RESOURCES

Alpha lipoic acid (ALA, thioctic acid) is an endogenous, potent antioxidant that is purported to be useful in the treatment of diabetes mellitus, diabetic neuropathy, dementia secondary to Alzheimer's disease or human immunodeficiency virus (HIV) infection, glaucoma, and alcoholic liver disease. Studies supporting the use of ALA in the treatment of diabetes and diabetic neuropathy are available. The majority of studies are short in duration (e.g., 3—5 weeks) and were completed with a small number of study participants; however, small studies of both 6 months and 24 months duration have been completed in patients with diabetic neuropathy. ALA has been used extensively in the treatment of diabetic neuropathy in Germany since 1959. Studies supporting the effectiveness of ALA in other purported indications in humans are lacking or inconclusive. Further investigations of ALA in the treatment of Alzheimer's disease, HIV-related dementia, or liver diseases are needed before it can be recommended for use for those conditions.

Current evidence indicates that alpha lipoic acid may have a role in improving insulin sensitivity in patients with type 2 diabetes mellitus as well as improving symptoms in patients with diabetic neuropathy. Data regarding use for other indications are either inconclusive or lacking.

For diabetes mellitus type 2: In 74 well-controlled patients with type 2 diabetes, ALA at a dosage of 600—1800 mg/day PO for 4 weeks (19 patients receiving 600 mg/day, 18 patients receiving 1200 mg/day, and 18 patients receiving 1800 mg/day) increased the metabolic clearance rate of glucose, a measure of insulin sensitivity, by 27% (p <0.01) as compared to placebo (n=19) (Jacob et al., 1999). In a second study, 600 mg PO twice daily of ALA for 4 weeks significantly increased insulin sensitivity in patients with type 2 diabetes mellitus; the glucose disposal rate increased from 3.2 +/- 1.9 at baseline to 6 +/- 2.7 mg/kg/min (p <0.01) at 4 weeks. The insulin sensitivity index increased from 4.7 +/- 2.7 to 7.7 +/- 3.6 mg/kg/min per mIU (p <0.05) (Kamenova, 2006). Adults: Other small, clinical studies utilizing IV ALA at doses of 1000 mg/day for 1 day or 500 mg/day for 10 days have demonstrated improvements in insulin sensitivity.

For diabetic neuropathy (neuropathic pain of diabetic origin): In 12 patients treated with ALA 600 mg PO three times daily for 3 weeks, total symptom score (TSS) and the neuropathy disability score (NDS) improved at week 3 compared to patients taking placebo; the TSS decreased by 47% in the ALA group compared to only 24% in the placebo group (p=0.021), and the NDS decreased by 0.27 points in the ALA group compared to an increase in 0.18 points in the placebo group (p=0.025) (Ruhnaut et al., 1999). Similarly, in 181 patients with diabetes, the use of ALA 600 mg/day PO (n=45), 1200 mg/day PO (n=47) or 1800 mg/day PO (n=46) for 5 weeks significantly decreased TSS of the feet by 4.5—4.9 points compared to a decrease of 2.9 points in patients taking placebo (n=43, p <0.05 for all groups of ALA vs. placebo). However, the incidence of side effects increased in a dose-dependent manner in patients taking ALA (Ziegler et al, 2006). In a trial of 26 patients with diabetic neuropathy, 600 mg of ALA once daily (route of administration not specified) for 3 months improved not only symptom scores, but also nerve conduction velocity of motor fibers (Negrisanu et al., 1999). Similarly, 600 mg/day IV of ALA for up to 3 weeks has been shown to be of benefit in improving TSS (Ametov et al, 2003). However, in a study comparing 1200 mg IV/day, 600 mg IV/day, 100 mg IV/day, and placebo for 3 weeks, TSS improved significantly in patients receiving 1200 mg IV or 600 mg IV as compared to placebo, but side effects occurred in 33% of patients taking 1200 mg/day, 18% in patients taking 600 mg/day, and 21% of patient receiving placebo (Ziegler et al., 1995). Several studies have also investigated the use of ALA 600 or 1200 mg/day IV for 1—3 weeks followed by either 600 or 1200 mg/day PO of ALA for 6—24 months; the study lasting only 6 months in duration did not find a significant difference between active treatment or placebo, but the study lasting 24 months did find a significant improvement in nerve conduction velocity without significant adverse effects. In addition to peripheral neuropathy, preliminary evidence indicates that ALA may be beneficial in patients with cardiac autonomic neuropathy. Patients with cardiac autonomic neuropathy received either 800 mg of ALA PO once daily (n=39) or placebo (n=34) for 4 months; heart rate variation improved significantly in patients taking ALA compared to placebo, although changes in cardiovascular autonomic symptoms did not differ between the 2 groups (Ziegler et al., 1997).

Ascorbic acid (Vitamin C) is a water-soluble vitamin found in fruits and vegetables such as citrus fruits and green peppers. Ascorbic acid is a free radical, an antioxidant scavenger, and plays a major role in oxidation-reduction reactions. Ascorbic acid is a cofactor for enzymes involved in the biosynthesis of collagen (essential for tissue maintenance and repair), carnitine, and neurotransmitters. Humans cannot synthesize ascorbic acid endogenously and a lack of dietary intake can lead to scurvy. Vitamin C is most frequently used as a nutritional supplement. It also is used as an adjunct treatment of idiopathic methemoglobinemia and with deferoxamine in the treatment of chronic iron toxicity. Ascorbic acid has been used for a variety of ailments including the common cold, gum infections, acne, depression, fertility, and cancer; however, these claims have not been substantiated and vitamin C is not recommended for these purposes. Ascorbic acid was approved by the FDA in 1939.

Ascorbic acid is necessary for collagen formation (e.g., connective tissue, cartilage, tooth dentin, skin, and bone matrix) and tissue repair. It is reversibly oxidized to dehydroascorbic acid. Both forms are involved in oxidation-reduction reactions. Vitamin C is involved in the metabolism of tyrosine, carbohydrates, norepinephrine, histamine, and phenylalanine. Other processes that require ascorbic acid include biosynthesis of corticosteroids and aldosterone, proteins, neuropeptides, and carnitine; hydroxylation of serotonin; conversion of cholesterol to bile acids; maintenance of blood vessel integrity; and cellular respiration. Vitamin C may promote resistance to infection by the activation of leukocytes, production of interferon, and regulation of the inflammatory process. It reduces iron from the ferric to the ferrous state in the intestine to allow absorption, is involved in the transfer of iron from plasma transferrin to liver ferritin, and regulates iron distribution and storage by preventing the oxidation of tetrahydrofolate. Ascorbic acid enhances the chelating action of deferoxamine during treatment of chronic iron toxicity Vitamin C may have a role in the regeneration of other biological antioxidants such as glutathione and α-tocopherol to their active state.

Ascorbate deficiency lowers the activity of microsomal drug-metabolizing enzymes and cytochrome P-450 electron transport. In the absence of vitamin C, impaired collagen formation occurs due to a deficiency in the hydroxylation of procollagen and collagen. Non-hydroxylated collagen is unstable, and the normal processes of tissue repair cannot occur. This results in the various features of scurvy including capillary fragility manifested as hemorrhagic processes, delayed wound healing, and bony abnormalities.

Currently, the use and dosage regimen of vitamin C in the prevention and treatment of diseases, other than scurvy, is unclear. Although further study is needed to recommend vitamin C therapy for the following ailments, recent data indicate a positive role for vitamin C for: overall increased mortality; the prevention of coronary heart disease (especially in women); management of diabetes mellitus; reducing the risk of stroke; management of atherosclerosis in combination with other antioxidants; osteoporosis prevention; reducing the risk of Alzheimer disease in combination with vitamin E; and the prevention of cataracts. In humans, an exogenous source of ascorbic acid is required for collagen formation and tissue repair.

• Cunningham JJ. The glucose/insulin system and vitamin C: implications in insulin-dependent diabetes mellitus. J Am Coll Nutr 1998;17:105-8.
• Yokoyama T, Chigusa D, Kokubo Y, et al. Serum vitamin C concentration was inversely associated with subsequent 20-year incidence of stroke in Japanese a rural community. The Shibata study. Stroke 2000;31:2287-94.
• Leveille SG, LaCroix AZ, Koepsell TD, et al. Dietary vitamin C and bone mineral density in postmenopausal women in Washington State, USA. J Epidemiol Community Health 1997;51:479-85.
• Zandi PP, Anthony JC, Khachaturian AS, et al. Reduced risk of alzheimer disease in user of antioxidant vitamin supplements. Arch Neurol 2004;61:82-8.
• Jacques PF, Taylor A, Hankinson SE, et al. Long term vitamin C supplement use and prevalence of early age-related lens opacities. Amer J Clin Nutr 1997;66:911-6.

Calcium plays an important role in preventing osteoporosis in postmenopausal women. It is not practical as a dietary supplement due to the small concentration of elemental calcium contained in the tablets.
Calcium plays a crucial role in the function of the nervous, muscular, and skeletal system, providing structural integrity and support for individual growth. Bone constantly undergoes remodeling and turnover. Mineral release during the process of bone resorption guards hydrogen ions, while the formation of bone produces them. Therefore, bone serves as a calcium repository and as a pool for buffers and electrolytes.

Inhibition of bone resorption is primarily the function of the hormone calcitonin. The control of plasma calcium concentration is maintained by several other hormones, including thyroxine, parathyroid hormone, and calcitriol (1,25-dihydroxycholecalciferol). Calcium is metabolized throughout the body. It assists in heart function, blood coagulation, neuromuscular reactions and more.  

Calcium gluconate can be administered intravenously, orally or intraosseously.  Calcium is required by tissues throughout the entire body. The majority of calcium (98%) is stored in the bone. Continuous bone remodeling and turnover of the skeletal system releases calcium into the systemic circulation on a daily basis.

About 40% of calcium binds to plasma proteins and 10% is in chelated form. Roughly 50% of serum calcium is ionized. The body distributes the nonprotein-bound calcium to protein-poor areas of the body like the cerebrospinal and extracellular fluids. About 80% of calcium is excreted in feces and bile, while urinary excretion accounts for the remaining 20%. The kidneys absorb about 99% of filtered calcium with less than 1% excreted.

Three hormones - calcitonin, parathyroid hormone, and calcitriol - control calcium equilibrium. Androgens, estrogens, insulin, growth hormone, and thyroxine also contribute.

