluoreson, fluorometholone, fluperolon, flupirtin, flupredniden, fluprednisolone, fluproquazon, flurlandrenolide, flurbiprofen, fluticasone, formocortar, phosphosal, gentisic acid, glafenin, glucame Tacin, glycol salicylate, guaiazulene, halcinonide, halobetazole, halomethasone, haloprednon, heroin, hydrocodone, hydrocortamate, hydrocortisone, hydrocortisone acetate, hydrocortisone succinate, hydrocortisone hemysuccinate, hydrocortisone 21-lysinate, hydrocortisone cypionate, hydromorphone, hydroxypethidine, ibufenac, ibuprofen, ibuproxam, imidazole salicylate, indomethacin, indoprofen, isofezolac,Isoflupredone, isoflupredone acetate, isoladol, isomethadone, isonixin, isoxepac, isoxicam, ketobemidone, ketoprofen, ketorolac, p-lactphenetide, refetamine, levallorphan, levofenacil-morphan, lofentanil, lonazolac, lornoxicam, loxoprofen, acetylsalicylic acid lysine, mazipredone, meclofenamic acid, medrizone, mefenamic acid, meloxicam, meperidine, meprednisone, meptazinol, mesalamine, me Tazosin, methadone, methotrimeprazine, methylprednisolone, methylprednisolone acetate, methylprednisolone succinate sodium, methylprednisolone suleptate, methiadic acid, metophorine, metopon, mofebutazone, mofezolac, mometasone, morazon, morphine, morphine hydrochloride, morphine sulfate, morpholine salicylate, mirofin, nabumeton, nalbuffine, nalorphine, 1-naphthylsalilate, naproxen, narcein, nehopam, nicomorphine, nifenazone, ni Flumic acid, nimeslide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol, normethadone, normorphine, norpipanone, olsalazine, opium, oxaseprole, oxamethacin, oxaprozin, oxycodone, oxymorphone, oxyfenbutazone, papaveretam, paramethasone, paraniline, palsalmid, pentazocine, perisoxal, phenacetin, phenadoxone, phenazosin, phenazopyridine hydrochloride, phenocol, phenoperidine, fenopirazone, phenomorphan, phenyl acetylsalicylate Phenylbutazone, phenyl salicylate, pheniramidol, piketoprofen, piminodin, pipebuzone, piperion, pyrazolac, pyritramide, piroxicam, pirprofen, pranoprofen, prednicarbate, prednisolone, prednisone, prednivar, prednylidene, proglummetacin, proheptadine, promedol, propacetamol, properidine, propiram, propoxyfen, propifenazone, proquazone, protidic acid, proxazole, lamifenazone, remifentanil, limafenyl methylsulfate,Examples of such substances include, but are not limited to, salacetamide, salicin, salicylamide, salicylamide-o-acetic acid, salicylic acid, salicylic acid sulfate, salsalate, salvelin, simetrid, sufentanil, sulfasalazine, sulindac, superoxide dismutase, suprofen, suxibuzone, tarniflumate, tenidap, tenoxicam, telofenamate, tetrandrin, thiazolinobutazone, tiaprofenic acid, tiaramide, tyridine, tinoridine, thixocortol, tolfenamic acid, tolmetin, tramadol, triamcinolone, triamcinolone acetonide, tropesin, biminol, xenbusin, xymoprofen, zaltoprofen, and zomepirac.

[0046] To further modulate or prevent the proliferative response, formulations IV provided herein, which may include NR(I) and its salts or solvates, or combinations of NR(I) and at least one nicotinyl compound / formula (II-X) or its salts or solvates, and / or combinations of the aforementioned with NAD+, may be further combined with anticancer agents or chemotherapeutic agents. Chemotherapy agents that can be administered concurrently or consecutively with NR(I) and its salts or solvates as described herein as having anticancer activity (for example, compounds that induce apoptosis, compounds that reduce lifespan, or compounds that make cells stress-sensitive) include aminoglutethimide, amsacrine, anastrozole, asparaginase, bicalutamide, bleomycin, buserelin, busulfan, campothecin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, exemestane, filgrastim, fludarabine, fludrocortisone, and Luoruracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ironotecan, letrozole, leucovorin, leuprolide, levamisol, lomustine, mechloretamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mi Toxantrone, niltamide, nocodazole, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, larcitrexed, rituximab, streptozocin, suramin, tamoxifen, temozolomide, teniposide, testosterone, thioguanine, thiotepa, titanocenedic chloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine,Examples include vindesine and vinorelbine. These chemotherapeutic agents can be classified according to their mechanism of action, for example, into the following groups: antimetabolites / anticancer agents, e.g., pyrimidine analogs (5-fluorouracil, phloxuridine, capecitabine, gemcitabine, and cytarabine) and purine analogs, folate antagonists and related inhibitors (mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine (cladribine)); antiproliferative / antimitotic agents, microtubule disruptors, e.g., taxanes (paclitaxel, docetaxel), vincristine, vinblastine, nocodazole, epothirone, and navelbine, epidipodophyllotoxin (Te DNA damaging agents (actinomycin, amsacrin, anthracyclines, bleomycin, busulfan, camptothecin, carboplatin, chlorambucil, cisplatin, cyclophosphamide, cytoxane, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, hexamethylmelamine oxaliplatin, ifosfamide, melphalan, merchlorethamine, mitomycin, mitoxantrone, nitrosourea, paclitaxel, plicamycin, procarbazine, teniposide, triethylenethiophosphoramide and etoposide (VP16)); antibiotics, such as dactinomycin (actinomycin). D) Daunorubicin, doxorubicin (adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycin, plicamycin (mitramycin), and mitomycin, etc.; enzymes (L-asparaginase, which systemically metabolizes L-asparagine and depletes cells that lack the ability to synthesize asparagine themselves); antiplatelet agents; antiproliferative / antimitotic alkylating agents, such as nitrogen mustard (mechloretamine, cyclophosphamide and analogs, melphalan, chlorambucil), ethyleneimine and methylmelamine (hexamethylmelamine and thiotepa), alkylsulfonates-busulfan, nitrosourea (carmustine (BCNU) and analogs, streptozocin),Trazenes-dacarbazinine (DTIC); antiproliferative / antimitotic antimetabolites, e.g., folic acid analogs (methotrexate); platinum-coordinated complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide, nilutamide) and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts and other thrombin inhibitors); thrombolytic agents (tissue plasminogen activator, streptokinase and urokinase, etc.), aspirin, COX-2 inhibitors, dipyridamole, ticlopidine, clopidogrel, absiximab; antimigratory agents Agents; antisecretory agents (breveldin); immunosuppressants (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil); anti-angiogenic compounds (TNP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor (VEGF) inhibitors, fibroblast growth factor (FGF) inhibitors, epidermal growth factor (EGF) inhibitors); angiotensin receptor blockers; nitric oxide donors; antisense oligonucleotides; antibodies (trastuzumab); cell cycle inhibitors and differentiation inducers (tretinoin); mTOR inhibitors Agents, topoisomerase inhibitors (doxorubicin (Adriamycin), amsacrin, camptothecin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan (CPT-11), and mitoxantrone, topotecan, irinotecan), corticosteroids (cortisone, dexamethasone, hydrocortisone, methylpednisolone, prednisone, and prednisolone); growth factor signaling kinase inhibitors; mitochondrial dysfunction inducers and caspase activators; and chromatin disruptors.

[0047] Furthermore, the IV formulation may contain anti-aging agents and cellular senescence modifiers. Other therapeutic agents may include such urolithin A, urolithin B, quercetin, metformin, etc.

[0048] (In case studies) Direct intravenous administration of NAD+ to human subjects over approximately 4 hours using standard IV infusion techniques has been reported to induce euphoria or general well-being in subjects. IV formulations of this disclosure containing NR(I) or compound / formula (II-X) or combinations of its salts or solvates, administered intravenously with or without NAD+ according to the methods described herein, may also induce euphoria or general well-being in subjects, but without the unintended adverse side effects discussed above, such as pain responses or inflammatory responses.

[0049] In particular, IV formulations that do not contain NAD+ are preferred. To alleviate known (case-specific) problems associated with NAD+ IV administration (e.g., pain, inflammation, prolonged administration), compound NR(I) or compound / formula (II-X) or its salts or solvates may be administered as substitutes for NAD+.

[0050] The IV formulations of this disclosure, which contain combinations of NR(I) or compounds / formula (II-X) or their salts or solvates with or without NAD+ as described herein, may be combined with electrolytes, vitamins (such as B12 and others discussed below), antioxidants, and the like.

[0051] Formulations can be prepared in any form suitable for use in a human organism, including reconstituteable powders, ready-to-drink liquids, parenteral (intravenous) formulations, and dilutable concentrates, as are well known in the field of nutritional formulation technology. As used in this application, the amount of a component present in a formulation or composition refers to the amount present when the formulation or composition is prepared for ingestion by a human organism.

[0052] Intravenous embodiment Large volumes of injections intended for intravenous administration are generally called "IV infusions" and belong to a group of sterile and / or bacteriostatic products known as large volumes of parenteral preparations. These typically consist of single injections with a volume of 100 mL or more, and do not contain liquid carriers or additives that act as inert drugs or nutritional vehicles. Intravenous infusions are commonly packaged in containers with a capacity of approximately 100–1000 mL.

[0053] In its primary embodiment, NR may be provided dissolved in an IV infusion in an intravenous (IV) formulation for administration to human subjects. The composition comprises NR or a salt or solvate thereof in a suitable aqueous-based intravenous (IV) formulation. The composition may include water or a water-based carrier, such as a pharmaceutically acceptable IV infusion or buffer solution. The water used for packaging is generally water for injection ("WFI"). Typical IV infusions or carriers may include, but are not limited to, water (e.g., USP grade, sterile, pyrogen-free), normal saline, half-normal saline, dextrose (e.g., 5% dextrose or glucose, also known as D5W or D5 / W), mannitol, Ringer's solution, Ringer's lactate solution (also known as Ringer's lactate solution), Ringer's acetate solution, sodium lactate, sodium dicarbonate, sterile and / or bacteriostatic water.

[0054] A useful vitamin is vitamin B3, also known as "nicotinic acid" or "niacin," which is a pyridine compound. It will be apparent to those skilled in the art that vitamin B3 is not functionally or chemically equivalent to, and is not interchangeable with, nicotinamide riboside (NR, I), NR-X salt, or its derivatives. Other useful vitamins include vitamins B1, B2, B5, B6, B7, B9, B12, A1, C, D3, D2, E, and K1.

[0055] While not bound by theory, depending on the availability of ThDP (B1), FAD (B2), and PLP (B6), vitamins B1, B2, B3, and B6 are thought to be closely linked in the maintenance and regeneration of the intracellular NAD(P)(H) pool and their biosynthetic pathways. Thiamine (vitamin B1), riboflavin (vitamin B2), and pyridoxine (vitamin B6) are recovered from food and converted into their individual physiologically active forms within cells: thiamine (ThDP); flavin adenine dinucleotide (FAD); nicotinamide adenine dinucleotide (NAD) + ); and converted back to pyridoxalphosphate (PLP). The conversion of vitamins B1, B2, and B6 to ThDP, FAD, and PLP is ATP-dependent, respectively. Vitamin B3 is converted to NAD + Two of the three reuse routes that convert to NAD depend on ThDP(B1) and tryptophan. + De novo production depends on the physiologically active forms of vitamins B1, B2, and B6. Vitamin B1 dependence is due to ThDP(B1) acting on these NADs mentioned above. + This stems from the fact that it is a cofactor for transketolase, which is involved in the biosynthesis of phosphoriboside pyrophosphate, an essential substrate for the salvage and de novo pathways.

[0056] The formulations or compositions may be optionally stabilized and subsequently used in a manner that allows for immediate administration, or may be stored as concentrates or powders. Concentrates may be prepared by spraying a liquid formulation prepared as described herein, and the formulations may be reconstituted by rehydrating the concentrates. The formulation concentrates are stable liquids and have a suitable shelf life. Reconstituteable powders may be prepared by lyophilization or freeze-drying. The formulation reconstituted powders are suitable solid powders and have a suitable shelf life. Reconstituteable powders (separate from any injectables or stabilizers) may be prepared in unit doses of 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg, and up to 3000 mg. The reconstituteable powder can be reconstituted in a small volume of water, ethyl alcohol, DMSO, or an aqueous buffer suitable for dilution into aqueous IV formulations.

[0057] Powders or freeze-dried preparations prepared in accordance with this disclosure may be stored at room temperature (25°C), refrigerated, or frozen (e.g., -15°C or -30°C) for later use.

[0058] In the IV formulation of this disclosure, NR chloride may be crystalline, that is, the final product may be derived from crystalline NR components.

[0059] The dosage of NR chloride as crystalline form I and / or form II in the IV formulation may range from about 25 mg to about 3 g per infusion over about 1 to 2 hours. In preferred embodiments, the dosage for infusion may be 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg, and up to 3000 mg.

[0060] Apart from IV formulations, compositions for oral formulations useful for delivering NR-containing compositions may be administered orally, for example, with an inert diluent or with an assimilated food carrier, or they may be encapsulated in hard shell gelatin or soft shell gelatin or hydroxypropyl methylcellulose (i.e., hypromellose) capsules, or compressed into tablets, or directly incorporated into food. For oral administration, NR-containing compositions may be incorporated with excipients and may be used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc. Tablets, lozenges, pills, capsules, etc. may also contain: binders, e.g., tragacanth gum, acacia, corn starch, or gelatin; excipients, e.g., dicalcium phosphate, microcrystalline cellulose; disintegrants, e.g., potato starch, alginic acid; lubricants, e.g., magnesium stearate; and sweeteners, e.g., sucrose, lactose, or saccharin may be added, or flavorings such as peppermint, wintergreen oil, or cherry flavoring may be added. If the dosage unit form is a capsule, it may contain a liquid carrier in addition to the above types of substances. Various other substances may be present as a coating or to modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar, or both. Syrups or elixirs may contain active compounds, sucrose as a sweetener, methyl and propylparaben as preservatives, colorants, and flavorings, e.g., cherry or orange flavoring. Oil-in-water emulsions are miscible with water, making them suitable for oral use in children, thus masking their oily properties. Such emulsions are well-known in pharmacy.

[0061] One objective of the IV formulations of the present invention is to treat conditions or diseases in animals such as mammals. Examples of animal subjects include large domestic mammals or farm mammals, such as dairy cows or cattle (or other bovine breeds), horses, pigs, sheep, goats, and other livestock. Thus, animal subjects may include companion animals and animals used for sports (e.g., cattle or dogs). Other animal subjects may include, but are not limited to, smaller domestic mammals, such as dogs, cats, rabbits, and rodents such as rats, mice, hamsters, gerbils, and guinea pigs. Mammals may also be human subjects. Typical conditions or diseases requiring IV treatment may include, but are not limited to, drug and / or alcohol addiction. Thus, IV formulations providing NR and / or nicotinyl compounds (I-X) or their derivatives, prodrugs, or salts may be used to treat addiction or addiction withdrawal, or to treat addiction withdrawal syndrome, or to treat alcohol withdrawal or hangover.

[0062] Other routes of parenteral administration for providing nutrition are being considered. The compound may be administered by any parenteral route, including but not limited to intravenous, intramuscular, intraparenchymal, intraarterial, intraperitoneal, intranasal, vaginal, intravesical (e.g., into the bladder), intradermal, transdermal, topical, or subcutaneous administration, by injection or infusion.

[0063] Further embodiments envision kits for IV infusion or injection and / or subcutaneous, intramuscular, or intradermal injection. In one embodiment, the kit is designed for IV infusion administration of a therapeutically effective amount of nicotinamide riboside chloride salt (or other salts or derivatives thereof, including reduced analogues) to a human subject, the kit comprising nicotinamide riboside chloride salt (NR-Cl), aqueous intravenous infusion solution for injection contained in an IV bag; and a venous needle suitably connected to the IV bag for placement in a human subject's vein for IV infusion administration. The nicotinamide riboside chloride salt may be in crystalline form I. In a preferred embodiment, crystalline form I nicotinamide riboside chloride salt is contained in the aqueous intravenous infusion solution in an IV bag for administration to a human subject.

[0064] In other embodiments, the kit is designed for the subcutaneous injection administration of a therapeutically effective amount of nicotinamide riboside chloride salt (or other salts or derivatives thereof, including reduced analogs) to a human subject, the kit comprising nicotinamide riboside chloride salt (NR-Cl), aqueous intravenous or aqueous parenteral infusion for injection; and a subcutaneous syringe having a needle for subcutaneous injection to a human subject. The nicotinamide riboside chloride salt may be in crystalline form I. In preferred embodiments, the crystalline form I nicotinamide riboside chloride salt is contained in an aqueous intravenous or aqueous parenteral infusion contained in a subcutaneous syringe for administration by subcutaneous injection to a human subject.

[0065] Embodiments of the Method for treating and / or preventing symptoms, diseases, disorders or conditions in mammalian subjects, such as humans, that have a pathogenesis associated with or involving vitamin B3 deficiency, and / or in which increased mitochondrial activity is effective, have not been previously shown, comprising administering or providing NR and / or nicotinyl compounds (I-X) or derivatives thereof, prodrugs or salts alone or in combination with the vitamins described herein.

[0066] Furthermore, embodiments of this method for treating and / or preventing symptoms, diseases, disorders, or conditions in mammals that have a pathogenesis associated with or involved in vitamin B3 deficiency and / or in which increased mitochondrial activity is effective address the limitations of existing techniques for treating or preventing symptoms, diseases, disorders, or conditions that have a pathogenesis associated with or involved in vitamin B3 deficiency and / or in which increased mitochondrial activity is effective.

[0067] In certain embodiments, the present invention provides methods for treating and / or preventing symptoms, diseases, disorders, or conditions having etiologies associated with or involving vitamin B3 deficiency. Representative symptoms, diseases, disorders, or conditions having etiologies associated with or involving vitamin B3 deficiency that can be treated and / or prevented according to the methods described include indigestion, fatigue, stomatitis, vomiting, poor circulation, burning sensation in the mouth, swollen red tongue, and depression. Severe vitamin B3 deficiency can cause a condition known as pellagra, a premature aging condition characterized by cracked, scaly skin, dementia, and diarrhea. Other conditions characterized by premature aging or accelerated aging include Cockayne syndrome, Neill-Dingwall syndrome, ataxia telangiectasia, and progeria.

[0068] In certain embodiments, the present invention provides methods for treating and / or preventing symptoms, diseases, disorders, or conditions selected from, but not limited to, chemical and food dependence, PTSD, chronic stress, depression and anxiety, chronic pain, "chemo brain," CTE, Parkinson's disease and Alzheimer's disease, Huntington's disease and ataxia, or long-term COVID-19. In other embodiments, the methods may be used for athletes and to support exercise, endurance training and muscle recovery.

[0069] In certain embodiments, the present invention provides methods for treating and / or preventing symptoms, diseases, disorders, or conditions in which increasing mitochondrial activity is effective. Increased mitochondrial activity refers to increasing mitochondrial activity while maintaining the total number of mitochondria (e.g., mitochondrial mass), increasing the number of mitochondria and the resulting increase in mitochondrial activity (e.g., by stimulating mitochondrial regeneration), or a combination thereof. In certain embodiments, symptoms, diseases, disorders, or conditions in which increasing mitochondrial activity is effective include symptoms, diseases, disorders, or conditions related to mitochondrial dysfunction.

[0070] In certain embodiments, methods for treating and / or preventing symptoms, diseases, disorders, or conditions in which increased mitochondrial activity is effective may include identifying subjects suffering from mitochondrial dysfunction. Methods for diagnosing mitochondrial dysfunction, which may include molecular genetic, pathological, and / or biochemical analysis, are summarized in Bruce H. Cohen & Deborah R. Gold, Mitochondrial cytopathy in adults: what we know so far, 68 CLEVELAND CLINIC J.MED. 625 (2001). One method for diagnosing mitochondrial dysfunction is the Thor-Byrneier scale (see, e.g., Cohen & Gold 2001; S. Collins et al., Respiratory Chain Encephalomyopathies: A Diagnostic Classification, 36 EUROPEAN NEUROLOGY 260 (1996)).

[0071] Mitochondria are essential for the survival and proper function of almost all types of eukaryotic cells. Mitochondria in virtually every cell type can have congenital or acquired deficiencies that affect their function. Thus, the clinically significant signs and symptoms of mitochondrial deficiencies affecting respiratory chain function are heterogeneous and variable, depending on the distribution of deficiencies among cells, the severity of those deficiencies, and the physiological requirements of the affected cells. Non-misteoretic tissues with high energy requirements, such as nerve tissue, skeletal muscle, and cardiac muscle, are particularly susceptible to mitochondrial respiratory chain dysfunction, but any organ system can be affected.

[0072] Mitochondria are a major source of free radicals and reactive oxygen species due to mitochondrial respiratory chain overflow, particularly when deficiencies in one or more respiratory chain components impair the orderly transfer of electrons from metabolic intermediates to molecular oxygen. To mitigate oxidative damage, cells can compensate by expressing mitochondrial uncoupling proteins (UCPs), several of which have been identified. UCP-2 is transcribed in response to oxidative damage, inflammatory cytokines, or excessive lipid load, such as fatty liver and steatohepatitis. UCPs reduce mitochondrial overflow of reactive oxygen species by discharging the proton gradient across the inner mitochondrial membrane, effectively depleting metabolically produced energy, and making the cell more vulnerable to energy stress as a trade-off for mitigating oxidative damage.

[0073] Symptoms, diseases, disorders, and conditions associated with mitochondrial dysfunction due to deficiencies in mitochondrial respiratory chain activity include symptoms, diseases, disorders, and conditions in mammals that contribute to the progression of such symptoms, diseases, disorders, or conditions. These include 1) congenital genetic defects in the activity of one or more components of the mitochondrial respiratory chain, such defects resulting from oxidative damage during aging; b) elevated intracellular calcium levels; c) exposure of diseased cells to nitric oxide; d) hypoxia or ischemia; e) microtubule-related defects in mitochondrial axonal transport; or f) expression of mitochondrial uncoupling proteins.

[0074] In general, symptoms, diseases, disorders, or conditions for which increasing mitochondrial activity is effective include, for example, diseases in which free radical-mediated oxidative damage leads to tissue degeneration, diseases in which apoptosis occurs improperly in cells, and diseases in which apoptosis cannot occur in cells. Representative symptoms, diseases, disorders, or conditions for which increasing mitochondrial activity is effective include, for example, AD (Alzheimer's disease), ADPD (Alzheimer's disease and Parkinson's disease), AMDF (ataxia, myoclonus, and hearing loss), autoimmune diseases, lupus, lupus erythematosus, SLE (systemic lupus erythematosus), cataracts, cancer, CIPO (chronic pseudo-obstruction with myopathy and ophthalmoplegia), congenital muscular dystrophy, CPEO (chronic progressive extraocular palsy), and DEAF. (Maternal inherited hearing loss or aminoglycoside-induced hearing loss), DEMCHO (dementia and chorea), diabetes (type 1 or type 2), DID-MOAD (diabetes insipidus, diabetes, optic nerve atrophy, hearing loss), DMDF (diabetes and hearing loss), dystonia, exercise intolerance, ESOC (epilepsy, stroke, optic nerve atrophy and cognitive decline), FBSN (familial bilateral striatal necrosis), FICP (fatal childhood cardiomyopathy plus, MELAS-associated cardiomyopathy), GER (gastrointestinal reflux), HD (Huntington's disease), KSS ( Kearns-Sayre syndrome), "late-onset" myopathy, LDYT (Leber's hereditary optic neuropathy and dystonia), Leigh syndrome, LHON (Leber's hereditary optic neuropathy), LIMM (lethal childhood mitochondrial myopathy), MDM (myopathy and diabetes mellitus), MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes), MEPR (myoclonus epilepsy and psychomotor developmental regression), MERME (MERRF / MELAS overlap disorder), MERRF (myoclo - Nusial epilepsy and red ragged muscle fibers), MHCM (maternally inherited hypertrophic cardiomyopathy), MICM (maternally inherited cardiomyopathy), MILS (maternally inherited Leigh syndrome), mitochondrial encephalomyopathy, mitochondrial encephalomyopathy, MM (mitochondrial myopathy), MMC (maternal myopathy and cardiomyopathy), MNGIE (myopathy and extraocular muscle palsy, neurosis, gastrointestinal disorders, encephalopathy), multiple system mitochondrial disorders (myopathy, encephalopathy, blindness, hearing loss, peripheral neuropathy), NARP (neurogenic myasthenia, ataxia and retinitis pigmentosa;Surnames of the disease include Parkinson's disease (a surname of the disease in this position), Parkinson's disease (PD), Pearson syndrome, progressive encephalopathy (PEM), progressive ophthalmoplegia (PEO), progressive myoclonic epilepsy (PME), Pearson myelopancreatic syndrome (PMPS), psoriasis, Rett syndrome (RTT), schizophrenia, sudden infant death syndrome (SIDS), sensorineural hearing loss (SNHL), varied familial presentation (ranging from spastic paraplegia to multiple system progressive disorder and lethal cardiomyopathy to truncal ataxia, dysarthria, severe hearing loss, mental regression, ptosis, ophthalmoplegia, distal cyclones, and diabetes mellitus), Wolfram syndrome or mild cognitive impairment, and symptoms associated with long-term COVID-19. Treatment is intended for cardiovascular diseases, including but not limited to atrial fibrillation, congestive heart failure, decreased right or left ejection fraction, or myocardial infarction. ;