 

• Kraft MD, Btaiche IF, Sacks GS, et al. Treatment of electrolyte disorders in adult patients in the intensive care unit. Am J Health Syst Pharm 2005;62:1663-1682.
• Kleinman ME, Chameides L, Schexnayder SM, et al. Part 14: pediatric advanced life support: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122:S876-908
• Broner CW, Stidham GL, Westenkirchner DF, et al. A prospective, randomized, double-blind comparison of calcium chloride and calcium gluconate therapies for hypocalcemia in critically ill children. J Pediatr 1990;117:986-989.
• Anger KE, Belisle C, Colwell MB, et al. Safety of compounded calcium chloride admixtures for peripheral intravenous administration in the setting of a calcium gluconate shortage. J Pharm Pract 2014;27:474-477.
• de Caen AR, Berg MD, Chameides L. Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015;132:S526-S542.
• Reid IR, Ames RW, Evans MC, et al. Effect of calcium supplementation on bone loss in postmenopausal women. N Engl J Med 1993;328:460-4.
• Straub DA. Calcium supplementation in clinical practice: A review of forms, doses, and indications. Nutr Clin Pract 2007;22(3):286-296.
• Roberts KE. Pediatric fluid and electrolyte balance: Critical care case studies. Crit Care Nurs Clin N Am 2005;17:361-373.
• Umpaichitra V, Bastian W, Castells S. Hypocalcemia in children: Pathogenesis and management. Clin Pediatr (Phila) 2001;40(6):305-312.
• Emkey RD, Emkey GR. Calcium metabolism and correcting calcium deficiencies. Endocrinol Metab Clin North Am 2012;41(3):527-556.
• Calcium gluconate tablets package insert. Eatontown, NJ: West-Ward Pharmaceuticals Corp.; 2017 Mar.
• Reber PM, Heath H, III. Hypocalcemic emergencies. Med Clin North Am 1995;79:93-106.
• Calcium chloride 10% injection syringe package insert. Lake Forest, IL: Hospira, Inc.; 2009 Nov.
• Hsu SC, Levine MA. Perinatal calcium metabolism: physiology and pathophysiology. Semin Neonatol 2004;9(1):23-36.
• Burke RR, Rybicki BA, Rao DS. Calcium and vitamin D in sarcoidosis: how to assess and manage. Semin Respir Crit Care Med 2010;31:474-484.

Dexpanthenol (Vitamin B5) is a synthetic derivative of pantothenic acid, a B complex vitamin that is widely distributed in plants and animals. Dexpanthenol is used parenterally as a gastrointestinal stimulant to treat and prevent ileus after GI surgery and in other conditions with impaired GI activity. Dexpanthenol was approved by the FDA in 1948.

Intravenous or intramuscular injections of B5 Dexpanthenol act as a skin protectant on account of their anti-inflammatory properties. They can improve the skin's elasticity and rehydrate it, making it appear smoother and more supple.

Dexpanthenol is a precursor needed for acetylcholine synthesis, which in turn causes parasympathetic activity to maintain normal GI activity. The exact mechanism is not known.

• Dexpanthenol package insert. Shirley, NY: American Regent, Inc.; 2006 July

Glutathione (GSH) is composed of three amino acids combined to produce a peptide that is both a powerful antioxidant and performs several critical roles in the body. According to researchers this peptide is so essential to optimum health that the level of Glutathione in cells could possibly be used to predict how long an organism lives. 

Glutathione catalyzes glutathione S-transferases (GST) and glutathione peroxidases (GPx). Thus, playing a role in detoxification by eliminating toxic electrophilic molecules and reactive peroxides. Glutathione plays a crucial role in a detoxification system that is fundamental in plants, mammals, and fungi. 

Aside from its detoxification role it is important for a variety of essential cellular reactions. Its presence in the glyoxalase system, is fundamental to DNA and RNA nucleotide reduction. Glutathione is also a constituent in the regulation of protein and gene expression, exchange reactions including thiol to disulfide ratios involve glutathione. 

Glutathione can exist intracellularly in either an oxidized (glutathione disulfide) or reduced (glutathione) molecular state. The ratio of reduced glutathione to glutathione disulfide has been shown to be critical in cell survival, this system is very tightly regulated.

Deficiency of glutathione puts the cell at risk for oxidative damage. An imbalance of glutathione is present in many pathologies including cancer, neurodegenerative disorders, cystic fibrosis (CF), HIV and aging.

While Glutathione is vitally essential to maintaining a healthy immune system, it isn’t classified as an essential nutrient; this is because the body does create its own supply from the amino acids:

• L-cysteine
• L-glutamic acid
• Glycine

One of the reasons why Glutathione is so important for optimum health is that it’s present in every cell in the body. One way antioxidants like glutathione help maintain good physical health is by neutralizing free radicals, which can cause cellular damage through oxidation. Since glutathione is naturally present within all types of cells, it is in a prime position to do this. It’s considered one of the most important antioxidants in the human body. 

Glutathione is an essential molecule required for detoxification. Glutathione acts by assisting the body’s machinery in the removal of harmful destructive oxygen containing molecules.

During the body’s normal functioning an excess of oxygen containing molecules are produced, these molecules are typically very reactive with other molecules they come in contact with. In modern biochemistry these are referred to as reactive O2 species.

Reactive O2 species molecules include peroxide (H2O2) and superoxide anions (O2 with unpaired electron) these molecules are very toxic to the cell. The toxicity can be explained by the tendency of these molecules to bind or destroy important biomolecules.

The body has a natural system to remove these reactive O2 species. These systems metabolize and scavenge for reactive oxygen species, in a controlled and precise fashion.

The system that removes these toxic reactive oxygen species includes a host of enzymes:

• Glutathione peroxidase (GPX): GPX detoxifies peroxides with glutathione acting as an electron donor in the reduction reaction, producing glutathione disulfide as an end product. GPX is a 80 kDa protein that is composed of four identical subunits. It is expressed throughout the entire body; individual isoforms are present in specific tissues. When the body is in a state of excess oxidative stress the expression of this enzyme is induced. Abnormal expression has been associated with a wide variety of pathologies, including hepatitis, HIV, and a wide variety of cancers, including skin, kidney, bowel, and breast. Glutathione reductase (GR)- catalyzes reduction of glutathione disulfide is by requires NADPH producing two glutathione molecules as an end product. GR is a member of the flavoprotein disulfide oxidoreductase family and exists as a dimer. Expression of GR is upregulated during periods of increased oxidative stress, to prepare for reactive oxygen species removal. The level at which regulation takes place is at the transcriptional level as well as at the post-translational level. Down regulation of GR production and activity are thought to be associated with cancer and aging. 
• Catalase: is involved in detoxification of reactive oxygen species.
• Superoxide dismutase (SOD): is involved in the removal of superoxide species.

Immune Function: Glutathione plays a significant role in immune function. It encourages the T-cell function that’s essential for a healthy immune system and protects from environmental toxins.

Additionally, glutathione is essential in a broad range of metabolic processes: 

• Glutathione acts to neutralize a toxic metabolic byproduct: Methylglyoxal.
• Glutathione is involved in the protein disulfide bond rearrangement that is necessary for the synthesis of one third of the body’s proteins.
• It protects the body from the oxidative damage caused by glutathione peroxidase by acting as a helper molecule for certain enzymes.
• The liver uses Glutathione to help detoxify fats before the gallbladder emits bile, supporting healthy digestion.

Detoxification: Glutathione may also be crucial in the removal and detoxification of carcinogens, and according to recent studies alterations in this metabolic pathway, can influence cell survival profoundly. Glutathione may be responsible for several vital roles within a cell besides antioxidation: 

• Maintenance of the redox state (chemical reactions in which the oxidation state of atoms are modified).
• Modulation of the immune response.
• Detoxification of foreign bacteria and viruses.

Chronic Disease: Research has demonstrated that glutathione deficiency may be a factor in many chronic conditions; HIV/AIDS, Alzheimer’s, Parkinson’s disease, asthma, different cancers, cataracts, macular degeneration, open angle glaucoma, diabetes, and many diseases of the liver, kidneys, lungs, and digestive system. 

Depletion Due to Aging and Alcohol Consumption: Glutathione plays a major role in the detoxification of ethanol (consumed as alcoholic beverages) and people who routinely drink will experience Glutathione depletion.  Aging is another factor; as the body ages glutathione levels may drop below the level necessary to maintain healthy immune function (among other processes). 

Depletion may also be caused by other cofactors: Besides alcohol consumption and the aging process, there are other factors that can deplete levels of Glutathione: 

• Acetaminophen
• Aspartame
• Benzopyrenes (tobacco smoke, fuel exhaust, etc.)
• Many household chemicals (detergents, fabric softeners, air fresheners, mothballs, cleaners, bleach, etc.)

Fertility: In a study of eleven infertile men, suffering from dyspermia associated with various andrological pathologies - Glutathione was observed to exert a significant effect on sperm motility. Glutathione appeared to have an observable therapeutic effect on certain andrological pathologies that cause male infertility. 

Artherosclerosis: In one study, ten patients with artherosclerosis were administered glutathione which resulted in a significant increase in blood filtration, in addition to a significant decrease in blood viscosity and platelet aggregation. Consequently, Glutathione infusion was determined to be an effective method of decreasing blood viscosity while increasing blood filtration. 

Dermatological Properties: In a three-month study of female subjects, the women taking Glutathione showed significantly improved skin elasticity and amelioration of wrinkles compared to test subjects who received a placebo.

 