[0075] Other conditions, diseases, disorders, and states for which increasing mitochondrial activity is effective include, for example, Friedreich's ataxia and other ataxias, amyotrophic lateral sclerosis (ALS) and other motor neuron diseases, macular degeneration, epilepsy, Alpers disease, multiple mitochondrial DNA deficiency syndrome, MtDNA depletion syndrome, complex I deficiency, complex II (SDH) deficiency, complex III deficiency, cytochrome c oxidase (COX, complex IV) deficiency, complex V deficiency, adenine nucleotide transporter (ANT) deficiency, pyruvate dehydrogenase (PDH) deficiency, ethylmalonate aciduria with lactic acidemia, refractory epilepsy with decline during infection, and decline during infection. These include Asperger's syndrome with infection, autism with reduced infection, attention deficit hyperactivity disorder (ADHD), cerebral palsy with reduced infection, dyslexia with reduced infection, substantially hereditary thrombocytopenia and leukemia syndrome, MARIAHS syndrome (mitochondrial ataxia, recurrent infections, aphasia, hypouricemia / myelin dysplasia, epileptic seizures and dicarboxylic aciduria), ND6 dystonia, cyclic vomiting syndrome with reduced infection, 3-hydroxyisobutyric aciduria with lactic acidemia, diabetes mellitus with lactic acidemia, uridine-responsive neurological syndrome (URNS), dilated cardiomyopathy, splenic lymphoma, or renal tubular acidosis / diabetes / ataxia syndrome (Ataxis syndrome).

[0076] In other embodiments, the present invention provides intravenous methods for treating mammals (e.g., humans) suffering from mitochondrial dysfunction resulting from, but not limited to, traumatic occipital lobe injury and cerebral edema, stroke (methods of the present invention useful for treating or preventing reperfusion injury), Lewy body dementia, hepatorenal syndrome, acute liver failure, NASH (non-alcoholic steatohepatitis), anti-metastasis / prodifferentiation therapy for cancer, idiopathic congestive heart failure, atrial fibrillation (non-valvular), Wolff-Parkinson-White syndrome, idiopathic heart block, prevention of reperfusion injury in acute myocardial infarction, familial migraine, irritable bowel syndrome, secondary prevention of non-Q wave myocardial infarction, premenstrual syndrome, prevention of renal failure in hepatorenal syndrome, antiphospholipid antibody syndrome, eclampsia / pre-eclampsia, opause infertility, ischemic heart disease / angina, and Shy-Drager and unclassified autonomic dysregulation syndromes. Viral or bacterial infections can be treated.

[0077] In yet another embodiment, an intravenous method is provided for the treatment of mitochondrial dysfunction associated with pharmacological drug-related side effects. Types of pharmaceuticals associated with mitochondrial dysfunction include reverse transcriptase inhibitors, protease inhibitors, DHOD inhibitors, antiviral agents, antibiotics, antibacterial agents, and antifungal agents. Examples of reverse transcriptase inhibitors include, for example, azidothymidine (AZT), stabuzine (D4T), zalcitabine (ddC), didanosine (DDI), fluoroiodolearauracil (FIAU), lamivudine (3TC), and abacavir. Examples of protease inhibitors include, for example, ritonavir, indinavir, saquinavir, and nelfinavir. Examples of dihydroorotate dehydrogenase (DHOD) inhibitors include, for example, leflunomide and breknal. In this specification, the pharmaceuticals described above may be combined in IV formulations with NR and / or nicotinyl compounds (I-X) or their derivatives, prodrugs, or salts.

[0078] Reverse transcriptase inhibitors not only inhibit reverse transcriptase but also polymerase gamma, which is necessary for mitochondrial function. Inhibition of polymerase gamma activity (e.g., by reverse transcriptase inhibitors) therefore leads to mitochondrial dysfunction and / or a decrease in mitochondrial mass, which manifests in patients as hyperlactatemia. Increasing the number of mitochondria and / or improving mitochondrial function may be beneficial in this type of condition.

[0079] Common symptoms of mitochondrial disorders include cardiomyopathy, muscle weakness and atrophy, developmental delay (including motor, language, cognitive, or executive function), ataxia, epilepsy, renal tubular acidosis, peripheral neuropathy, optic neuropathy, autonomic neuropathy, neurogenic bowel dysfunction, sensorineural hearing loss, neurogenic bladder dysfunction, dilated cardiomyopathy, migraines, liver failure, lactic acidemia, and diabetes.

[0080] In a typical embodiment, the present invention provides a method for treating diseases or disorders in which increased mitochondrial activity is effective, by administering a therapeutically effective amount of NR(I) and / or at least one nicotinyl compound (II-X) or its derivatives, prodrugs, or salts alone or in combination with at least one vitamin to a mammal (e.g., human) using an IV dose. Typical diseases or disorders include, for example, neuromuscular disorders (e.g., Friedreich's ataxia, muscular dystrophy, multiple sclerosis, etc.), neurological instability disorders (e.g., epilepsy disorders, migraines, etc.), developmental delays, neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, etc.), ischemia, renal tubular acidosis, age-related neurodegeneration and cognitive decline, chemotherapy-induced fatigue, age-related or chemotherapy-induced menopause or irregular menstrual cycle or ovulation, mitochondrial myopathy, mitochondrial damage (e.g., calcium accumulation, excitotoxicity, nitric oxide exposure, hypoxia, etc.), and mitochondrial deregulation.

[0081] The underlying gene abnormality for Friedreich's ataxia (FA), the most common hereditary form of ataxia, has recently been identified and is called "frataxin." In FA, after a normal developmental period, typically between the ages of 30 and 40, a disorder of coordination appears, which progresses to paralysis and death. The tissues most severely affected are the spinal cord, peripheral nerves, myocardium, and pancreas. Patients generally lose motor control, become wheelchair-bound, and commonly suffer from heart failure and diabetes. The genetic basis for FA involves the presence of GAA trinucleotide repeats in the intron region of the gene encoding frataxin. The presence of these repeats results in reduced transcription and expression of this gene. Frataxin is involved in regulating mitochondrial iron content. When cellular frataxin content is below normal, excess iron accumulates in mitochondria, promoting oxidative damage and resulting mitochondrial degeneration and dysfunction. If an intermediate number of GAA repeats are present in the frataxin gene intron, the severe clinical phenotype of ataxia may not appear. However, these intermediate-length trinucleotide elongations are observed in 25–30% of non-insulin-dependent diabetic patients, while they are observed in only about 5% of the non-diabetic population. In certain embodiments, NR(I) and / or at least one nicotinyl compound (II–X) or its derivatives, prodrugs or salts alone or in combination with vitamins may be used to treat mammals (e.g., humans) with disorders associated with deficiency or lack of frataxin, including complications of Friedreich's ataxia, myocardial insufficiency, diabetes, and diabetic-like peripheral neuropathy.

[0082] Muscular dystrophy refers to a family of diseases involving deterioration of neuromuscular structure and function, often resulting in skeletal muscle atrophy and myocardial insufficiency. In Duchenne muscular dystrophy, mutations or deletions in the specific protein dystrophin are involved in its pathogenesis. Mice with inactivated dystrophin genes exhibit several features of muscular dystrophy, with approximately 50% reduction in mitochondrial respiratory chain activity. The ultimate common pathway to neuromuscular degeneration is, in most cases, calcium-mediated mitochondrial dysfunction. In certain embodiments, NR(I) and / or at least one nicotinyl compound (II-X) or its derivatives, prodrugs, or salts alone or in combination with vitamins may be used in mammals with muscular dystrophy (e.g., humans) to mitigate the rate of decline in muscle function and to improve the state of muscle function.

[0083] Epilepsy often occurs in patients with mitochondrial cytotoxicity and is associated with a range of epileptic seizures of severity and frequency, such as single episodes or multiple seizures per day, absence, tonic, flaccid, myoclonic epilepsy, and status epilepticus. In certain embodiments, NR(I) and / or at least one nicotinyl compound (II-X) or its derivatives, prodrugs or salts alone or in combination with vitamins may be used to treat mammals (e.g., humans) with epileptic seizures secondary to mitochondrial dysfunction, including a reduction in the frequency and severity of seizure activity.

[0084] Children with mitochondrial disorders often exhibit neurological or neuropsychological developmental delays. The development and remodeling of neural connections require potent biosynthetic activity, particularly in the synthesis of neuronal membranes and myelin, both of which require pyrimidine nucleotides as cofactors. Uridine nucleotides are involved in activation and the transfer of sugars to glycolipids and glycoproteins. Cytidine nucleotides, derived from uridine nucleotides, are crucial for the synthesis of major membrane phospholipid components such as phosphatidylcholine, which receives its choline portion from cytidine diphosphocholine. Mitochondrial dysfunction (due to mitochondrial DNA defects or any acquired or conditional defects, such as excitotoxic or nitric oxide-mediated mitochondrial dysfunction) or other conditions causing abnormalities in pyrimidine synthesis, cell proliferation, and axonal elongation results in insufficient functioning at critical stages in the development of neuronal interconnections and circuits, leading to delayed or halted development of neuropsychological functions and cognitive skills such as language, motor skills, social skills, and executive function. In autism, for example, magnetic resonance spectroscopy of phosphate compounds in the cerebrum indicates an overall deficiency in the synthesis of membranes and membrane precursors, as evidenced by reduced levels of uridine diphosphosugars and cytidine nucleoti derivatives involved in membrane synthesis. Disorders characterized by developmental delay include Rett syndrome, pervasive developmental delay (or PDD-NOS, "Pervasive Developmental Mental Retardation Not Otherwise Specified," to distinguish it from specific subcategories such as autism), autism, Asperger's syndrome, and attention-deficit / hyperactivity disorder (ADHD), which are beginning to be recognized as delays or discrepancies in the development of the neural circuits underlying executive function. In certain embodiments, NR(I) and / or at least one nicotinyl compound (II-X) or its derivatives, prodrugs, salts alone or in combination with vitamins may be useful for treating mammals (e.g., humans) that have neurodevelopmental delays (including, for example, motor, language, executive function, and cognitive skills) or other delays or cessation of neurological and neuropsychological development in the nervous system, as well as delays or cessation of physical development in non-neuronal tissues such as muscles and endocrine glands.

[0085] Oxygen deficiency results in both direct inhibition of mitochondrial respiratory chain activity by depriving cells of the final electron acceptor for cytochrome c reoxidation in complex IV, and indirectly, particularly in the nervous system, secondary post-hypoxia excitotoxicity and inhibition via nitric oxide formation. In conditions such as cerebral anoxia, anguina, or sickle cell anemia, tissues are relatively hypoxic. In such cases, compounds that increase mitochondrial activity protect tissues affected by the harmful effects of hypoxia, attenuate secondary delayed cell death, and accelerate recovery from hypoxic tissue stress and damage. In certain embodiments, NR(I) and / or at least one nicotinyl compound (II-X) or its derivatives, prodrugs, or salts alone or in combination with vitamins may be useful to treat and / or prevent delayed cell death (apoptosis in areas such as the hippocampus or cortex, occurring approximately 2-5 days after an episode of cerebral ischemia) following cerebral ischemia or acute hypoxia.