• Richie JP Jr, Leutzinger Y, Parthasarathy S, Malloy V, Orentreich N, Zimmerman JA. Methionine restriction increases blood glutathione and longevity in F344 rats. FASEB J. 1994 Dec;8(15):1302-7.
• Cascella R, Evangelisti E, Zampagni M, Becatti M, D'Adamio G, Goti A, Liguri G, Fiorillo C, Cecchi C. S-linolenoyl glutathione intake extends life-span and stress resistance via Sir-2.1 upregulation in Caenorhabditis elegans. Free Radical Biol Med. 2014 Aug;73:127-35. doi: 10.1016/j.freeradbiomed.2014.05.004. Epub 2014 May 15.
• Anderson, M.E., Glutathione Injections: an overview of biosynthesis and modulation. Chem Biol Interact, 1998. 111-112: p. 1-14.
• P., M. and C. G.P., Glutathione reductase: regulation and role in oxidative stress, in Oxidative stress and the molecular biology of antioxidant defenses. 1997, Cold Spring Harbor Laboratory Press
• Lu, Shelly C. “REGULATION OF Glutathione SYNTHESIS.” Molecular aspects of medicine 30.1-2 (2009): 42–59. PMC. Web. 2 Oct. 2017.
• Downey, J.S., et al., The LEC rat possesses reduced hepatic selenium, contributing to the severity of spontaneous hepatitis and sensitivity to carcinogenesis. Biochem Biophys Res Commun, 1998. 244(2): p. 463-7.
• Banki, K., et al., Molecular ordering in HIV-induced apoptosis. Oxidative stress, activation of caspases, and cell survival are regulated by transaldolase. J Biol Chem, 1998. 273(19): p. 11944-53.
• Shisler, J.L., et al., Ultraviolet-induced cell death blocked by a selenoprotein from a human dermatotropic poxvirus. Science, 1998. 279(5347): p. 102-5.
• Okamoto, K., et al., Formation of 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins in human renal-cell carcinoma. Int J Cancer, 1994. 58(6): p. 825-9.
• Chinery, R., et al., Antioxidants reduce cyclooxygenase-2 expression, prostaglandin production, and proliferation in colorectal cancer cells. Cancer Res, 1998. 58(11): p. 2323-7.
• Lee, Y.J., et al., Glucose deprivation-induced cytotoxicity and alterations in mitogen-activated protein kinase activation are mediated by oxidative stress in multidrug-resistant human breast carcinoma cells. J Biol Chem, 1998. 273(9): p. 5294-9.
• P., M. and C. G.P.,
• Glutathione reductase: regulation and role in oxidative stress, in Oxidative stress and the molecular biology of antioxidant defenses. 1997, Cold Spring Harbor Laboratory Press
• Hauser, R.A., et al., Randomized, double-blind, pilot evaluation of intravenous glutathione in Parkinson's disease. Mov Disord, 2009. 24(7): p. 979-83.
• Dröge W, Breitkreutz R. Glutathione and immune function. Proc Nutr Soc. 2000 Nov;59(4):595-600.
• Chang WK, Yang KD, Chuang H, Jan JT, Shaio MF. Glutamine protects activated human T cells from apoptosis by up-regulating glutathione and Bcl-2 levels. Clin Immunol. 2002 Aug;104(2):151-60.
• Oxidative Medicine and Cellular Longevity.Volume 2013 (2013), Article ID 972913, 10 pages http://dx.doi.org/10.1155/2013/972913.
• pubchem.ncbi.nlm.nih.gov/compound/124886?from=summary#section=Related-Compounds
• Balendiran GK1, Dabur R, Fraser D. The role of glutathione in cancer. Cell Biochem Funct. 2004 Nov-Dec;22(6):343-52.
• Ballatori, Nazzareno et al. “Glutathione Dysregulation and the Etiology and Progression of Human Diseases.” Biological chemistry 390.3 (2009): 191–214. PMC. Web. 2 Oct. 2017.
• Vogt, Barbara L., and John P. Richie. “Glutathione Depletion and Recovery After Acute Ethanol Administration in the Aging Mouse.” Biochemical pharmacology 73.10 (2007): 1613–1621. PMC. Web. 2 Oct. 2017.
• Dimova S, Hoet PH, Dinsdale D, Nemery B. Acetaminophen decreases intracellular glutathione levels and modulates cytokine production in human alveolar macrophages and type II pneumocytes in vitro. Int J Biochem Cell Biol. 2005 Aug;37(8):1727-37. Epub 2005 Apr 26.
• Abhilash, M., Varghese, M.V., Paul, M.V.S. et al. Comp Clin Pathol (2015) 24: 927. https://doi.org/10.1007/s00580-014-2013-8
• Romero DL, Mounho BJ, Lauer FT, Born JL, Burchiel SW. Depletion of glutathione by benzo(a)pyrene metabolites, ionomycin, thapsigargin, and phorbol myristate in human peripheral blood mononuclear cells. Toxicol Appl Pharmacol. 1997 May;144(1):62-9.
• National Research Council (US). Multiple Chemical Sensitivities: A Workshop. Washington (DC): National Academies Press (US); 1992. Considerations for the Diagnosis of Chemical Sensitivity.
• Lenzi A1, Lombardo F, Gandini L, Culasso F, Dondero F. Glutathione therapy for male infertility. Arch Androl. 1992 Jul-Aug;29(1):65-8.
• Coppola L, Grassia A, Giunta R, Verrazzo G, Cava B, Tirelli A, D'Onofrio F. Glutathione (Glutathione) improved hemostatic and hemorheological parameters in atherosclerotic subjects. Drugs Exp Clin Res. 1992;18(11-12):493-8.
• Weschawalit, Sinee et al. “Glutathione and Its Antiaging and Antimelanogenic Effects.” Clinical, Cosmetic and Investigational Dermatology 10 (2017): 147–153. PMC. Web. 2 Oct. 2017.

Glycine is, structurally, the simplest amino acid that has been discovered. It was one of the earliest amino acids to be isolated from gelatin back in 1820. Glycine is one of the nonessential amino acids for mammals; meaning that they can create it internally from two other amino acids: serine and threonine. 

Glycine is found principally in gelatin and silk fibroin. It’s been used therapeutically as a nutrient, and also functions as a rapid inhibitory neurotransmitter in the central nervous system (CNS).  Although glycine is both a simple and nonessential amino acid; experimental animals on low-glycine diets show reduced growth. The average adult will ingest 3 to 5 grams of glycine daily from dietary sources.  Glycine is an amino acid that’s involved in the production of DNA, phospholipids, and collagen. It’s also involved in the release of energy. 

Joint Repair: Glycine plays a vital role in collagen formation. It’s an important component for promoting joint, tendon, and ligament function and growth.  Roughly 1/3 of collagen in the body is composed of glycine, and collagen is critical for the formation of the connective tissues that keep joints flexible and capable of successfully withstanding shocks. 

Muscle Growth: The body uses glycine during the biosynthesis of creatine; which supplies all muscles with a source of fuel to repair damage and grow stronger.  It also provides cells with energy due to its role in converting dietary nutrient to help feed muscle tissues and may potentially boost:

• Endurance
• Strength
• Performance

Glycine also benefits hormone production and regulation. It helps the body to naturally synthesize steroid hormones essential to regulating both the fat to muscle ratio and control energy expenditure. 

Anxiety: Glycine will work with other amino acids, including taurine and gamma-amino butyric acid (GABA), to act as an inhibitory neurotransmitter.  This role in nerve and neurotransmitter functions has implications for improving; sleep quality, mental performance, moods, memory, and behavior. Some evidence suggests that glycine may help reduce hyperactivity in the brain and play an effective role in the treatment and prevention of certain mental disorders, such as learning disabilities, schizophrenia, bipolar disorder, and epilepsy.  Other studies have demonstrated that glycine can help minimize psychotic symptoms and seizures when used with other supplements as part of a treatment plan for neurological illness. 

Digestion: Amino acids, including glycine, help to rebuild the tissue that lines the digestive tract; keeping bacteria and food particles contained inside the gut, rather than exiting through tiny openings that pass this matter into the bloodstream where it can trigger an inflammatory response.  Glycine plays a role in forming the two most important substances in the gut lining: collagen and gelatin. 

Inside the GI tract; glycine will be utilized as a metabolic fuel.  It’s required in the production of bile (to break down fats), nucleic acids, creatine phosphate and the porphyrins used to break down nutrients.  It helps move glycogen to the cells for the production of ATP for energy.  Studies show that glycine may help stabilize blood sugar levels, preventing food cravings and fatigue. 

Aging: Glycine is used to produce glutathione, an antioxidant that prevents cell damage and several signs of aging. A paper published in the American Journal of Clinical Nutrition concluded that; while glutathione deficiency in the elderly occurs because of a distinct reduction in glutathione synthesis; supplementing the diet with the glutathione precursors cysteine and glycine can restore normal glutathione production. 

Glycine plays a role in:

• The production of human growth hormone.
• Preventing sarcopenia (muscle wasting or deterioration). 
• Improving sleep quality.
• Mental performance and memory.
• Protecting skin from signs of aging.
• Protecting collagen in joints and reducing joint pain.
• Boosting energy levels.
• Stabilizing blood sugar.

• https://www.calstatela.edu/sites/default/files/dept/chem/07summer/158/25-words-glycine.pdf
• National Center for Biotechnology Information. PubChem Compound Database; CID=750, https://pubchem.ncbi.nlm.nih.gov/compound/750 (accessed Oct. 6, 2017).
• Guo, Zhi-li et al. “DanHong Injection Dose-Dependently Varies Amino Acid Metabolites and Metabolic Pathways in the Treatment of Rats with Cerebral Ischemia.” Acta Pharmacological Sinica 36.6 (2015): 748–757. PMC. Web. 6 Oct. 2017.
• Yang, Guang, Benjamin B. Rothrauff, and Rocky S. Tuan. “Tendon and Ligament Regeneration and Repair: Clinical Relevance and Developmental Paradigm.” Birth defects research. Part C, Embryo today : reviews 99.3 (2013): 203–222. PMC. Web. 6 Oct. 2017.
• Alfonso E. Bello & Steffen Oesser. Current Medical Research and Opinion Vol. 22 , Iss. 11,2006.
• Da Silva, Robin P. et al. “Creatine Synthesis: Hepatic Metabolism of Guanidinoacetate and Creatine in the Rat in Vitro and in Vivo.” American Journal of Physiology - Endocrinology and Metabolism 296.2 (2009): E256–E261. PMC. Web. 6 Oct. 2017.
• Arwert LI, Deijen JB, Drent ML. Effects of an oral mixture containing glycine, glutamine and niacin on memory, GH and IGF-I secretion in middle-aged and elderly subjects. Nutr Neurosci. 2003 Oct;6(5):269-75.
• Bowery, N G, and T G Smart. “GABA and Glycine as Neurotransmitters: A Brief History.” British Journal of Pharmacology 147.Suppl 1 (2006): S109–S119. PMC. Web. 6 Oct. 2017.
• Shen, Hai-Ying et al. “Glycine Transporter 1 Is a Target for the Treatment of Epilepsy.” Neuropharmacology 99 (2015): 554–565. PMC. Web. 6 Oct. 2017.
• Algon, Sibel et al. “Evaluation and Treatment of Children and Adolescents with Psychotic Symptoms.” Current psychiatry reports 14.2 (2012): 101–110. PMC. Web. 6 Oct. 2017.
• Ruth, Megan R, and Catherine J Field. “The Immune Modifying Effects of Amino Acids on Gut-Associated Lymphoid Tissue.” Journal of Animal Science and Biotechnology 4.1 (2013): 27. PMC. Web. 6 Oct. 2017.
• Li P, Wu G. Roles of dietary glycine, proline, and hydroxyproline in collagen synthesis and animal growth. Amino Acids. 2017 Sep 20. doi: 10.1007/s00726-017-2490-6. [Epub ahead of print].
• Ruth and Field; licensee BioMed Central Ltd. 2013. Journal of Animal Science and Biotechnology20134:27 https://doi.org/10.1186/2049-1891-4-27.
• Wang WW, Qiao SY, Li DF. Amino acids and gut function. Amino Acids. 2009 May;37(1):105-10. doi: 10.1007/s00726-008-0152-4. Epub 2008 Aug 1.
• Sheth, H., Hafez, T., Glantzounis, G. K., Seifalian, A. M., Fuller, B. and Davidson, B. R. (2011), Glycine maintains mitochondrial activity and bile composition following warm liver ischemia-reperfusion injury. Journal of Gastroenterology and Hepatology, 26: 194–200. doi:10.1111/j.1440-1746.2010.06323.x
• Li, Changhong et al. “Regulation of Glucagon Secretion in Normal and Diabetic Human Islets by Γ-Hydroxybutyrate and Glycine.” The Journal of Biological Chemistry 288.6 (2013): 3938–3951. PMC. Web. 6 Oct. 2017.
• Sekhar RV, Patel SG, Guthikonda AP, Reid M, Balasubramanyam A, Taffet GE, Jahoor F. Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation. Am J Clin Nutr. 2011 Sep;94(3):847-53. doi: 10.3945/ajcn.110.003483. Epub 2011 Jul 27.
• Kasai K, Kobayashi M, Shimoda SI. Stimulatory effect of glycine on human growth hormone secretion. Metabolism. 1978 Feb;27(2):201-8.
• Lustgarten MS, Price LL, Phillips EM, Fielding RA. Serum glycine is associated with regional body fat and insulin resistance in functionally-limited older adults. PLoS One. 2013 Dec 31;8(12):e84034. doi: 10.1371/journal.pone.0084034. eCollection 2013.
• Alfonso E. Bello & Steffen Oesser.Current Medical Research and Opinion Vol. 22 , Iss. 11,2006.
• Schwieler L, Linderholm KR, Nilsson-Todd LK, Erhardt S, Engberg G. Clozapine interacts with the glycine site of the NMDA receptor: electrophysiological studies of dopamine neurons in the rat ventral tegmental area. Life Sci. 2008 Aug 1;83(5-6):170-5. doi: 10.1016/j.lfs.2008.05.014. Epub 2008 Jun 10.
• Gusev EI, Skvortsova VI, Dambinova SA, Raevskiy KS, Alekseev AA, Bashkatova VG, Kovalenko AV, Kudrin VS, Yakovleva EV. Neuroprotective effects of glycine for therapy of acute ischemic stroke. Cerebrovasc Dis. 2000 Jan-Feb;10(1):49-60.

L-lysine is an essential amino acid and is one of the key building block of muscle tissue. Human body is not able to synthesize lysine hence it needs to be acquired through diet or pharmaceutical supplementation. The recommended uptake of lysine in adults for regular biological functions are reported in the range of 12 to 45 mg·kg−1·d−1. Besides being essential for regular growth, this important amino acid participates in various vital biological processes like proteinogenesis, crosslinking of collagen polypeptides, uptake of essential mineral nutrients, and in the production of carnitine. Carnitine is established to play a crucial role in energy production by transporting long-chain fatty acids into the mitochondria and generated toxic compounds out from the cell.

A few conflicting studies also suggest its role for enhancement of athletic performance. Some patented preparations to increase growth hormone in the body and for stimulating overall growth, cell repair and regeneration also used L-lysine HCl as a major component. Lysine is also been recognized as an important precursor for glutamate synthesis, which works as a neurotransmitter in the vertebrate nervous system. 

L-lysine HCl can improve calcium absorption as well as improvise collagen quality and muscle well-being in general, and has helped patients suffering from osteoporosis. It contributes to a positive calcium balance by boosting intestinal calcium absorption and improving the renal conservation of the absorbed calcium.  L-lysine HCl has also been suggested to be used in combination with minocycline hydrochloride, and metronidazole to treat reactive arthritis or bursitis.  With common occurrence in young men and women, this disease can be caused by species of Shigella bacteria, species of Salmonella, genitourinary pathogens, Chlamydia trachomatis, Neisseria gonorrhea, Ureaplasma urealyticum, Streptococcus pyogenes etc.

According to a few research and patented concepts, L-lysine HCl alone or with other active pharma ingredients can be used to treat Herpes simplex I and II infections which are viral by origin. 

Usage of L-lysine HCl independently as well as in compounded form has been reported for nephroprotection when radioactive therapy is conducted especially against cancer. The proximal tubular uptake of radionuclide in the renal pathway is inhibited temporarily due to intravenous infusion of concomitant amino acid like lysine protecting the kidney from the radio toxicity. 

Treatment with L-lysine HCl has also been reported to be well tolerated and showed a significant decrease in positive symptoms of schizophrenia. 

Results have shown that administration by ingestion, especially with food, have much higher safety and lower possibility of adverse effects compared to injections. 

Among the indispensable amino acids, lysine is most strongly conserved and is less rapidly catabolized.  Proteins of high biological value invariably have high lysine content. Most of the several essential functions of the lysine residue in cell and body proteins are largely related to its e-amino group. The positively charged lysine residue execute several important functions in protein like;

• Receptor affinity: Lysine-rich regions in LDL particles are essential for their "docking" at hepatic LDL receptors.
• Endoplasmic reticulum retention: Mammalian cytoplasmic proteins at fresh synthesis have specific lysine-containing motifs present at carboxyl groups which act as identifying tags allowing them to be retained in the endoplasmic reticulum.
• Muscle function: Titin is a large sized muscle protein which appears to control elasticity of different types of muscle. At its center, it contains a lysine-rich motif termed PEVK (abbreviated for proline, glutamate, valine, and lysine) which is believed to provide it the required elasticity acting as a "spring”.

It has a tendency to be stored in muscle tissues where it may act as a binding agent besides playing an important role in collagen formation and wound healing. 

Lysine competes with other dibasic amino acids like arginine and ornithine for transportation not only in intestinal mucosa and renal tubule but also in mitochondria.  It antagonizes arginine by way of the following five mechanisms. Lysine functions as an antimetabolite of arginine. Lysine competes with arginine for reabsorption in the renal tubules thereby increasing arginine excretion in urine. Lysine also competes with arginine for transport into cells and at absorption sites in the intestines. If there is excess concentration of lysine in the gut, then absorption of arginine is decreased. Lastly, lysine induces enzyme arginiase, which degrades arginine. 

Excess lysine in rats has been shown to inhibit liver arginase activity. A study with of 0.5 mmol/kg intravenous infusion of L-lysine monohydrochloride caused an increase in plasma concentration of arginine with its increased leakage in urine which was inferred to be due to inhibitory effect of lysine on arginine activity. This allows lysine to control growth of herpes simplex virus which exploits the growth-promoting action of arginine. The competing nature of lysine against arginine and ornithine was also shown to interfere with the ammonia cycle and could lead to an increase in urinary ammonia.

Infusion of lysine with a dosage of 0.4 g/kg did not show blood pressure reduction or increase in extracellular fluid volume which are primarily markers of vasodilatation necessary for use against cardiovascular diseases, however, it did lead to an increase in plasma cyclic GMP as well as effected plasma electrolytes and atrial natriuretic peptide concentrations positively. It has also been shown to reduce stress by blocking the stress receptors and improving the cardio vascular response in general. 

L-lysine HCl injection has been reported to induce kaliuresis, i.e. elimination of significant amount of potassium in urine, when injected at a pH of 7.4. It is believed to achieve this by extracellular acidosis and intracellular alkalosis, thereby suppressing the kidney’s ability to secrete H+ ion and facilitating K+ secretion. 

• D. Tomé and C. Bos, “Lysine Requirement through the Human Life Cycle,” J. Nutr., vol. 137, no. 6, pp. 1642S-1645S, Jun. 2007.
• E. Volpi, A. A. Ferrando, C. W. Yeckel, K. D. Tipton, and R. R. Wolfe, “Exogenous amino acids stimulate net muscle protein synthesis in the elderly.,” J. Clin. Invest., vol. 101, no. 9, pp. 2000–2007, May 1998.
• S. H. Kim, Y. kyung Chung, J. Y. Chang, S. K. Lee, M. S. Lee, and S. K. Park, “Stable liquid formulation of human growth hormone,” US8409586B2.
• F. Papes, M. J. Surpili, F. Langone, J. R. Trigo, and P. Arruda, “The essential amino acid lysine acts as precursor of glutamate in the mammalian central nervous system,” FEBS Lett., vol. 488, no. 1–2, pp. 34–38, Jan. 2001.
• R. Civitelli, D. T. Villareal, D. Agnusdei, P. Nardi, L. V Avioli, and C. Gennari, “Dietary L-lysine and calcium metabolism in humans.,” Nutrition, vol. 8, no. 6, pp. 400–5.
• E. L. J. Bonner and R. Hines, “Method for treatment of reactive arthritis or bursitis,” US6765000B2, 2004.
• K. Gerzon, “Herpes treatment,” US4415590A, 1983.
• M. Singh et al., “Medicinal Uses of L-Lysine: Past and Future,” Int. J. Res. Pharm. Sci., vol. 2, pp. 637–642, 2011.
• C. Wass et al., “L-lysine as adjunctive treatment in patients with schizophrenia: a single-blinded, randomized, cross-over pilot study.,” BMC Med., vol. 9, p. 40, Apr. 2011.
• N. W. Flodin, “The metabolic roles, pharmacology, and toxicology of lysine.,” J. Am. Coll. Nutr., vol. 16, no. 1, pp. 7–21, Feb. 1997.
• T. Kato, M. Sano, and N. Mizutani, “Inhibitory effect of intravenous lysine infusion on urea cycle metabolism,” Eur. J. Pediatric., vol. 146, no. 1, pp. 56–58, Jan. 1987.
• S. Guo and L. A. Dipietro, “Factors affecting wound healing.,” J. Dent. Res., vol. 89, no. 3, pp. 219–29, Mar. 2010.
• K. F. Harlow, “L-Lysine Hydrochloride: An Alternative Prophylactic Therapy Reducing the Recurrence Rate of Herpes Labialis,” Pacific University, 2015.
• R. S. Griffith, D. C. DeLong, and J. D. Nelson, “Relation of Arginine-Lysine Antagonism to Herpes simplex Growth in Tissue Culture,” Chemotherapy, vol. 27, no. 3, pp. 209–213, 1981.
• F. Vuvor and T. Ndanu, “Effect of lysine supplementation on cardiovascular response to stressors of households in two peri-urban communities in Ghana,” J. Heal. Res. Rev., vol. 3, no. 3, p. 92, 2016.
• W. G. Walker, H. Dickerman, and L. J. Jost, “Mechanism of lysine-induced kaliuresis,” Am. J. Physiol. Content, vol. 206, no. 2, pp. 409–414, Feb. 1964.
• V. J. Mailoo and S. Rampes, “Lysine for Herpes Simplex Prophylaxis: A Review of the Evidence.,” Integr. Med. (Encinitas)., vol. 16, no. 3, pp. 42–46, Jun. 2017.
• F. C. I. Fellows and M. H. R. Lewis, “Lysine metabolism in mammals,” Biochem. J., vol. 136, no. 2, pp. 329–334, Oct. 1973.
• R. Elango and R. O. Ball, “Protein and Amino Acid Requirements during Pregnancy,” Adv. Nutr. An Int. Rev. J., vol. 7, no. 4, pp. 839S-844S, Jul. 2016.
• M. Payne, T. Stephens, K. Lim, R. O. Ball, P. B. Pencharz, and R. Elango, “Lysine Requirements of Healthy Pregnant Women are Higher During Late Stages of Gestation Compared to Early Gestation,” J. Nutr., vol. 148, no. 1, pp. 94–99, Jan. 2018.
• L. Bumpstead, “Long-term use of supplemental lysine - is it safe?,” J. Aust. Tradit. Soc., vol. 19, no. 4, pp. 228–231, 2013.
• P. J. Garlick, “The Nature of Human Hazards Associated with Excessive Intake of Amino Acids,” J. Nutr., vol. 134, no. 6, pp. 1633S-1639S, Oct. 2004.