[0086] Regardless of whether the underlying respiratory chain dysfunction is congenital or induced by ischemia or cytotoxic agents such as cisplatin, acidosis due to renal dysfunction is frequently observed in patients with mitochondrial disease. Renal tubular acidosis often requires the administration of exogenous sodium bicarbonate to maintain blood and tissue pH. In certain embodiments, NR(I) and / or at least one nicotinyl compound (II-X) or its derivatives, prodrugs, salts alone, or in combination with vitamins may be useful for treating and / or preventing renal tubular acidosis and other forms of renal dysfunction caused by mitochondrial respiratory chain deficiencies.

[0087] Mitochondrial DNA damage is greater and longer-lasting than nuclear DNA damage in cells subjected to oxidative stress or cancer chemotherapy agents such as cisplatin, due to both the greater fragility and lower efficacy of repair of mitochondrial DNA. Despite the potential for mitochondrial DNA to be more sensitive to damage than nuclear DNA, in some situations it is relatively resistant to mutagenesis by chemical carcinogens. This is because, in response to certain types of mitochondrial DNA damage, mitochondria respond by disrupting rather than attempting to repair those deficient genomes. As a result, overall mitochondrial dysfunction occurs over the period following cytotoxic chemotherapy. Clinical use of chemotherapy agents such as cisplatin, mitomycin, and cytoxanes is often accompanied by debilitating "chemotherapy fatigue," long-term weakness and exercise intolerance that can persist even after recovery from the hematological and gastrointestinal toxicity of such drugs. In certain embodiments, NR(I) and / or at least one nicotinyl compound (II-X) or its derivatives, prodrugs, or salts alone or in combination with vitamins may be useful in treating and / or preventing cancer chemotherapy side effects associated with mitochondrial dysfunction.

[0088] In certain embodiments, NR(I) and / or at least one nicotinyl compound (II-X) or its derivatives, prodrugs, or salts alone or in combination with vitamins may be useful for the treatment and / or prevention of mitochondrial myopathy. The range of mitochondrial myopathy is from mild, slowly progressive extraocular muscle weakness to severe, fatal childhood myopathy and multisystem brain myopathy. Several symptoms have been defined, with some overlap among them. Established symptoms affecting muscles include progressive extraocular muscle palsy, Kearns-Sayre syndrome (with ophthalmoplegia, retinopathy pigmentosum, cardiac conduction disorders, cerebellar ataxia and sensorineural hearing loss), MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes), MERFF syndrome (myoclonus epilepsy and red ragged fibers), limb-girdle weakness distribution and childhood myopathy (benign or severe and fatal). Muscle biopsy specimens stained with modified Gomori trichrome show red, ragged fibers due to excessive accumulation of mitochondria. Biochemical defects in substrate transport and utilization, the Krebs cycle, oxidative phosphorylation, or the respiratory chain can be detected. Many mitochondrial DNA point mutations and deletions have been described and are transmitted in maternal, non-Mendelian inheritance patterns. Mutations occur in mitochondrial enzymes encoded in the nucleus.

[0089] In certain embodiments, NR(I) and / or at least one nicotinyl compound (II-X) or its derivatives, prodrugs, salts alone or in combination with vitamins may be useful for treating patients with mitochondrial toxic damage, such as calcium accumulation, excitotoxicity, toxic damage due to nitric oxide exposure, drug-induced toxic damage, or hypoxia.

[0090] The fundamental mechanisms of cell damage, particularly in excitable tissues, include excessive calcium influx into cells as a result of either leakage across the plasma membrane or a deficiency in intracellular calcium manipulation mechanisms. Mitochondria are the primary site of calcium isolation and preferentially utilize energy from the respiratory chain for calcium uptake rather than ATP synthesis, resulting in a negative chain reaction of mitochondrial dysfunction because the resulting calcium uptake into mitochondria reduces their capacity for energy transfer.

[0091] Excessive stimulation of neurons by excitatory amino acids is a common mechanism of cell death or injury in the central nervous system. Activation of glutamate receptors, particularly a subtype called NMDA receptors, results in mitochondrial dysfunction, partly through elevated intracellular calcium levels during excitotoxic stimuli. Conversely, deficiencies in mitochondrial respiration and oxidative phosphorylation make cells sensitive to excitotoxic stimuli, leading to cell death or injury upon exposure to levels of excitotoxic neurotransmitters or toxins that are harmless to normal cells.

[0092] Nitric oxide (at a concentration of approximately 1 micromolar) inhibits cytochrome oxidase (complex IV), thereby inhibiting mitochondrial respiration; furthermore, prolonged exposure to nitric oxide (NO) irreversibly reduces the activity of complex I. Physiological or pathophysiological concentrations of NO thereby inhibit pyrimidine biosynthesis. Nitric oxide is involved in a variety of neurodegenerative disorders, including inflammatory and autoimmune diseases of the central nervous system, and is involved in mediating excitotoxicity and post-hypoxia neuronal damage.

[0093] Oxygen is the final electron acceptor in the respiratory chain. Oxygen deficiency impairs electron transport chain activity, resulting in decreased pyrimidine synthesis and reduced ATP synthesis via oxidative phosphorylation. Human cells, when supplied with uridine and piruvate (or similarly effective agents for oxidizing NADH to optimize glycolytic ATP production), can proliferate and maintain viability under substantially anaerobic conditions.

[0094] In certain embodiments, nicotinyl compounds (derivative I, II, and / or III) or their derivatives, prodrugs, salts alone, or in combination with vitamins (IV, V, VI, and / or VII) may be useful for treating and / or preventing diseases or disorders associated with mitochondrial disregard.

[0095] The transcription of mitochondrial DNA, which codes for respiratory chain components, requires nuclear transcription factors. In nerve axons, mitochondria must travel back and forth between the nucleus and the nucleus to maintain respiratory chain activity. When axonal transport is impaired due to hypoxia or by drugs such as Taxol that affect microtubule stability, loss of cytochrome oxidase activity occurs in mitochondria away from the nucleus. Therefore, treatment with NR(I) and / or at least one nicotinyl compound (II-X) or its derivatives, prodrugs, salts alone, or in combination with vitamins may be useful in promoting nuclear-mitochondrial interactions.

[0096] The compositions and methods described in the embodiments above may be further understood in connection with the following embodiments. Furthermore, the following non-limiting examples are provided to illustrate the present invention. However, those skilled in the art will recognize that it may be necessary to modify the procedure, for example, to change the order or steps of the method, for certain embodiments of the present invention.

[0097] Example 1 A typical IV preparation containing NR chloride (as a crystalline component) NR chloride was obtained from ChromaDex, Inc. (Los Angeles, California).

[0098] In one embodiment, NR chloride as crystalline form I and / or form II is available in lots, batches, or units of 25 mg to 3 g (including both ends) as a lyophilized powder or crystalline powder prepared as follows.

[0099] In one embodiment, the lyophilized powder (or crystalline powder) is reconstituted by standard methods in bacteriostatic and sterile, pyrogen-free USP water for dilution in an IV infusion for IV administration. In one embodiment, a batch of 25 mg to 3 g of NR chloride form I is added to a bag of normal saline solution. The resulting IV infusion is stored at room temperature (25°C), refrigerated, or frozen for later use.

[0100] Example 2 IV administration of NR chloride In one embodiment, the NR chloride provided in Example 1 is administered by intravenous infusion to a human subject (e.g., a male weighing approximately 70-80 kg or a female weighing 50-70 kg) over approximately one hour. This delivery method is expected to have improved therapeutic delivery characteristics compared to direct intravenous infusion of NAD+ to similar subjects. For example, compared to NAD+ or other NAD+-containing infusions, less burning, chest discomfort, discomfort / labor breathing, or other pain sensations are expected during and after the infusion of NR chloride. Furthermore, NAD+ levels can be measured in serum or tissue using standard methods.

[0101] When using the VAS pain scale (units from "0" to "10"), human subjects showed a significant decrease of several units on the pain scale or did not report significant pain ("0" to "1" on the VAS pain scale). If a subject experienced a stinging sensation in the lip during the procedure, the pain may be recorded in the range of 1 to 3, and thus may decrease during subsequent IV treatment.

[0102] Example 3 Bacteriostatic and sterile dilution in IV infusion using the standard methods described above, followed by IV administration of NR chloride in pyrogen-free USP water, is expected to increase serum or tissue NAD+ more significantly than with chronic IV administration of higher dose levels of NR chloride (100-200 mg / kg / day) or with oral administration of NR chloride. See Example 4 and Figure 3, where the dose is 500 mg / day.

[0103] Example 4 A randomized, placebo-controlled pilot clinical trial evaluating Niagen®+IV (NR IV) and NAD+IV in healthy adults. background Nicotinamide riboside (NR) is a promising compound for increasing the intracellular NAD+ pool, potentially alleviating age-related weakness and associated conditions. While the safety and bioavailability of oral NR supplementation have been demonstrated in multiple animal and human studies, the efficacy of intravenous NR (NR IV) remains largely unknown. To date, pharmaceutical-grade NR has not been available for injection studies.

[0104] the purpose Given that intravenous administration may be beneficial in certain conditions and situations, a systemic study of the clinical efficacy of NR IV is justified.

[0105] method This randomized, double-blind, placebo-controlled pilot clinical trial was initiated with the primary objective of investigating the safety, tolerability, and blood NAD+-boosting efficacy of acute single doses of NR IV (500 mg, study), NAD+ IV (500 mg, active comparator), oral NR (500 mg, bridged), and saline IV (placebo control) in generally healthy adult participants. The trial consisted of two parts; data from 37 and 16 participants were analyzed in Phase 1 and Phase 2, respectively.

[0106] result No significant differences in vital signs were detected between the groups. Compared to NAD+IV, adverse experiences during infusion associated with NR IV were less frequent and of lower severity; no attributable adverse events were reported in either treatment group throughout the 14-day follow-up period. Furthermore, the mean tolerable infusion time for NR IV was 75% shorter than that for NAD+IV. No clinically significant changes in blood chemistry markers were described in the NR IV condition, while increases in white blood cell count and neutrophils were observed in the NAD+IV condition, suggesting the presence of an inflammatory response. Finally, NR IV appeared to promote the most robust increase in NAD+ concentration when measured by dry blood spot analysis, with peak NAD+ levels increasing by 20.7% compared to baseline, and being acutely better at 3 hours than NAD+IV (p<0.01) and oral NR (p<0.01). See, for example, Figures 3-7.

[0107] conclusion This is the first trial to clinically evaluate NR IV. Overall, acute intravenous infusion of 500 mg NR was safe in trial participants, with no attributable adverse events and only short-term and transient infusion-related experiences. Compared to NAD+IV, NR IV infusion was faster and better tolerated. Three hours post-infusion, serum NAD+ levels were significantly higher in the NR IV group compared to the NAD+IV group.