Levocarnitine (L-3-hydroxy-4-N-trimethylaminobutyrate) is synthesized in the liver from the amino acids methionine and lysine. This naturally occurring substance is found in all mammalian tissues, especially striated muscle, and is required in energy metabolism, such as the oxidation of fatty acids, facilitating the aerobic metabolism of carbohydrates, and enhancing the excretion of certain organic acids. While only the L isomer is present in the biologic system, commercial synthesis of carnitine produces a D, L racemic mixture, from which the L-isomer is obtained. The D-isomer has pharmacologic effects but does not participate in lipid metabolism. Commercially, carnitine is available as both a prescription and non-prescription product. The prescription version is levocarnitine, while most dietary supplements contain D, L-carnitine which is commonly sold in health food stores.

Levocarnitine has been used in the treatment of primary and secondary carnitine deficiency in adults and neonates, Alzheimer's disease, dilated cardiomyopathy in adults and children, valproic acid-induced hepatotoxicity in children, and hyperlipoproteinemia. It has been designated an orphan drug for a variety of conditions. Its use in alcohol induced fatty liver, Down's syndrome, and chronic fatigue syndrome has shown varying results. Some athletes use carnitine supplements to increase exercise performance, however, the concept of carnitine loading does not appear to be very effective.  Further, D, L-carnitine competitively inhibits levocarnitine. This inhibition may lead to a deficiency. Prescription forms of levocarnitine were approved by the FDA in 1985 (tablets), 1986 (oral solution), and 1992 (injection).

Levocarnitine facilitates long-chain fatty acid transport from the cytosol to the mitochondria, providing substrates for oxidation and subsequent cellular energy production. Levocarnitine can promote the excretion of excess organic or fatty acids in patients with defects in fatty acid metabolism or specific organic acidopathies that bioaccumulate acyl CoA esters. Levocarnitine clears the acyl CoA esters by formation of acylcarnitine which is rapidly excreted.

Carnitine acetyltransferases (CATs) catalyze the interconversion of fatty acid esters of coenzyme A and carnitine, which are located in the cytosol and mitochondrial membranes. Translocases, which exist in mitochondrial membranes, rapidly transport both free carnitine and its esters in and out of cells. Fatty acid esters of CoA, formed in the cytosol, inhibit enzymes of the Krebs cycle, and are involved in oxidative phosphorylation. Hence, the oxidation of fatty acids requires the formation of acylcarnitines and their translocation into mitochondria where the CoA esters are reformed and metabolized. If oxygen tension is limited, carnitine serves to maintain a ratio of free to esterified CoA within mitochondria that is optimal for oxidative phosphorylation and for the consumption of acetyl CoA.

• Brass EP. Supplemental carnitine and exercise. Am J Clin Nutr 2000;72(suppl):618S-623S.

Methionine: Methionine helps the liver maintain the optimal ability to process fatty acids. Methionine is a major constituent of S-adenosylmethionine which has been shown to be associated in genetic regulation and activation of certain genes. Methionine contributes to methyl donation to histones that activate certain genetic processes that may be involved in the increase in lean tissue. Although indirectly linked to lipolysis, it is believed that the increase in lean tissue increases resting metabolic rate, therefore increasing the overall required calories that must be obtained from storage or dietary intake. Methionine, via S-adenosylmethionine, has been shown in animal models to increase CNS activity, therefore increasing the caloric requirements required by the CNS.  The downstream effects of this may ultimately lead to increased caloric requirements for the entire organism. Although studies have not been replicated in humans, there may be an association due to the similarity in pathways shared between organisms.

Inositol: Inositol is a sugar-like molecule, referred to as a sugar alcohol. Even though very similar in molecular structure to glucose, this molecule does not exhibit the traits that simple carbohydrates exhibit. Contrary to simple carbohydrates, this sugar alcohol has been shown to not actively increase adipose storage. In fact, Inositol has been found to decrease fatty acid synthase activity, a multi-enzyme protein that catalyzes fatty acid synthesis. This set of enzymes ultimately enables the body to produce triglycerides fat molecules that reside in adipose tissue (body fat). 

Inositol may be effective in reducing insulin resistance, a common condition associated with increase adiposity (body fat).  Insulin resistance, a condition to which your body becomes resistant to the activities of the hormone insulin. This condition leads to excess blood glucose levels and a host of symptoms and dysfunctions. A chemical called Inositol phosphoglycan is known to regulate the body’s sensitivity to insulin signaling. Inositol phosphoglycan structurally incorporates Inositol, thus inositol is required for this molecule to exert its regulating behavior.

The proper functioning and sensitivity to insulin is found in most healthy individuals, and is essential in maintaining overall health. Excessive exposure to blood glucose ultimately leads to insulin resistance and poor nutrient transport. Inositol may be effective in reducing this condition while at the same time reducing fatty acid (fat) synthesis.

Choline: Choline is a simple molecule usually classified as a B vitamin. The B vitamin class is usually involved in the generation of energy and support of metabolism. Choline is an important precursor to the neurotransmitter acetylcholine. This neurotransmitter is involved in a host of activities, one of which includes muscular function and contraction. Acetylcholine is a fundamental neurotransmitter that enables the communication between neurons. Increased neural communication results in increased CNS activity which ultimately leads to increased energy expenditure. Energy expenditure requires nutrient input, either from stored energy (fat), or dietary nutrients. Choline exist in a delicate balance and homeostasis with methionine and folate. When these nutrients are not in balance adverse health effects may be present. Along with the increase in CNS activity comes increased cognitive ability, reported by many users. Choline may be effective as a nootropic, or a substance with ability to increase cognition. Increased neural cognition is thought to be due to choline’s role as a precursor to acetylcholine.

The supplementation of choline has been shown to reduce serum and urinary carnitine.  The reduction of carnitine in these fluids may indicate carnitine has been partitioned in tissues that utilize it as a fatty acid mitochondrial transport. When carnitine is used in the mitochondria it transports fatty acids to the location which they are broken down and used as energy. It has also been reported that molecular fragments of fat have been found in urine after carnitine and choline supplementation, which may be due to incomplete fatty acid oxidation and the removal of the subsequent byproducts. This means, choline supplementation may increase the utilization of carnitine and increase the removal of fatty acids, even though all fatty acids are not burned as energy. The fragments of fatty acids not burned as energy are extruded in the urine as molecular fragments.

Methionine, which helps the liver maintain the optimal ability to process fatty acids; Choline, which stimulates the mobilization of fatty acids and prevents their deposition in a given part of the body; and, Inositol, which aids in the transport of fat into and out of the liver and intestinal cells, acts synergistically with choline, exhibiting more lipotropic activity than when administered alone. 

As soon as the effect of all 6 of these substances wears out, the body gradually begins returning to its normal rate of fat and general metabolism.

Typically, these compounds are administered in concert. Injections can be administered up to twice a week. B12 is purported by its users and practitioners to help speed up overall metabolic processes and create a greater feeling of overall energy & well-being.  Because these lipotropics are structurally and functionally closely related to the B-vitamins, they are often employed together in the hope of potentiating the potential for fat-loss, thus while the MIC mixture and B vitamin(s) are often injected separately, they are part of the same overall injection cycle. The non-vitamin compounds (MIC) that are injected into the body stimulate the liver into optimizing the process of metabolism, elevate the movement of and utilization of fat, and boost the metabolic power of the body for a while.

• Best, C.H. and J.H. Ridout, The lipotropic action of methionine. J Physiol, 1940. 97(4): p. 489-94.
• Jones, P.A. and D. Takai, The role of DNA methylation in mammalian epigenetics. Science, 2001. 293(5532): p. 1068-70.
• Young, S.N. and M. Shalchi, The effect of methionine and S-adenosylmethionine on S-adenosylmethionine levels in the rat brain. J Psychiatry Neurosci, 2005. 30(1): p. 44-8.
• Hongu, N. and D.S. Sachan, Carnitine and choline supplementation with exercise alter carnitine profiles, biochemical markers of fat metabolism and serum leptin concentration in healthy women. J Nutr, 2003. 133(1): p. 84-9.
• Corrado, F., et al., The effect of myoinositol supplementation on insulin resistance in patients with gestational diabetes. Diabetic Med, 2011. 28(8): p. 972-5.
• Best CH, Ridout JH. "The Lipotropic Action of Methionine". Journal of Physiology. 3 Oct 1939;97:489-494.
• Artom C. "Mechanism of Action of Choline". American Journal of clinical Nutrition
• Gavin G, Patterson J, McHenry W. " Comparison of the Lipotropic Effects of Choline, Inositol, and Lipocaic in Rats". Journal of Biochemistry. 29 Jan 1943;148:275-279.
• Solomon L. "Disorders of cobalamin (Vitamin B12) metabolism: Emerging concepts in pathophysiology, diagnosis and treatment". Elsevier Review. pp. 1-15. Web.

Magnesium, a divalent cation as well as the second most common intracellular cation in the body after potassium, plays a fundamental role in a significant number of enzymatic reactions pertaining to nucleic acid synthesis and energy metabolism.  Additionally, magnesium is important for glycolysis, oxidative phosphorylation, osteogenesis and bone ossification, and RNA as well as DNA synthesis. Magnesium also is integral in the regulation of the enzyme Na+/K+ ATPase which controls the intracellular as extracellular flow of sodium and potassium in living cells. Generally, magnesium is typically found in food sources such as cereals and legumes, and is excreted renally from the body. 

Clinically, magnesium is administered in the body as magnesium salts. Magnesium chloride is one of the most common magnesium salts that is used clinically. Highly water-soluble, it comprises a magnesium halide bound to two inorganic chloride ions.  Administered parenterally, some clinical indications for the use of magnesium chloride include peritoneal dialysis, total parenteral nutrition (TPN), fluid and electrolyte replacement, and the management of cardiovascular diseases such as congestive heart failure, supraventricular tachycardia, ventricular arrhythmia, and atherosclerosis.  

Magnesium is essential to practically all body systems. Its mechanism of action varies depending on the organ system involved. In the cardiovascular system, it is important in regulating atrioventricular conduction due to its calcium antagonistic property; it decreases calcium uptake as well as potassium efflux across the myocardial cell membrane. As such, one of the clinical manifestations of hypomagnesemia is arrhythmias such as torsades de pointe and ventricular tachycardia. Some studies have shown that parenteral magnesium chloride administration may be effective in the management of ventricular tachyarrhythmias following digitalis toxicity. There has also been a demonstrated improvement in left ventricular end-diastolic pressure in patients with coronary artery disease following the administration of parenteral magnesium chloride. 

Neurologically, magnesium acts to block the release of acetylcholine at the neuromuscular junction, thereby inhibiting peripheral neuromuscular transmission. By depressing the central nervous system, magnesium is also used as an anticonvulsant in the management of seizures and preeclampsia. In the brain, magnesium functions as a voltage dependent antagonist and a noncompetitive inhibitor of the N-methyl-D- aspartic acid (NMDA) receptors and ion channels; hypomagnesemia can result in brain injury due to the activation of the NMDA receptors, opening of the calcium channels, and activation of nuclear factor kappa B (NFKB). Magnesium additionally has a direct impact on the blood-brain barrier; hypomagnesemia has been linked to an increase in endothelial permeability, decreased vasodilatation and an increase in the production of vasoconstrictor substances, and rapid damage to micro vessels, leading to focal hemorrhages and cerebral edema. Conversely, normal levels of blood magnesium increase the proliferation of endothelial cells and assists in restoring the integrity of the blood brain barrier following a brain insult. 