[0108] Preliminary Information While NAD+ is commercially available as a pyridine nucleotide in the form of dietary supplements and intravenous medications, NAD+ itself cannot be directly absorbed by the intestines or taken up by cells in an intact state when administered exogenously (Nikiforov et al., Pathways and Subcellular Compartmentation of NAD Biosynthesis in Human Cells. J Biol Chem (2011) 286:21767-21778). The majority of NAD+ is instead hydrolyzed to nicotinamide mononucleotide (NMN) in the extracellular environment, which is then further cleaved by CD73 to form nicotinamide riboside (NR), some of which can be further broken down into nicotinamide and nicotinic acid (Nikiforov et al., 2011; Anthony A. Sauve et al., Triple-Isotope Tracing for Pathway Discernment of NMN-Induced NAD+ Biosynthesis in Whole Mice. Int J Mol Sci (2023) 24:11114).NRK is readily taken up by cells via equilibrative nucleoside transporters and directed towards NAD+ biosynthesis in a two-step process involving the nicotinamide riboside kinase enzyme (Bieganowski and Brenner, Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD+ in Fungi and Humans. Cell (2004) 117:495-502; Nikiforov et al., 2011; Ratajczak et al., NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat Commun (2016) 7:13103; Kropotov et al., Equilibrative Nucleoside Transporters Mediate the Import of Nicotinamide Riboside and Nicotinic Acid Riboside into Human Cells. Int J Mol Sci (2021) 22:1391). Therefore, providing exogenous NR rather than NAD+ itself appears to be more efficient in increasing intracellular NAD+ concentration.In fact, oral NR administration has been described as safe and effective in increasing NAD+ levels and has shown promise for neurodegenerative states and other age-related disorders (Samuel AJTrammell et al., Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun (2016) 7:12948; Elhassan et al., Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Cell Rep (2019) 28:1717-1728.e6; Brakedal et al., The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease. Cell Metab (2022) 34:396-407.e6; Berven et al., NR-SAFE: a randomized, double-blind trial). Safety trial of high dose nicotinamide riboside in Parkinson's disease. Nat Commun (2023) 14:7793; Bita et al., Nicotinamide Riboside, a Promising Vitamin B3 Derivative for Healthy Aging and Longevity: Current Research and Perspectives. Molecules (2023) 28:6078). Other NAD+ precursors of note include NRH and NMNH, which are known to significantly increase NAD+ and NADH levels.(Ruben Zapata-Perez et al.,Reduced nicotinamide mononucleotide is a new and potent NAD+ precursor in mammalian cells and mice.The Faseb Journal(2021)35:e21456.Judith Giroud-Gerbetant et al.,A reduced form of nicotinamide riboside defines a new path for NAD+ biosynthesis and acts as an orally bioavailable NAD+precursor.Mol Metab.(2019)30:192-202)。

[0109] Despite the aforementioned limitations on the provision of outpatient NAD+, intravenous (IV) administration of NAD+ ("NAD+IV") has gained popularity in recent years and is available worldwide in thousands of high-end specialist medical and hydration clinics. Initially described in the clinical literature in 1961 for its use in the treatment of multiple addictions (O'Hollaren, Diphosphopyridine Nucleotide in the Prevention, Diagnosis and Treatment of Drug Addiction, West J. Surg., Obst. & Gynec. May-June 1961, pp. 1-2), NAD+ infusion therapy is now widely used to promote overall health and longevity. Claimed effects of NAD+IV include, but are not limited to, reduction of depression and anxiety, treatment of drug and alcohol dependence, relief of hangovers, fatigue, neurological disorders, athletic performance, and, most recently, recovery from symptoms of acute complications following COVID-19 and SARS-CoV-2 infection (PASC, "long-COVID"). Intravenous infusion may be preferable to oral administration in certain clinical situations because direct delivery to the bloodstream can provide 100% bioavailability that cannot be achieved through oral supplementation. Nevertheless, despite the wide availability and extensive, anecdotally reported benefits of NAD+IV, there is a lack of human data to investigate its use as a treatment or health-improving modality.

[0110] Aside from the metabolic inefficiencies associated with direct exogenous NAD+ administration (via oral, IV, or intramuscular pathways) due to the essential need for its degradation to pyridine metabolites of its constituent components before cell entry, elevated extracellular NAD+ (eNAD+) can also induce maladaptive effects. Under normal physiological conditions, NAD+ is reported to circulate in the extracellular fluid of mammals at concentrations of 0.1–0.5 μM (Adriouch et al., Extracellular NAD+: a danger signal hindering regulatory T cells. Microbes Infect (2012) 14:1284-1292; Gasparrini et al., Enzymology of extracellular NAD metabolism. Cell Mol Life Sci (2021) 78:3317-3331). Elevations of eNAD+ beyond the range regulated by homeostasis may constitute a pathophysiological trigger, potentially leading to toxic effects in T cells in preclinical models, including pro-inflammatory signaling and apoptosis (Adriouch et al., Rapid Induction of Naive T Cell Apoptosis by Ecto-Nicotinamide Adenine Dinucleotide: Requirement for Mono(ADP-Ribosyl)Transferase 2 and a Downstream Effector. J Immunol (2001) 167:196-203; Liu et al., Extracellular Nicotinamide Adenine Dinucleotide Induces T Cell Apoptosis In Vivo and In Vitro. J Immunol (2001) 167:4942-4947), and potentially suppressing the immune response (Liu et al., 2001). These findings highlight the need for caution regarding NAD+IV, as it has the ability to increase eNAD+ to hyperphysiological, and potentially pathophysiological, levels.Surprisingly, systematic studies addressing the safety and tolerability of NAD+IV remain limited despite its widespread use. Adverse experiences reported by clinicians and participants include nausea, diarrhea, muscle cramps, chest pain, and dizziness.

[0111] Given these concerns, clinical research into alternative strategies for increasing NAD levels via intravenous administration is justified. Due to its recognition as an NAD precursor and an endogenous form of vitamin B3, nicotinamide riboside (NR) has been a research topic in many preclinical and clinical trials (Canto et al., The NAD+ Precursor Nicotinamide Riboside Enhances Oxidative Metabolism and Protects against High-Fat Diet-Induced Obesity. Cell Metab (2012) 15:838-847; Samuel AJ Trammell et al., 2016; Airhart et al., An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS ONE (2017) 12:e0186459; Martens et al., Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults.Nat Commun(2018)9:1286;Conze et al.,Safety and Metabolism of Long-term Administration of NIAGEN(Nicotinamide Riboside Chloride) in a Randomized,Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults.Sci Rep(2019)9:9772;Elhassan et al.,2019;Brakedal et al. al.,2022;Wu et al.Boosting NAD+ blunts toll-like receptor-4 induced type-I interferon in control and systemic lupus erythematosus monocytes. J Clin Invest (2022) 132:e139828). Furthermore, the patented form of NR chloride, Niagen®, has received favorable safety reviews from multiple regulatory bodies, including the US Food and Drug Administration (FDA), and has obtained General Approval (GRAS) for use in food supplements and foods. Although oral Niagen® supplementation has shown safety and efficacy in consistently dose-dependently improving NAD+ levels in human intervention studies at doses up to 3,000 mg / day (Conze et al., 2019; Berven et al., 2023), its effects after IV administration have not yet been systematically evaluated. Almost certainly, intravenous administration of NR may exert a more potent effect on systemic NAD+ levels compared to oral administration by bypassing possible gastrointestinal enzyme and microbiome-mediated degradation and first-pass metabolism in the liver. Furthermore, evidence from multiple directions and an understanding of the mechanism support the rationale for intravenous NR ("NR IV") offering superior safety and NAD-promoting efficiency compared to NAD+IV. Since December 2022, NR chloride has been included in the FDA's Bulk Drug Substances Category 1 list under evaluation as an injectable compound under Section 503B of the Federal Food, Drug, and Cosmetic Act (FDA, 2023).

[0112] The objective of this pilot clinical trial is to compare the effects of a single intravenous administration and oral NR supplementation with NAD+, NR, or saline vehicle controls in terms of changes in vital signs, changes in whole blood NAD+, and tolerable infusion rates during and after administration. The second objective is to compare the clinical chemistry and safety profiles of the two approaches to IV supplementation and to identify consumer preferences.

[0113] method Approval from ethical and regulatory authorities This trial was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines. The clinical trial was conducted by the Nutraceuticals Research Institute at Hopewell Family Care (Hermitage, TN) and received full approval from the Sterling IRB (Protocol Number 23-08-0010), an independent ethics board registered with the National Institutes of Health's Office for Human Research Protections (OHRP). This approval remains valid throughout the trial and has been expanded to include the addition of Trial 2. This trial was also registered on ClinicalTrials.gov, NCT06382688. All participants provided written informed consent prior to any intervention procedure.

[0114] Clinical trial plan This was a two-part trial. The first trial was a four-arm randomized, placebo-controlled, parallel trial. Three IV arms were double-blinded, while the fourth arm, which included oral administration, was necessarily open-label. Participants were randomly assigned in a 10:10:10:6 ratio to receive intravenous placebo (saline), NAD+, NR, or oral NR (oral). The second trial was a randomized, parallel-design trial with two arms to evaluate the actual differences in infusion rates in real time. Participants were randomized in a 1:1 ratio to receive intravenous NR or NAD+.

[0115] participants Participants were deemed eligible for this study if they met the following patient eligibility criteria: signing and dated an informed consent form; demonstrating a firm ability to follow study procedures; residing within 100 miles of the Nutraceuticals Research Institute (Franklin, TN) study site; being 40 years of age or older; being in good overall health; and, if fertile, women who had used highly effective contraception for at least one month prior to screening and agreed to use such methods during study participation and for one month after the end of the study. Study 1 was open to both men and women; Study 2 was restricted to biological males.

[0116] Participants were deemed ineligible for any trial if they met any of the following exclusion criteria: any seizure disorder, diabetes or insulin resistance, any renal or hepatic impairment, heart disease, cancer or Parkinson's disease, currently diagnosed with pregnancy, attempting to become pregnant or breastfeeding, or any known allergy to any component of the intervention.

[0117] Sample size (1 page) The purpose of this study was to identify the continuity and variability between two approaches to IV dosing, in order to serve as a pilot study to collect data for further research and to provide data for further power testing.

[0118] To determine the power of the test, G * A post-hoc power analysis was performed using Power. Using findings from the first trial, with an effect size (F) of 10.12 and a p-value of <0.001, the actual detection rate of this trial was found to be 99% at the acceptable infusion rates in the four groups.

[0119] Randomized and blinded Participants were adaptively randomized by age and sex using a method developed by Kang et al., Issues in outcomes research: an overview of randomization techniques for clinical trials, J. Athl. Train. (2008) 43(2):215-211. This ensured that patients were evenly distributed across all groups based on these potentially confounding variable factors.

[0120] Except for the oral administration group, which was inevitably unblinded, blinding was performed for both participants and the study staff interacting with them regarding the administration of the intervention. To maintain blinding, participants were seated in comfortable chairs for IV administration, and the IVs were prepared in a separate area out of their sight. The IVs were labeled with the participant's ID.

[0121] intervention The trial intervention for both studies was pharmaceutical-grade NR chloride (Niagen®), obtained from WRGrace (South Haven, MI) for pharmacy preparation. The first study, consisting of four groups, included a placebo (saline IV), an active comparator (NAD+), and a control group for oral administration of NR chloride. The second study, consisting of two groups, included the trial intervention and an active comparator.

[0122] DCA Pharmacy (Franklin, Tennessee) prepared 50 mg / ml vials of NR or NAD+ in 10 ml of sterile water using a prescription for study doses only, and kept refrigerated until use. Participants were randomly assigned to either the test group or the active comparator group. Before intravenous administration, NR or NAD+ was added to 500 ml of physiological saline (B Braun 0.9% sodium chloride injection USP, preservative-free). Participants randomly assigned to the physiological saline group received 500 ml of standard physiological saline. Participants randomly assigned to the oral group received 500 mg of NR, which was taken with water.

[0123] In the first trial, participants started their infusion at a rate of 20 drops / minute for the first 15 minutes to ensure safety and comfort. After this initial period, participant input was used to increase or decrease the infusion rate to match or maintain the participant's comfort throughout the infusion period. In the second trial, all participants started with the IV line fully open. Participants were closely monitored throughout the infusion period, and the infusion rate was decreased where applicable, at the participant's request.

[0124] Participants who consented were instructed to fast for at least 8 hours before the infusion and at least 8 hours before the 24-hour evaluation (Study 1 only), and to consume only water, black coffee, or tea. In the event of anticipated adverse events such as nausea, stomach upset, or vomiting, participants were offered salted crackers and ginger during and after the infusion. Participants were provided with a standardized lunch after administration of the test substance (Study 1).

[0125] Outcome The safety of IV infusions was evaluated using a combination of endpoints including acceptable infusion rates, total number of adverse events, participant vital signs, complete blood count (CBC), total metabolic panel (CMP), glucose and insulin levels, and participant self-reported subjective experiences.

[0126] Variable factors controlling socioeconomic conditions included age, race, height, weight, BMI, household income, academic performance, marital status, and employment status.

[0127] Adverse event monitoring began on the first day of the trial and continued for 14 days (Trial 1) or 7 days (Trial 2). Participants were instructed to report any new or unusual symptoms during the trial to the research staff, and unexpected side effects were asked in open-ended questions during data collection.

[0128] NAD+ analysis Finger pricks were performed using a lancet. The blood was then applied to a circle on a dried blood spot (DBS) card and allowed to dry for at least 3 hours. The dried cards were stored at -20°C until shipment for LC / MS analysis. See, for example, Figure 3.

[0129] statistical methods A two-sample t-test was used to assess the success of continuous demographic and randomization. Chi-squared test analysis was used to assess the variability of categorical demographic and randomization.

[0130] Mixed between-and-within-subjects ANOVA was used to evaluate group comparisons of each outcome measured by CMC and CMP, with time points being within-subjects factors and group assignment being between-subjects factors. The assumption was confirmed using Mockley's test of sphericity. Violations of the sphericity assumption were addressed by Greenhouse-Geyser correction.

[0131] To assess vital signs and subdomains on sleep and energy scales, we evaluated group comparisons using analysis of covariance (ANCOVA) and Bonferroni correction with baseline scores as covariates. The assumption of homogeneity of variances was examined and confirmed using the Leben test.

[0132] Sleep and energy results Tables A-D below reflect the mean scores for each group on days 7 and 14. ANCOVA is used to identify statistically significant differences using baseline scores as a covariate to help account for natural variability in psychological measurements, thereby improving the power of the test.

[0133] Regarding the energy scale, the greatest improvement on day 7 was in the mental energy domain and the subjective domain, which measure the patient's perceived level of fatigue. By day 14, motivational energy was identified as the greatest improvement. Due to the small sample size, these data points are not statistically significant; larger trials may allow for the determination of statistical significance.

[0134] [Table 1]

[0135] [Table 2]

[0136] The energy scale measures the contribution to the energy level; it should be noted that lower scores reflect higher energy levels.

[0137] Regarding the sleep scale, the greatest improvement was observed in the sleep latency scale, which refers to the ability to fall asleep at night and sleep-related cognitive effects.

[0138] [Table 3]

[0139] [Table 4]

[0140] Participants were analyzed using an inclusive-to-touch (ITT) analysis. In the statistical analysis, participants were randomly assigned to groups and evaluated upon starting the trial. All data were analyzed using STATA v17.

[0141] Further analysis Further analysis was performed using GraphPad Prism (Ver. 10.0.2). Statistical significance was determined as p < 0.05, and the test product was compared to physiological saline or an intergroup comparison was performed. Significance in hematology, clinical chemistry, and vital signs was determined using a two-way ANOVA with Tukey's multiple comparison test using single pooled variance. Treatment time (time in chair) was analyzed for trial 1 using a one-way ANOVA in multiple comparisons, and trial 2 was analyzed using an independent t-test. The baseline variable of age was analyzed for differences in trials using a one-way ANOVA in multiple comparisons.

[0142] result Participant Flow A total of 45 participants were evaluated on the first day. Of these participants, 2 did not submit informed consent, leaving 43 eligible, and informed consent was provided. Of these, 6 withdrew due to scheduling conflicts. A total of 37 participants were randomly assigned to one of four groups and received the intervention: NAD+IV (n=10); NR IV (n=11); saline (n=6); or oral NR (n=10). In the second trial, a total of 22 participants were evaluated; 16 were eligible, informed consent was submitted, and they were randomly assigned to groups and received the intervention: NAD+IV (n=8); NR IV (n=8). No participants were excluded or withdrawn from either trial since the start of the clinical trial. All participants in both trials submitted written informed consent before any intervention-related procedure. Participants were followed up for 14 days (first trial) or 7 days (second trial) post-trial for reporting of adverse events.

[0143] Baseline target data Baseline descriptive statistics were evaluated, and t-tests were performed to ensure balance between the groups. No differences were identified between the two groups, indicating that randomization was well balanced across the groups for known factors. In the first trial, participants were predominantly Caucasian (89%) and 41 years old (27%). Sex was determined by sex assigned at birth. The sex ratio for this trial was 59% male and 41% female. In the second trial, all participants were male, with a mean age of 45.57 years (ranging from 40 to 64). Health history was similar between the groups. There were no differences between the groups in any of the baseline control variables. However, these results should be interpreted with caution due to the small sample size, as shown in Table 1. Note that both trials 1 and 2 are combined.

[0144] [Table 5]

[0145] Comprehensive analysis For the first trial, data from 37 patients were available for the comprehensive analysis; for the second trial, data from 16 patients were available for the comprehensive analysis. Table 2 lists the time points for the various assessments performed.

[0146] [Table 6]

[0147] Vital signs Post-intervention systolic blood pressure (mmHg) values ​​were 117.20 (SD: 14.54), 121.40 (SD: 13.84), 115.50 (SD: 4.23), and 108.56 (SD: 9.08) in the NAD+IV, NR IV, saline, and oral administration groups, respectively. ANCOVA using baseline systolic blood pressure as a covariate revealed no significant difference in scores between groups (F(1,34)=0.22, p=0.882).

[0148] Post-intervention diastolic blood pressure (mmHg) values ​​were 73.40 (SD:13.15), 79.60 (SD:6.24), 74.83 (SD:6.59), and 71.00 (SD:6.24) in the NAD+IV, NR IV, saline, and oral administration groups, respectively. ANCOVA using baseline systolic blood pressure as a covariate revealed no significant difference in scores between groups (F(1,34)=1.61, p=0.21).

[0149] Post-intervention heart rate (beats / minute, BPM) values ​​were 68.40 (SD: 8.10), 63.45 (SD: 9.42), 65.83 (SD: 12.69), and 65.78 (SD: 7.95) in the NAD+IV, NR IV, saline, and oral administration groups, respectively. ANCOVA using baseline systolic blood pressure as a covariate revealed no significant difference in scores between groups (F(1,34)=2.15, p=0.143).

[0150] Acceptable infusion rate In the first trial, the time taken for NR IV infusion varied from 1 hour 10 minutes to 3 hours 7 minutes, with an average of 2 hours 7 minutes (127.2 ± 40.82 minutes). On the other hand, the time taken for NAD+ IV infusion varied from 1 hour 47 minutes to 4 hours 32 minutes, with an average of 3 hours 3 minutes (182.9 ± 55.93 minutes). In the saline group, the range was 1 hour 10 minutes to 1 hour 39 minutes, with an average of 1 hour 25 minutes (85.17 ± 9.745 minutes). A one-way ANOVA identified significant differences between the groups (F(1,26)=10.12, p=<.001). Post-hoc Bonferroni tests identified significant differences between the NAD+IV group and the NR group (t=-2.94, p=.022) and between the NAD+IV group and the saline group (t=-4.36, p=.001). The effect size, calculated as partial eta-squared, was 0.457, which far exceeds the classification of "large" as described by Cohen, et al. (Cohen, J. (1988). Statistical power analysis for the behavioral sciences (2nd ed.). Hillsdale, NJ: Erlbaum. Cohen, J., & Cohen, P. (1983). Applied multiple regression / correlation analysis for the behavioral sciences (2nd ed.). Hillsdale, NJ: Erlbaum). See Figure 2A.

[0151] In the second trial, to further clarify the variation in total infusion time between NR IV and NAD+IV, 16 additional male patients received IV infusions of each substance in a 1:1 ratio (n=16). NR IV infusions ranged from 11 to 41 minutes, while NAD+IV infusions ranged from 20 to 184 minutes. The mean infusion rate for NR IV was 24.75 minutes (SD: 8.33), compared to 98.88 minutes (SD: 46.70) for NAD+IV. A two-sided t-test was used to compare the differences, revealing that the NR-IV infusion rate was significantly and substantially lower than the NAD+IV infusion rate (t(14) = -4.42, p = < .001), resulting in a 75% reduction in total time required for NR IV compared to NAD+IV. See Figure 2B.

[0152] Patient's subjective experience Among NR IV patients, the most commonly reported sensation was tingling in the mouth and extremities, such as nerve throbbing. This was described by patients as "prickling," "slightly painful," "burning," and "unpleasant." One patient described it as feeling "like eating pop rocks." Patients also reported feeling pressure in the head and ears to nursing staff. These patients described it as a feeling of blockage, and occasionally experienced nasal discharge during IV.

[0153] On the other hand, many NAD+IV patients reported feeling "unwell." These patients self-reported anxiety, headache, nausea, and sudden, urgent bowel movements or diarrhea. They also reported feeling "chest tightness and slight dizziness," "hot flashes," "nausea," and "stomach cramps."

[0154] Nursing staff reported descriptive terms for general discomfort or further symptoms of gastrointestinal (GI) discomfort / discomfort, including "feeling gassy," "muscle weakness," "stomach instability," and "stomach cramps." Approximately half of patients who took NAD+IV experienced bowel motility during IV administration.

[0155] clinical chemistry Blood chemistry remained relatively stable throughout the intervention period. Mixed between- and within-subject ANOVA was performed to assess the potential for between-group and between-time variability. While several significant time-point effects were observed, no significant between-group effects were observed for endpoints obtained in the CMC and CMP trials. Significant between-group differences were identified for glucose and insulin outcomes.

[0156] The overall model was significant for glucose outcomes (Wald χ²). 2 (11, n=37) = 41.76, p = < .001). Post-hoc testing showed a difference between the NAD+IV group and the saline group (χ²). 2 =7.61; p=.022) and oral group (χ 2 A significant difference was identified between the two (=18.42; p=<.001). For insulin outcomes, the overall model was significant (Wald χ²). 2 (11, n=37) = 56.30, p = < .001), but no significant difference was identified between the groups.

[0157] Further analysis While statistically significant differences were observed between saline, the test group (NR IV), and the active comparator group (NAD+IV), the changes were not considered clinically significant. ANOVA analysis showed significant differences in estimated glomerular filtration rate changes from baseline to 3 hours post-infusion between NAD+IV and NR IV versus saline (NAD+IV: 1.400±8.462; p=0.0341, NR IV: 1.273±4.941; p=0.0330, saline: -8.500±12.91). These changes were not considered clinically significant. Globulin changes from baseline to 24 hours post-infusion were significantly different in NAD+IV compared to saline (0.1300±0.1829 and -0.1167±0.2137, respectively; p=0.0418).

[0158] ANOVA analysis revealed a significant difference in absolute neutrophils between the NAD+IV and NR IV groups at 3 hours post-infusion (4724±2159 and 2883±1184, respectively; p=0.0164), which also demonstrated clinical significance, suggesting a change in NAD+IV likely due to inflammation. Baseline absolute neutrophil levels were statistically different in the NR IV group compared to the saline group (2183±858.5; p=0.0203). Absolute eosinophils were significantly different in the NR IV group compared to saline at all three time points (baseline: 112.2±82.69; p=0.0413, 3 hours post-infusion: 86.64±60.50; p=0.0448, 24 hours post-infusion: 102.5±48.33; p=0.0350). Mean blood cell volume differed significantly for NR IV at all three time points compared to the saline group (baseline: 91.55±2.306 and 90.85±4.826; p<0.0001, respectively; 3 hours post-infusion: 90.54±3.205 and 89.92±4.596; p<0.0001, respectively; 24 hours post-infusion: 90.85±2.872 and 90.82±5.055; p<0.0001, respectively). MCV also differed significantly between NAD+IV and NR IV at all three time points (baseline: 88.43±3.772 and 91.55±2.306, respectively; p<0.0001; 3 hours post-infusion: 87.38±3.991 and 90.54±3.205, respectively; p<0.0001; 24 hours post-infusion: 87.34±3.035 and 90.85±2.872, respectively; p<0.0001). White blood cell counts showed statistically significant differences in the NR IV group compared to normal saline at baseline (4.236±1.174 and 6.783±2.506, respectively; p=0.0161) and 3 hours post-infusion (4.909±1.454 and 7.233±1.908, respectively; p=0.0336). A difference was observed between NAD+IV and NR IV 3 hours post-infusion (6.990±2.386 and 4.909±1.454, respectively; p=0.0249), but this was not considered clinically significant.

[0159] Adverse events During the intervention, participants were monitored for adverse events and the occurrence of all exclusion criteria. One participant in the NR IV group tripped over the bottom corner of a bookshelf during exercise in the waiting room. This resulted in a small cut, which was treated with a bandage. This AE was classified as mild and was deemed unrelated to the intervention. No other AEs were identified during the intervention or follow-up period.