With 60% of magnesium within the body found in the bones and 27% in the skeletal muscle, magnesium plays an essential role in maintaining the integrity of the musculoskeletal system. Magnesium promotes bone mineralization through the activation of vitamin D; the metabolism of vitamin D into the active form of 1,25(OH)2D is a magnesium-dependent process.  Additionally, magnesium is a cofactor in the synthesis of parathyroid hormone, which is important in calcium absorption. Therefore, magnesium deficiency can result in loss of skeletal muscle (sarcopenia) as well as loss of bone density through the inhibition of vitamin D activation and reduced calcium absorption. Furthermore, with hypomagnesemia, bone protection from cytokine induced stimulation of osteoclast activity is also lost which can also predispose to osteoporosis. 

Magnesium is also known to play a prominent role in the respiratory system, though its mode of action is not clearly defined. There are several studies that have been conducted which demonstrate that hypomagnesemia is associated with increased incidence of wheezing, airway hyperreactivity, and impaired lung function. Pulmonary function values are decreased in individuals with magnesium deficiency in contrast to their normal counterparts. For patients with acute severe asthma, the use of parenteral magnesium is part of the treatment protocol in an inpatient setting if there is no response to traditional first-line treatment modalities.

• W.J.Fawcett, E.J.Haxby and D.A.Male, “Magnesium: physiology and pharmacology”, British Journal of Anaesthesia, vol.83, no.2, pp.302 – 320, 1999
• L.Grycova, P.Sklenovsky, Z.Lansky, M.Janovska, M.Otyepka, E.Amler, J.Teisinger, and M.Kubala, “ATP and magnesium drive conformational changes of the Na+/K+ -ATPase cytoplasmic headpiece”, Biochimica et Biophysica Acta (BBA) – Biomembranes, vol. 1788, issue 5, pp. 1081 -1091, May 2009
• “Magnesium: Fact Sheet for Health Professionals”, National Institutes of Health.[Online].
• W.J.Fawcett, E.J.Haxby and D.A.Male, “Magnesium: physiology and pharmacology”, British Journal of Anaesthesia, vol.83, no.2
• “Magnesium chloride”, National Center for Biotechnology Information (2020). [Online].
• “DiNicolantonio JJ, Liu J, and O’Keefe JH, “’Magnesium for the prevention and treatment of cardiovascular disease” Open Heart vol. 5, issue 2, 2018.[Online].
• M.Liu, E.Jeong, H.Liu, A.Xie, E.Young So, G.Shi, G.E.Jeong, A.Zhou, and S.C.Dudley Jr., “Magnesium supplementation improves diabetic mitochondrial and cardiac diastolic function”, JCI insight. [Online].
• “Magnesium Chloride”, Drug Bank. [Online].
• M.J. Allen, S. Sharma, “Magnesium”, Treasure Island (FL). StatPearls Publishing, Jan.2020. [Online].
• M.J. Specter, E. Schweizer, and R.H. Goldman, “Studies on Magnesium's Mechanism of Action in Digitalis-induced Arrhythmias”. [Online}.
• M.F. Ghani, J.R. Smith, “The effectiveness of magnesium chloride in the treatment of ventricular tachyarrhythmias due to digitalis intoxication”, American Heart Journal, vol. 88, issue 5, pp. 621 – 626, November 1974. [Online}.
• F. Kraus, “Reversal of diastolic dysfunction by intravenous magnesium chloride”, The Canadian Journal of Cardiology, vol.9, issue 7, pp. 618-620, September 1999. [Online].
• Kaya M, Ahishali B. “The role of magnesium in edema and blood brain barrier disruption.”, Magnesium in the Central Nervous System [Internet]. University of Adelaide Press, 2011. [Online]
• A.M. Uwitonze, M.S. Razzaque, “Role of Magnesium in Vitamin D Activation and Function”, The Journal of the American Osteopathic Association, Vol. 118, pp. 181-189, March 2018. [Online].
• A.A. Welch, J. Skinner, and M. Hickson, “Dietary Magnesium May Be Protective for Aging of Bone and Skeletal Muscle in Middle and Younger Older Age Men and Women: Cross-Sectional Findings from the UK Biobank Cohort”, National Institutes of Health. [Online].
• B. J. Stojak, E. Halajian, R.A. Guthmann, and J. Nashelsky, “Intravenous Magnesium Sulfate for Acute Asthma Exacerbations”, American family physician, vol. 99, no.2, pp. 127–128. [Online].
• W. Jahnen-Dechent, M. Ketteler, “Magnesium basics”, Clinical Kidney Journal. [Online].
• F.A. Ajib, J.M. Childres, “Magnesium Toxicity”. Treasure Island (FL): StatPearls Publishing; Jan. 2020. [Online].
• M.P. Guerrera, S.L. Volpe, J.J Mao, “Therapeutic Uses of Magnesium), American Family Physician, vol. 80, issue 2, pp. 157-162, July 2009. [Online].
• S.J. Bird, “Overview of the treatment of myasthenia gravis”, UpToDate. [Online].
• “Magnesium Chloride: Drug information”, UpToDate. [Online].
• “Magnesium chloride Pregnancy and Breastfeeding Warnings”. [Online].
• U. Grober, “Magnesium and Drugs”, International Journal of Molecular Sciences, vol. 20, issue 9, May 2019. [Online].
• “Magnesium”. RxLIst. [Online].

ZINC has been identified as a cofactor for over 70 different enzymes, including alkaline phosphatase, lactic dehydrogenase and both RNA and DNA polymerase. Zinc facilitates wound healing, helps maintain normal growth rates, normal skin hydration and senses of taste and smell.

COPPER is essential as a cofactor for serum ceruloplasmin, an oxidase necessary for proper formation of the iron carrier protein, transferrin. Copper also helps maintain normal rates of red and white blood cell formation.

MANGANESE is an activator for enzymes such as polysaccharide polymerase, liver arginase, cholinesterase and pyruvate carboxylase.

SELENIUM is part of glutathione peroxidase which protects cell components from oxidative damage due to peroxides produced in cellular metabolism.

Nicotinamide Adenine Dinucleotide (NAD+) is a universal cellular electron transporter, coenzyme, and signaling molecule present in all cells of the body and is essential for cell function and viability. Along with NAD+, its reduced (NADH) and phosphorylated forms (NADP+ and NADPH) are also important. NAD+ and its redox partner NADH are vital for energy (ATP) production in all parts of cellular respiration: glycolysis in the cytoplasm and the Krebs cycle and electron transport chain in the mitochondria.

NADP+ and NADPH tend to be used in anabolic reactions, including biosynthesis of cholesterol and nucleic acids, elongation of fatty acids, and regeneration of glutathione, a key antioxidant in the body.  In other cellular processes, NAD+ and its other forms are used as substrates by NAD+-dependent/-consuming enzymes to make post-translational modifications to proteins.  NAD+ also serves as a precursor for the secondary messenger molecule cyclic ADP ribose, which is important for calcium signaling. 

NAD+ is naturally synthesized de novo in the body from the amino acid tryptophan or vitamin precursors, nicotinic acid and nicotinamide, collectively known as vitamin B3 or niacin; it can also be synthesized from biosynthetic intermediates, including nicotinamide mononucleotide and nicotinamide riboside.  Within salvage pathways, NAD+ is continuously recycled within cells being interconverted to and from its other forms.  Cell culture studies also suggest that mammalian cells can take up extracellular NAD+.

NAD+ levels are highest in newborns and steadily decline with increasing chronological age.  After age 50, they are approximately half of the levels seen in younger adults.  The question of why NAD+ levels decline with age has been investigated in model organisms.  During redox reactions NAD+ and NADH are not consumed but continuously recycled; however, during other metabolic processes, NAD+ is consumed by NAD+-dependent enzymes and thus could become depleted over time, contributing to increased DNA damage, age-related conditions and diseases, and mitochondrial dysfunction.  Age-related decline in mitochondrial health and function is prominent in theories of aging and senescence, and studies of NAD+ depletion and subsequent oxidative damage and stress support these ideas. 

A 2016 study in mice, which present age-related declines in NAD+ levels similar to those observed in humans, revealed that the age-related decline in NAD+ levels is driven by increasing levels of CD38, a membrane-bound NADase that breaks down both NAD+ and its precursor nicotinamide mononucleotide.  The study also confirmed elevated CD38 gene expression in human adipose tissue from older adults (mean age, 61 years) relative to younger adults (mean age, 34 years).  However, other studies in mice have demonstrated that inflammation and oxidative stress caused by aging reduce NAD+ biosynthesis.  Thus, it is likely that a combination of mechanisms contribute to age-related decline of NAD+ in humans.

The clinical importance of maintaining NAD+ levels was established in the early 1900s, when it was discovered that the disease pellagra, which is characterized by diarrhea, dermatitis, dementia, and death, could be cured with foods containing NAD+ precursors, in particular vitamin B3.  Notably, in contrast to vitamin B3 (niacin) supplementation, which causes the skin to flush, this side effect has not been observed with NAD+ injection.  In recent years, low NAD+ levels have been linked to a number of age-related conditions and illnesses associated with increased oxidative/free radical damage, including diabetes, heart disease, vascular dysfunction, ischemic brain injury, Alzheimer’s disease, and vision loss. 

IV infusion of NAD+ has been used extensively for the treatment of addiction, stemming from a study a 1961 report by Paul O’Hollaren, MD, of Shadel Hospital in Seattle, Washington.  Dr. O’Hollaren described the successful use of IV-infused NAD+ for the prevention, alleviation, or treatment of acute and chronic symptoms of addiction to a variety of substances, including alcohol, heroin, opium extract, morphine, dihydromorphine, meperidine, codeine, cocaine, amphetamines, barbiturates, and tranquilizers, in over 100 cases.  However, no clinical trials to date have evaluated the safety and efficacy of NAD+ treatment in addiction.

NAD+-replacement therapy may promote mitochondrial health and homeostasis, genome stability, neuroprotection, healthy aging, and longevity and may aid in treating addiction.  Clinical trials evaluating these effects in humans treated with NAD+ injection have not yet been published; however, numerous clinical trials evaluating the efficacy and safety of NAD+-replacement therapy or augmentation in the context of human disease and aging have recently been completed, and many others are ongoing.

The exact mechanisms of NAD+ restoration or augmentation for potential health benefits, such as supporting healthy aging and treating age-related conditions, metabolic and mitochondrial diseases, and addiction, are unknown. 

NAD+ replacement may counterbalance age-related degradation of NAD+ and its precursor nicotinamide mononucleotide by NADases, in particular CD38, thereby preventing mitochondrial dysfunction and maintaining metabolic function/energy (ATP) production.  However, studies in animal models and humans (and/or samples and cell lines) indicate that NAD+ replacement supports several other biological pathways via NAD+-dependent enzymes. 