[0160] NAD+ analysis The use of dried blood spots (DBS) enabled the analysis of NAD+ levels based on samples prepared in the clinic or by study participants at home. Of the 37 participants in Study 1, 36 utilized DBS at all time points, although not all samples were analyzable. For baseline DBS collected for NAD+IV, NR IV, saline, and oral NR, usable samples were (n=6, 6, 4, 8) at t=10 minutes (n=9, 7, 6, 7), t=3 hours (n=8, 9, 6, 8), t=6 hours (n=9, 9, 6, 10); and t=24 hours (n=8, 8, 5, 8) after infusion completion (Figure 3). NAD+IV did not appear to increase whole blood NAD+ up to 24 hours, with a mean increase of 2% compared to baseline. Compared to NR IV, NAD+ levels appeared to peak at 3 hours, increasing by 20.7% compared to baseline, and decreasing to 16% at 24 hours. In group analyses, there were no statistically significant differences (ANOVA) at baseline and 24 hours (p=0.242; R2=0.151). However, significant differences were observed between the NAD+ and NR IV groups (t=2.81, p=0.009), between the NR-IV and saline groups (t=-2.63, p=0.014), between the NR IV and oral NR groups (t=-3.27, p=0.003), and at 6 hours (p=0.032; R2=0.251). Therefore, the model was significant at the 3-hour time point (p=0.010; R2=0.337). Therefore, the NR IV results showed a statistically significant increase in whole blood NAD+ at 3 hours compared to the placebo and NAD+ IV groups. At 6 hours, a near-significant difference was observed between the NAD+ group and the NR IV group (t=1.99, p=0.055), and significant differences were observed between the NR IV group and the saline group (t=-2.80, p=0.009), and between the NR IV group and the oral NR group (t=-2.59, p=0.015). See Tables 3-9 below.

[0161] Results of dry blood spots Tables 3-9 below reflect the mean / SD for each group at each of the seven time points. Basic ANOVA was performed to examine the data.

[0162] [Table 7]

[0163] [Table 8]

[0164] [Table 9]

[0165] [Table 10]

[0166] [Table 11]

[0167] Consideration NAD+ is an essential coenzyme necessary for cellular function and maintaining health. During aging, the accumulation of metabolic stressors that activate NAD+-consuming enzymes, including CD38 and poly(ADP-ribose) polymerase (PARP), reduces or contributes to the reduction of NAD+ availability (McReynolds et al., Age-related NAD+decline. Exp Gerontol (2020) 134:110888). While the definition of "normal" NAD+ levels in the blood and tissues has not yet been scientifically established, it is widely recognized that maintaining a sufficient intracellular NAD+ pool is necessary for optimal health.

[0168] The clinical use of intravenous NAD+ in the United States was popularized in the early 2000s by Paula Norris Mestayer and Dr. Richard Mestayer of the Springfield Wellness Center, and it is now offered in clinics worldwide to treat certain addictions and neurological conditions as well as general health support. Despite its popularity, the scientific knowledge behind the safety and efficacy of NAD+IV is limited. Furthermore, there are concerns that, on a mechanistic basis, the presence of increased eNAD+ after NAD+IV administration may be recognized by the immune system as a pathophysiological signal, potentially leading to an inflammatory response (Adriouch et al., 2012; Audrito et al., The Extracellular NADome Modulates Immune Responses. Front Immunol (2021) 12:704779). Case-wise, the infusion has been described as painful or uncomfortable, leading to gastrointestinal upset, and therefore requiring a very slow administration rate. Consistent with these reports, Grant et al., A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD+. Front Aging Neurosci (2019) 11:257 required an intravenous infusion rate of 2 mg / min over 6 hours to administer 750 mg of NAD+ to participants without adverse events. The need for a 6-hour infusion period highlights the time inefficiency of such a method (Grant et al., 2019). In this study, tolerance to intravenous NAD+ and NR varied and differed from person to person. The majority of participants reported adverse experiences during NAD+ IV infusion, such as nausea, headache, diarrhea, and muscle stiffness, while the NR IV group reported stinging pain, mild nausea, and coldness. In both groups, symptoms resolved upon completion of the infusion.In Study 1, since the infusion rate and associated side effects were not previously documented in the literature, the infusion rate was normalized for all participants at the start of the infusion to ensure safety. Because overall safety was established in Study 1, Study 2 was used to perform a true one-to-one comparison of infusion tolerance and rate between NAD+IV and NR IV, given the nature of the infusion administration in Study 1. The results showed that the mean infusion time for NR IV was one-quarter of the time for NAD+IV.

[0169] To evaluate the clinical safety of intravenous administration, changes in laboratory metrics were examined compared to the first trial with respect to a saline control group, the test group receiving NR 500 mg, NAD+ 500 mg as an activity comparator, and oral Niagen 500 mg to bridge the effects of oral and intravenous administration of NR. Participants in the NR IV, saline, and oral groups showed no clinically significant changes in a comprehensive metabolic panel including BUN, creatinine, sodium, potassium, calcium, CO2, AST, ALT, Alk Phos, protein, and albumin, or in differential CBC. These results are generally consistent with the observations made by Grant et al. in a trial investigating the effects of 6-hour NAD+ IV infusion (Grant et al., 2019). Similarly, intravenous administration of NR was well-tolerated with no clinically significant changes in laboratory markers. However, unlike Grant et al., 2019, who reported statistically significant (though clinically unrelated) changes in circulating bilirubin and AST levels 8 hours after the start of NAD+IV, no significant differences were detected in any indicator of liver function at the 3-hour and 24-hour time points in the NAD+IV group. These apparent inconsistencies may be explained by the fact that blood samples for clinical chemistry measurements were collected at different time points, as well as the differences in the doses used between the two studies. Similarly, consistent with findings from previously published clinical trials, oral Niagen administration was safe and well-tolerated.

[0170] Of particular note was the shift in the upward trend for both glucose and insulin concentrations in all four participant groups, including the control group. These parameters may have been influenced by food consumption prior to the 3-hour assessment, which would have constituted a deviation from the original protocol. Therefore, this prevents the inventors from determining the actual effect of the intervention on these blood parameters.

[0171] Regarding changes in hematological parameters, the NAD+IV group showed a significantly clinically significant increase in leukocytes, with elevated absolute and percentage neutrophils. The increase in neutrophils from baseline to 3 hours after infusion is generally attributed to inflammatory responses, physiological or psychological stressors, including immunological responses (Tahir and Zahra, Neutrophilia. Study Guide from StatPearls Publishing, Treasure Island, FL, 26 May 2021). Therefore, these observations are consistent with the view that NAD+IV elevates eNAD+, which is then judged by the immune system as a pathological event (Audrito et al., 2021). These changes were not observed in the saline, NR IV, or oral groups.

[0172] While hematological and clinical chemistry assessments were not included as part of the inclusion criteria, it is noteworthy that mean CO2 levels across all groups were lower than those commonly seen in clinical practice; two participants had elevated baseline AST / ALT levels, and two participants were borderline anemic. Furthermore, glucose and insulin levels in one participant at baseline and 24 hours suggest that the fasting protocol was not followed and that a carbohydrate-rich meal was consumed prior to the study. Additionally, in one participant, the neutrophil response at the 3-hour mark suggests a possible immunological response to infection, stress, or other inflammatory response.

[0173] The results of this study are broadly consistent with the study by Kimura et al., which reported that intravenous administration of another NAD+ precursor, nicotinamide mononucleotide (NMN, 300 mg dissolved in 100 mL of saline and infused at a rate of 5 mL / min), was safe and well-tolerated in 10 healthy Japanese adults in a single-arm, open-label trial, without evidence of adverse effects on organ function (Kimura et al., Nicotinamide Mononucleotide Is Safely Metabolized and Significantly Reduces Blood Triglyceride Levels in Healthy Individuals. Cureus (2022) 14:e28812). Furthermore, these researchers found that intravenous NMN increased blood NAD+ levels at multiple time points compared to baseline. Similar to NAD+, NMN is a phosphorylated compound that requires extracellular dephosphorylation to form NR or nicotinamide, which are more readily taken up by cells and generate NAD+ (Ratajczak et al., 2016; Anthony A Sauve et al., 2023). Therefore, it has been proposed that NR constitutes a more efficient means of enhancing the intracellular NAD+ pool, and that the necessary extracellular dephosphorylation to NR is mediated by the health benefits of NMN administration.

[0174] Oral supplementation of NAD+ precursors has gained popularity over the past decade as a strategy to support healthy aging. NAD+ is directly or indirectly involved in each of the molecular characteristics of aging, which explains the cellular mechanisms of the aging process (Lopez-Otin et al., Hallmarks of aging: An expanding universe. Cell (2023) 186:243-278). The use of oral supplementation of NR has become a strategy to increase NAD+ to support healthy aging. Similarly, the use of intravenous methods to boost NAD+ is gaining popularity, although there is little evidence of the safety and efficacy of NAD+IV in the peer-reviewed literature. To date, Ross et al., "A pilot study investigating changes in the human plasma and urine NAD+ metabolome during a 6-hour intravenous infusion of NAD+," Front. Aging Neurosci. (2019) 11:1-10, showed an increase in plasma NAD+ after NAD+IV infusion, but prior to this paper, no such information relating to changes in whole blood had been reported. In this study, NAD+IV did not significantly increase whole blood NAD+ within 24 hours. It can be hypothesized that NAD+ infusion results in an increase in extracellular NAD+, which triggers an immune response and consequently leads to adverse physical experiences (Adriouch et al., 2001; Liu et al., 2001). There was an increase in mean whole blood NAD+ across all groups, which can be explained by increased fluid intake from saline in all groups except the oral group. The mechanism by which NR IV participants experienced mild stinging pain is still unknown, but it appeared that the level of stinging pain increased with a faster infusion rate. NR IV results showed a statistically significant increase in whole blood NAD+ at 3 hours compared to NAD+ IV and saline controls, and a statistically significant increase at 6 hours compared to saline, and significantly close to NAD+ IV (p=0.055). The pharmacokinetics of NR IV and oral NR showed that IV NAD+ reached its peak concentration at 3 hours (C max) was thought to reach, so this study was different, on the other hand, oral NR C max This was observed at 24 hours. This was observed in human peripheral blood mononuclear cells at 9 hours (n=1) (Trammell et al. 2016a) and at 3 hours on day 9 of the supplementation study (Airhart et al. 2017) with a single oral dose of NR 1000 mg. max This appears to differ from previous evaluations. These differences are likely to be explained by differences in medication, changes in collected body fluids, and protocol differences, as whole blood NAD was not measured on day 1 in naive participants in later studies. For future clinical studies, more trial participants would be beneficial to improve the statistical power of these analyses.

[0175] limit Because this was a Phase 0 / 1 evaluation, a prior statistical power analysis was not performed, and such one-to-one comparisons were not available in the literature for clinical or preclinical models. Despite the selected population being judged to be healthy, several participants were anemic / borderline anemia, and several had elevated baseline liver enzymes. In clinical trials, since most tests measure in units of measurement, often weight or number per dilution, it is important to adjust for hydration status during serum sample collection (e.g., ng / dl or cell count / microliter). This adjustment ensures the accuracy and reliability of the results. Furthermore, the acceptance of restricted food and beverage consumption 3 hours prior to evaluation interfered with the results for glucose and insulin. The results of this trial suggest that, as a result of NAD+ infusion, these participants may have experienced an inflammatory response due to neutrophilia 3 hours after infusion. To validate these results, future studies should incorporate additional clinical parameters of inflammation, including C-reactive protein, erythrocyte sedimentation rate, procalcitonin, calprotectin, and plasma viscosity, or assessment of inflammatory cytokines in plasma or serum.

[0176] Regarding the treatment dose, NAD+ may be offered in various doses of 250–1250 mg / day in clinics, administered intravenously or by injection over multiple days; however, this study compared only single intravenous infusions of each intervention. To improve environmental validity, future studies would benefit from evaluating multiple infusions and dose variability. This study utilized the mass equivalence of NR and NAD+. The scientific community has not verified the existence of cellular NAD+ transporters; therefore, NAD+ requires the release of its two phosphate groups and ultimately enters cells as nicotinamide or nicotinamide riboside (Nikiforov et al., 2011). To determine why NAD+IV did not alter whole blood NAD+, direct comparison of molecular equivalents of NR and NAD+, as well as analysis of NAD+ from muscle and skin biopsies and other body fluids, is necessary. To determine whether oral supplementation can maintain an elevation of NAD+ between infusions, it may also be beneficial to evaluate intravenous infusion and subsequent oral administration of NR.