There are several notable NAD+-dependent enzymes. Poly-ADP ribose polymerases (PARP 1-17) control DNA repair and nuclear stability. CD38 and CD157 are NADases whose products (cADP-ribose, ADP-ribose and nicotinic acid adenine dinucleotide) are used in Ca2+ signaling and intercellular immune communication.  Sirtuins (Sirt 1-7) are a family of histone deacetylases that regulate of several proteins associated with cellular metabolism, cellular stress responses, circadian rhythms, and endocrine functions; Sirts have also been linked to longevity in model organisms and protective effects in cardiac and neuronal models. Sterile Alpha and Toll/Interleukin-1 Receptor motif-containing 1 (SARM1), is a recently discovered NAD+ hydrolase involved in neuronal degeneration and regeneration. 

Some insight into the mechanism of action of NAD+ replacement has been obtained from studies of progeroid (premature aging) syndromes, which mimic the clinical and molecular features of aging. Werner Syndrome (WS) is believed to most closely resemble natural aging and is characterized by extensive metabolic dysfunction, dyslipidemia, premature atherosclerosis, and insulin-resistant diabetes. WS is caused by mutations in the gene encoding the Werner (WRN) DNA helicase, which regulates transcription of a key NAD+ biosynthetic enzyme called nicotinamide nucleotide adenylyltransferase.

A 2019 study found that NAD+ depletion is a major driver of the metabolic dysfunction in WS through dysregulation of mitochondrial homeostasis.  Cells with depleted NAD+ from samples of WS patients and WS animal models showed impaired mitophagy (selective degradation of defective mitochondria). NAD+ repletion restored NAD+ metabolic profiles, improved fat metabolism, reduced mitochondrial oxidative stress, and improved mitochondrial quality by restoring normal mitophagy in human cells with mutated WRN. In animal models, NAD+ repletion significantly extended lifespan and delayed accelerated aging, including increased numbers of proliferating stem cells in the germ line.  Replacement of NAD+ by administering various NAD+ precursor molecules recapitulated the results, confirming that the beneficial effects are due to NAD+ repletion. 

Providing additional support for the role of NAD+ in promoting mitochondrial and metabolic health, murine cells overexpressing the NADase CD38 consumed less oxygen, had increased lactate levels, and possessed irregular mitochondria, including features such as lost or swollen cristae.  Isolated mitochondria from these cells showed severe loss of NAD+ and NADH compared to controls. In mice lacking CD38, NAD+ levels, mitochondrial respiratory rates, and metabolic functions were preserved during aging.

• Cantó C, Menzies KJ, Auwerx J. NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus. Cell Metab. 2015;22(1):31-53. doi:10.1016/j.cmet.2015.05.023
• Johnson S, Imai SI. NAD+ biosynthesis, aging, and disease. F1000Research. 2018;7. doi:10.12688/f1000research.12120.1
• Belenky P, Bogan KL, Brenner C. NAD+ metabolism in health and disease. Trends Biochem Sci. 2007;32(1):12-19. doi:10.1016/j.tibs.2006.11.006
• Guse AH. The Ca2+-Mobilizing Second Messenger Cyclic ADP-Ribose. In: Calcium: The Molecular Basis of Calcium Action in Biology and Medicine. Springer Netherlands; 2000:109-128. doi:10.1007/978-94-010-0688-0_7
• Billington RA, Travelli C, Ercolano E, et al. Characterization of NAD uptake in mammalian cells. J Biol Chem. 2008;283(10):6367-6374. doi:10.1074/jbc.M706204200
• Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin GJ. Age-Associated Changes In Oxidative Stress and NAD+ Metabolism In Human Tissue. Polymenis M, ed. PLoS One. 2012;7(7):e42357. doi:10.1371/journal.pone.0042357
• Camacho-Pereira J, Tarragó MG, Chini CCS, et al. CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell Metab. 2016;23(6):1127-1139. doi:10.1016/j.cmet.2016.05.006
• Yoshino J, Mills KF, Yoon MJ, Imai SI. Nicotinamide mononucleotide, a key NAD + intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011;14(4):528-536. doi:10.1016/j.cmet.2011.08.014
• Goldberger J. Public Health Reports, June 26, 1914. The etiology of pellagra. The significance of certain epidemiological observations with respect thereto. Public Health Rep. 1975;90(4):373-375. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1437745/. Accessed October 11, 2020.
• Grant R, Berg J, Mestayer R, 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. doi:10.3389/fnagi.2019.00257
• Wu J, Jin Z, Zheng H, Yan LJ. Sources and implications of NADH/NAD+ redox imbalance in diabetes and its complications. Diabetes, Metab Syndr Obes Targets Ther. 2016;9:145-153. doi:10.2147/DMSO.S106087
• Pillai JB, Isbatan A, Imai SI, Gupta MP. Poly(ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2α deacetylase activity. J Biol Chem. 2005;280(52):43121-43130. doi:10.1074/jbc.M506162200
• Csiszar A, Tarantini S, Yabluchanskiy A, et al. Role of endothelial NAD+ deficiency in age-related vascular dysfunction. Am J Physiol - Hear Circ Physiol. 2019;316(6):H1253-H1266. doi:10.1152/ajpheart.00039.2019
• Ying W, Xiong Z-G. Oxidative Stress and NAD+ in Ischemic Brain Injury: Current Advances and Future Perspectives. Curr Med Chem. 2010;17(20):2152-2158. doi:10.2174/092986710791299911
• Zhu X, Su B, Wang X, Smith MA, Perry G. Causes of oxidative stress in Alzheimer disease. Cell Mol Life Sci. 2007;64(17):2202-2210. doi:10.1007/s00018-007-7218-4
• Abeti R, Duchen MR. Activation of PARP by oxidative stress induced by β-amyloid: Implications for Alzheimer’s disease. Neurochem Res. 2012;37(11):2589-2596. doi:10.1007/s11064-012-0895-x
• Lin JB, Apte RS. NAD + and sirtuins in retinal degenerative diseases: A look at future therapies. Prog Retin Eye Res. 2018;67:118-129. doi:10.1016/j.preteyeres.2018.06.002
• O’Hollaren P. Diphosphopyridine nucleotide in the prevention, diagnosis and treatment of drug addiction. West J Surg Obstet Gynecol. May 1961.
• Mestayer PN. Addiction: The Dark Night of the Soul/ Nad+: The Light of Hope - Paula Norris Mestayer - Google Books. Balboa Press; 2019. https://books.google.com/books?id=t7qEDwAAQBAJ&lr=&source=gbs_navlinks_s. Accessed October 11, 2020.
• Braidy N, Villalva MD, van Eeden S. Sobriety and satiety: Is NAD+ the answer? Antioxidants. 2020;9(5). doi:10.3390/antiox9050425
• Gerdts J, Brace EJ, Sasaki Y, DiAntonio A, Milbrandt J. SARM1 activation triggers axon degeneration locally via NAD+ destruction. Science (80- ). 2015;348(6233):453-457. doi:10.1126/science.1258366
• Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J. The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron. 2017;93(6):1334-1343.e5. doi:10.1016/j.neuron.2017.02.022
• Oshima J, Sidorova JM, Jr. Monnat RJ. Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev. 2017;33:105-114.
• Yu CE, Oshima J, Fu YH, et al. Positional cloning of the Werner’s syndrome gene. Science (80- ). 1996;272(5259):258-262. doi:10.1126/science.272.5259.258
• Fang EF, Hou Y, Lautrup S, et al. NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome. Nat Commun. 2019;10(1):1-18. doi:10.1038/s41467-019-13172-

Pyridoxine is a form of vitamin B6 – a water-soluble vitamin. Pyridoxine hydrochloride is the stable salt form of pyridoxine.  Pyridoxine hydrochloride injection is prescribed when oral administration is not feasible, e.g., in case of gastric malabsorption syndromes, and pre-operative and post-operative conditions requiring parenteral nutrition.

Pyridoxine, or vitamin B6, is a naturally occurring vitamin found in food such as cereal grains, legumes, vegetables, liver, meat, and eggs. Pyridoxine is used to treat and prevent vitamin B6 deficiency; to prevent or treat toxicity from isoniazid, cycloserine, or hydralazine; and to treat sideroblastic anemia associated with elevated serum iron levels. It also has been used in pyridoxine-dependent neonates to treat seizures that are unresponsive to conventional therapy and in patients with metabolic disorders such as xanthurenic aciduria, primary hyperoxaluria, primary cystathioninuria, and primary homocystinuria. Pyridoxine hydrochloride has been commercially available since approval by the FDA in 1940.

Inside the body, pyridoxine is converted into its active form, the coenzyme pyridoxal 5’-phosphate. Pyridoxal 5’-phosphate is a versatile coenzyme participating in over 100 biochemical reactions mediating protein, carbohydrate, and lipid metabolism.  It is crucial for the production of neurotransmitters, including dopamine, serotonin, norepinephrine, and GABA. It is also involved in regulating steroid hormone receptors and modulating the affinity of hemoglobin for oxygen.

Since humans lack the enzymes required for vitamin B6 (and pyridoxine) biosynthesis, it is an essential nutrient that needs to be procured through the diet. Dietary sources rich in vitamin B6 are fish, liver and other organ meats, potatoes and other starchy vegetables, and non-citrus fruits.  Isolated vitamin B6 deficiency due to inadequate dietary intake is rare. Deficiency of vitamin B6 may occur in individuals with impaired renal function, genetic or autoimmune disorders, high alcohol intake, and with prolonged use of drugs including isoniazid, cycloserine, anti-epileptics, and oral contraceptives.  In individuals with rheumatoid arthritis and inflammatory bowel disease, inflammatory cytokines cause low vitamin B6 levels, with greater deficiency associated with higher disease severity. People with celiac disease and other malabsorptive autoimmune disorders have vitamin B6 deficiency due to consuming a gluten-free diet low in essential vitamins.  In people with alcohol dependence, the acetaldehyde produced from alcohol competes with the active form of pyridoxine for protein binding. Unbound pyridoxal 5’-phosphate – the active coenzyme form of pyridoxine – is rapidly hydrolyzed, resulting in vitamin B6 deficiency with high alcohol intake.  Drugs like isoniazid and cycloserine interfere with enzymes that convert pyridoxine into pyridoxal-5-phosphate or enhance the catabolism and excretion of pyridoxine, resulting in vitamin B6 deficiency with prolonged use. 

Vitamin B6 deficiency may produce symptoms such as electroencephalogram abnormalities, seizures, peripheral neuropathy, depression, confusion, dermatitis with scaling lips and cracks at the corners of the mouth, glossitis, microcytic anemia, and a weakened immune system.  Low levels of vitamin B6 are associated with an increased risk of cardiovascular disorders, cognitive impairment, and certain types of cancer.  However, more evidence is needed to conclusively demonstrate whether vitamin B6 supplementation reduces the risk or severity of these conditions.