[0177] While NAD+ dried blood spots are convenient for home collection, obtaining 100% usable samples was not possible. There were some initial challenges in understanding the instructions and ensuring that multiple blood droplets did not touch the designated locations on the card. If blood samples were duplicated or had other defects during sample collection, these samples were unusable and therefore excluded from analysis.

[0178] conclusion This is the first trial to clinically evaluate nicotinamide riboside (NR) administered via intravenous infusion. Acute intravenous infusion of 500 mg of pharmaceutically prepared NR IV was safe in trial participants, with minimal or transient infusion-related experiences and no attributed adverse events for up to 14 days post-infusion. Compared to NAD+IV, NR IV was infused more rapidly and the infusion experience was more tolerable. NR IV increased NAD+ levels within 24 hours, which, surprisingly, was not observed with NAD+IV. For future trials, it is recommended to replace protocols providing multiple infusions of NAD+ with NR IV to determine whether nicotinamide riboside may offer the same or greater benefits as NAD+IV, but with fewer side effects and a faster infusion rate.

[0179] In other embodiments, other NAD+ precursors, such as nicotinyl riboside compounds selected from nicotinic acid riboside (NAR, II), nicotinamide mononucleotide (NMN, III), reduced nicotinamide mononucleotide (NMNH), nicotinic acid mononucleotide (NaMN, IV), reduced nicotinic acid mononucleotide (NaMNH), reduced nicotinamide riboside (NRH, V), reduced nicotinic acid riboside (NARH, VI), NR triacetate (NRTA, VII, a species of Ia), NAR triacetate (NARTA, VIII), NRH triacetate (NRH-TA, IX), or NARH triacetate (NARH-TA, X) and their salts, solvates, mixtures thereof, or derivatives thereof, are expected to have similar or better benefits compared to NR-IV.

[0180] The use of the terms “a,” “an,” “the,” and similar references in the context of describing the claimed invention (particularly in the context of the claims) should be interpreted as including both singular and plural unless otherwise indicated herein or unless the context clearly contradicts this interpretation. Unless otherwise indicated herein, descriptions of ranges of values ​​herein serve simply as a way to individually refer to each individual value that falls within the range, and each individual value is incorporated herein as if it were individually cited herein. The use of the term “about” means that a value is either above or below the specified value within a range of approximately ±10%; in other embodiments, the value may be within a range of either above or below the specified value within a range of approximately ±5%; in other embodiments, the value may be within a range of either above or below the specified value within a range of approximately ±2%; in other embodiments, the value may be within a range of either above or below the specified value within a range of approximately ±1%. The aforementioned ranges are made clear by the context and do not imply any further limitation. Unless otherwise indicated herein or the context makes it clear, all methods described herein may be carried out in any preferred order. The use of any examples or representative terms provided herein (e.g., "etc.") is merely for illustrative purposes and, unless otherwise asserted, does not impose any limitation on the scope of the invention. The terms in this specification should not be construed as indicating any unclaimed element as essential to the practice of the invention.

[0181] While the present invention has been described in relation to certain embodiments in the aforementioned specification, and many details have been proposed for illustrative purposes, it will be apparent to those skilled in the art that the invention is open to further embodiments, and that certain details described herein can be substantially modified without departing from the fundamental principles of the invention.

[0182] All references cited herein are incorporated by reference in their entirety. The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics, and therefore, when indicating the scope of the invention, refer to the appendix rather than the above specification. See the claims of the patent.

Claims

1. A pharmaceutical composition for intravenous or infusion use comprising nicotinamide riboside or a salt thereof or a solvate thereof and / or a pharmaceutically acceptable carrier.

2. The pharmaceutical composition according to claim 1, wherein the nicotinamide riboside salt is a chloride salt (NR-Cl).

3. The pharmaceutical composition according to claim 1, wherein the nicotinamide riboside salt is selected from the group consisting of bromide, iodide, fluoride, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbatate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methyl sulfate, nitrate, phosphat, diphosphat, succinate, sulfate, tartrat, hydrogen tartrat, malat, hydrogen malat, maleat, fumarate, citrate, stearat, palmitate, myristate, laurate, caprate, caprilate, caproate, oleate, linoleate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, trichloroacetate, tribromoacetate, and trifluoroacetate.

4. The pharmaceutical composition according to claim 2, wherein the nicotinamide riboside chloride salt (NR-Cl) is in crystalline form I, form II, or a combination thereof, or is a lyophilized powder or freeze-dried powder.

5. The pharmaceutical composition according to claim 4, wherein the carrier is an aqueous liquid.

6. The pharmaceutical composition according to claim 4, wherein the amount of NR-Cl is approximately 25 mg to approximately 3000 mg.

7. The pharmaceutical composition according to claim 5, wherein the pharmaceutically acceptable carrier is sterile, pyrogen-free, or physiological saline.

8. A method for administering nicotinamide riboside, a salt thereof, or a solvate thereof to a human subject, comprising: (a) providing an aqueous-based IV or injectable formulation containing NR, a salt thereof, or a solvate thereof; (b) administering an effective amount of the formulation to the human subject intravenously, subcutaneously, parenterally or intramuscularly by injection or infusion such that one or more adverse side effects causing discomfort in the human subject are reduced and / or comfort is maintained; and (c) continuously measuring and monitoring the adverse side effects and / or comfort level of the human subject during administration of the formulation to ensure that the adverse side effects are reduced compared to an aqueous-based IV or injectable formulation containing NAD+ being administered.

9. The method according to claim 8, wherein the one or more side effects causing discomfort are selected from the group consisting of pain response, burning sensation, general discomfort, headache, nausea, gastrointestinal discomfort, digestive problems, abdominal pain attacks, nerve aches, chest discomfort, labored breathing, and muscle weakness.

10. The method according to claim 8, wherein the side effects of steps (b) and (c) are pain responses that are minimized during and after administration of the aqueous formulation.

11. The method according to claim 8, wherein the side effect is a systemic discomfort that is minimized during and after administration of the aqueous formulation.

12. The method according to claim 8, wherein the pain response is measured using a numerical variable analog scale (VAS) pain scale level.

13. The method according to claim 8, wherein the aqueous IV formulation is administered over a period of approximately 0.5 hours to approximately 3 hours.

14. The method according to claim 8, wherein the nicotinamide riboside salt is a chloride salt (NR-Cl).

15. The method according to claim 8, wherein the nicotinamide riboside salt is selected from the group consisting of bromide, iodide, fluoride, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbatate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methyl sulfate, nitrate, phosphat, diphosphat, succinate, sulfate, tartrate, hydrogen tartrate, malate, hydrogen malate, maleate, fumarate, citrate, steartrate, palmitate, myristate, laurate, caprate, caprilate, caproate, oleate, linoleate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, trichloroacetate, tribromoacetate, and trifluoroacetate.

16. The method according to claim 14, wherein the nicotinamide riboside chloride salt is crystalline form I, form II, or a combination thereof.

17. The method according to claim 14, wherein the aqueous IV preparation is administered over a period of approximately one hour or less.

18. The method according to claim 14, wherein the total daily dose of NR-Cl is approximately 25 mg to 3000 mg.

19. The method according to claim 14, wherein the total daily dose of NR-Cl is approximately 500 mg to 1000 mg when administered IV.

20. The method according to claim 10, wherein the pain response measured during steps (b) and (c) is about 50% to 75% lower compared to an IV dose of NAD+ alone.

21. The aqueous-based IV or injectable formulation contains nicotinamide adenine dinucleotide (NAD+), -(2',3',5'-triacetyl-beta-D-ribofuranosyl)-nicotinamide (NRTA), nicotinic acid riboside (NAR), reduced nicotinamide mononucleotide (NMNH), nicotinamide mononucleotide (NMN), nicotinic acid mononucleotide (NaMN), reduced nicotinic acid mononucleotide (NaMNH), reduced nicotinamide riboside (NRH), and reduced nicotinic acid The method according to claim 8, further comprising a compound selected from the group consisting of riboside (NARH), 1-(2',3',5'-triacetyl-beta-d-ribofuranosyl)-nicotinic acid (NARTA), 1-(2',3',5'-triacetyl-beta-d-ribofuranosyl)-1,4-dihydronicotinamide (NRH-TA), and 1-(2',3',5'-triacetyl-beta-d-ribofuranosyl)-1,4-dihydronicotinic acid (NARH-TA) or salts thereof.

22. The method according to claim 21, wherein the one or more side effects measured during steps (b) and (c) are lower compared to administration of NAD+ alone.

23. A method for IV administration of nicotinamide riboside, a salt thereof, or a solvate thereof to a human subject, comprising the steps of (a) providing an aqueous-based IV formulation containing NR, a salt thereof, or a solvate thereof; and (b) intravenously administering an effective amount of the IV formulation to the human subject by injection or infusion; wherein the whole blood level of NAD+ increases by approximately 10% to approximately 25% in situ compared to administration of NAD+ alone at the same concentration.

24. The method according to claim 23, wherein the nicotinamide riboside salt is a chloride salt (NR-Cl).

25. The method according to claim 23, wherein the nicotinamide riboside salt is selected from the group consisting of bromide, iodide, fluoride, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbatate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methyl sulfate, nitrate, phosphat, diphosphat, succinate, sulfate, tartrate, hydrogen tartrate, malate, hydrogen malate, maleate, fumarate, citrate, steartrate, palmitate, myristate, laurate, caprate, caprilate, caproate, oleate, linoleate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, trichloroacetate, tribromoacetate, and trifluoroacetate.

26. The method according to claim 24, wherein the nicotinamide riboside chloride salt is crystalline form I, form II, or a combination thereof.

27. The method according to claim 24, wherein the aqueous IV preparation is administered over a period of approximately one hour or less.

28. The method according to claim 24, wherein the total daily dose of NR-Cl is approximately 25 mg to 3000 mg.

29. The method according to claim 24, wherein the total daily dose of NR-Cl is approximately 500 mg to 1000 mg.

30. A kit for IV infusion administration of a therapeutically effective dose of nicotinamide riboside chloride salt to human subjects, Nicotinamide riboside chloride salt (NR-Cl), I.V. Aqueous intravenous infusion solution for injection contained in the bag, A needle for intravenous injection, suitably connected to the I.V. bag for placement in a vein of the human subject for administration by I.V. infusion to the human subject, A kit that includes this.

31. The kit according to claim 30, wherein the nicotinamide riboside chloride salt is in crystalline form I, form II, or a combination thereof.

32. The kit according to claim 31, wherein the nicotinamide riboside chloride salt in crystalline form I, form II, or a combination thereof is contained in the aqueous intravenous infusion in the I.V. bag for administration to the human subject.

33. A kit for subcutaneous injection administration of a therapeutically effective dose of nicotinamide riboside chloride salt to human subjects, Nicotinamide riboside chloride salt (NR-Cl), Aqueous intravenous or parenteral infusion solution for injection, A subcutaneous syringe having a needle for subcutaneous injection in the aforementioned human subject, A kit that includes this.

34. The kit according to claim 33, wherein the nicotinamide riboside chloride salt is in crystalline form I, form II, or a combination thereof.

35. The kit according to claim 34, wherein the nicotinamide riboside chloride salt in crystalline form I, form II, or a combination thereof is contained in an aqueous intravenous or aqueous parenteral infusion contained in the subcutaneous syringe for administration to the human subject by subcutaneous injection.

36. A method for IV or injection administration of one or more NAD-increasing compounds, salts thereof, or solvates thereof to a human subject, comprising: (a) providing an aqueous-based IV formulation containing a compound comprising formulas (II-X), NMNH and NAMNH, combinations thereof, salts thereof, or solvates thereof; (b) intravenously administering an effective amount of the IV formulation to the human subject by infusion or drip infusion such that one or more adverse side effects causing discomfort in the human subject are reduced and / or comfort is maintained; and (c) continuously measuring and monitoring the adverse side effects and / or comfort level of the human subject during IV administration of the IV formulation to ensure that the adverse side effects are reduced compared to an aqueous-based IV formulation containing NAD+ administered at the same concentration.

Images