Vitamin B6 is composed of pyridoxine, pyridoxal, and pyridoxamine, and food usually contains all three forms. Pyridoxine is converted in erythrocytes to its active moiety, pyridoxal phosphate (requiring riboflavin for the conversion), while pyridoxamine is converted into pyridoxamine phosphate. These active forms act as coenzymes for no fewer than 60 metabolic processes including the metabolism of fat, protein, and carbohydrate. Their role in protein metabolism includes decarboxylation of amino acids, conversion of tryptophan to niacin or serotonin, deamination, and transamination of amino acids. In carbohydrate metabolism, it is necessary for the conversion of glycogen to glucose-1-phosphate. Pyridoxine is essential for synthesis of gamma aminobutyric acid (GABA) in the CNS and synthesis of heme.

Pyridoxine hydrochloride is used for the prophylaxis and treatment of vitamin B6 deficiency. Vitamin B6 is the collective term encompassing six closely-related compounds: pyridoxine, pyridoxal, and pyridoxamine, as well as their 5’-phosphate esters. Pyridoxal 5’-phosphate (PLP) and pyridoxamine 5’-phosphate (PMP) are the biologically active forms of vitamin B6. 

PLP is the primary coenzyme used by pyridoxine-dependent enzymes. It catalyzes various transamination, decarboxylation, and racemization reactions in the body by acting as an electron sink. PLP-catalyzed transamination of amino acids to keto acids occurs during gluconeogenesis. PLP-mediated decarboxylation of L-amino acids yields biogenic amines that are precursors of neurotransmitters and hormones. PLP also acts as a coenzyme for the synthesis of nucleic acids, sphingomyelin, and heme precursors. 

PLP plays a crucial role in the one-carbon unit generation and homocysteine metabolism. Therefore, pyridoxine is used in the management of B6-responsive homocystinuria. Homocystinuria is a genetic disorder caused by mutations in the gene encoding for the enzyme cystathionine β-synthase that converts methionine to cysteine.  It is characterized by elevated plasma homocysteine and methionine levels.

Given its role in the synthesis of heme precursors, pyridoxine is used to treat congenital and acquired sideroblastic anemia. Sideroblastic anemia is characterized by iron overload and decreased production of mature red blood cells.  Congenital sideroblastic anemia is caused by mutations in enzymes of the heme biosynthesis pathway. Acquired sideroblastic anemia is also linked to impaired heme biosynthesis due to excessive alcohol consumption, heavy metal toxicity, and prolonged use of certain medications.

• Pyridoxine Hydrochloride Injection, USP. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a56d11c0-b033-4201-85ff-fc710506481a&type=display.
• Spinneker, A. et al. Vitamin B6 status, deficiency and its consequences - An overview. Nutricion Hospitalaria (2007).
• Vitamin B6 - Health Professional Fact Sheet. https://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/#h3.
• Wilson, S. M., Bivins, B. N., Russell, K. A. & Bailey, L. B. Oral contraceptive use: impact on folate, vitamin B 6 , and vitamin B 12 statusn ure_419 572..583. (2011) doi:10.1111/j.1753-4887.2011.00419.x.
• Abosamak, N. E. R. & Gupta, V. Vitamin B6 (Pyridoxine). (2020).
• Hallert, C. et al. Evidence of poor vitamin status in coeliac patients on a gluten-free diet for 10 years. Aliment. Pharmacol. Ther. 16, 1333–1339 (2002).
• Veitch, R. L., Lumeng, L. & Li, T. K. Vitamin B6 metabolism in chronic alcohol abuse. The effect of ethanol oxidation on hepatic pyridoxal 5’ phosphate metabolism. J. Clin. Invest. 55, 1026–1032 (1975).
• Sacharow, S. J., Picker, J. D. & Levy, H. L. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. GeneReviews® (University of Washington, Seattle, 1993).
• Abu-Zeinah, G. & Desancho, M. T. Understanding sideroblastic anemia: An overview of genetics, epidemiology, pathophysiology and current therapeutic options. Journal of Blood Medicine vol. 11 305–318 (2020).
• Kennedy, A. & Schaeffer, T. Pyridoxine. in Critical Care Toxicology 1–4 (Springer International Publishing, 2016). doi:10.1007/978-3-319-20790-2_174-1.
• Zempleni, J. & Kübler, W. Metabolism of vitamin B6 by human kidney. Nutr. Res. 15, 187–192 (1995).
• Zempleni, J. & Kübler, W. The utilization of intravenously infused pyridoxine in humans. Clin. Chim. Acta 229, 27–36 (1994).
• Pyridoxine hydrochloride injection, USP package insert. Schaumburg, IL: American Pharmaceutical Partners; 2008 April.
• Mars, H. Levodopa, Carbidopa, and Pyridoxine in Parkinson Disease: Metabolic Interactions. Arch. Neurol. 30, 444–447 (1974).
• Vitamin B-6 - Mayo Clinic. https://www.mayoclinic.org/drugs-supplements-vitamin-b6/art-20363468.
• Diclegis (doxylamine; pyridoxine) package insert. Bryn Mawr, PA: Duchesnay USA, Inc.; 2013 Apr.
• Sahakian, V., Rouse, D., Sipes, S., Rose, N. & Niebyl, J. Vitamin B6 is effective therapy for nausea and vomiting of pregnancy: A randomized, double-blind placebo-controlled study. Obstet. Gynecol. 78, 33–36 (1991).
• Vutyavanich, T., Wongtra-ngan, S. & Ruangsri, R. aroon. Pyridoxine for nausea and vomiting of pregnancy: A randomized, double-blind, placebo-controlled trial. Am. J. Obstet. Gynecol. 173, 881–884 (1995).
• Matthews, A., Haas, D. M., O’Mathúna, D. P., Dowswell, T. & Doyle, M. Interventions for nausea and vomiting in early pregnancy. Cochrane Database of Systematic Reviews vol. 2014 (2014).
• ACOG Practice Bulletin #52: Nausea and Vomiting of Pregnancy. Obstet. Gynecol. (2004) doi:10.1097/00006250-200404000-00045.
• American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776-89.
• AlSaad, D. et al. Is pyridoxine effective and safe for post-partum lactation inhibition? A systematic review. Journal of Clinical Pharmacy and Therapeutics vol. 42 373–382 (2017).
• Shrim, A. et al. Pregnancy outcome following use of large doses of vitamin B6 in the first trimester. J. Obstet. Gynaecol. (Lahore). 26, 749–751 (2006).
• Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (National Academies Press, 1998). doi:10.17226/6015.
• Schaumburg H, Kaplan J, Windebank A, et al. Sensory neuropathy from pyridoxine abuse. N Engl J Med 1983;309:445-8.
• Parry GJ, Breesen DE. Sensory neuropathy with low-dose pyridoxine. Neurology 1985;35:1466-1468.
• Lheureux P, Penaloza A, Gris M. Pyridoxine in clinical toxicology: a review. Eur J Emerg Med 2005;12:78-85

We use sodium bicarbonate as a buffer system to create a pH and Osmolality for our IV infusions that most closely mimics the body own pH and Osmolality.  Sodium bicarbonate is administered orally and intravenously. Sodium bicarbonate is not metabolized, and bicarbonate ions are filtered and reabsorbed by the kidneys. With IV administration the sodium bicarbonate dissociates to bicarbonate ions, which constitute the conjugate base portion of the body's extracellular buffer system (bicarbonate/carbonic acid buffer). Administration of sodium bicarbonate can restore acid-base balance in patients.

Studies strongly suggest that Taurine supplementation, even when taken short-term; may support better physical function, mitigate the cardiovascular risks that can be present after exercising, and improve issues associated with heart failure. 

Taurine may accomplish this by reducing inflammation and lowering blood pressure. Some research suggests that taurine may calm the nervous system and even improve the function of the left ventricle of the heart.

Although more studies must be conducted to confirm these benefits; the research already conducted is promising for anyone concerned with cardiac health or suffering from heart disease. 

A meta-analysis review published in the journal Food & Function found, after analyzing animal and human studies; that Taurine has an effective action against the symptoms of metabolic syndrome (central obesity). 

The study found that Taurine may reduce triglycerides, prevent obesity, improving insulin resistance, regulate glucose metabolism, lower cholesterol, and reduce blood pressure.

Taurine might also help heal the damage from periodontal disease. Patients with chronic periodontitis were observed to determine if Taurine could help the healing process.  It was determined that Taurine significantly improved the healing process. According to this research, it may have done so by enhancing levels of lipid peroxidation products and antioxidant enzymes. 

A study conducted at the University of Stirling evaluated athletes who ran middle distance races before and after they consumed supplemental Taurine. The test-subjects consumed 1,000 milligrams of Taurine two hours before running, and they were checked to confirm that there was no effect on the athlete’s respiratory system, heart rate or blood lactate levels. Afterward, 90% of the runners showed faster times. According to this research; there is a 99.3% chance that Taurine was responsible for the improved performance of the athletes during the time trial. 

Other studies indicate that Taurine may have a powerful mood-boosting effect when combined with caffeine. Scientists have found strong evidence that a combination of Taurine and caffeine may improve mood and possibly boost cognitive performance. 

Taurine is one of the most copious amino acids in the human eye; where it exceeds the concentration of any other amino acid. Consequently, recent studies have found that maintaining high levels of Taurine is crucial to prevent the degeneration of cells in the eye.

 

• Yamori Y, Taguchi T, Hamada A, Kunimasa K, Mori H, Mori M. Taurine in health and diseases: consistent evidence from experimental and epidemiological studies. J Biomed Sci. 2010 Aug 24;17 Suppl 1:S6. doi: 10.1186/1423-0127-17-S1-S6.
• Ahmadian M, Dabidi Roshan V, Ashourpore E. Taurine Supplementation Improves Functional Capacity, Myocardial Oxygen Consumption, and Electrical Activity in Heart Failure. J Diet Suppl. 2017 Jul 4;14(4):422-432. doi: 10.1080/19390211.2016.1267059. Epub 2017 Jan 24.
• Chen W1, Guo J1, Zhang Y1, Zhang J1. The beneficial effects of taurine in preventing metabolic syndrome. Food Funct. 2016 Apr;7(4):1849-63. doi: 10.1039/c5fo01295c.
• Sree, S. Lakshmi, and S. Sethupathy. “Evaluation of the Efficacy of Taurine as an Antioxidant in the Management of Patients with Chronic Periodontitis.” Dental Research Journal 11.2 (2014): 228–233. Print.
• Balshaw TG1, Bampouras TM, Barry TJ, Sparks SA. The effect of acute taurine ingestion on 3-km running performance in trained middle-distance runners. Amino Acids. 2013 Feb;44(2):555-61. doi: 10.1007/s00726-012-1372-1. Epub 2012 Aug 2.
• Seidl, R., Peyrl, A., Nicham, R. et al. Amino Acids (2000) 19: 635. https://doi.org/10.1007/s007260070013
• Ripps, Harris & Shen, Wen. (2012). Review: Taurine: A “very essential” amino acid. Molecular vision. 18. 2673-86.
• Shao, Andrew & N Hathcock, John. (2008). Risk assessment for the amino acids taurine, L-glutamine and L-arginine. Regulatory toxicology and pharmacology : RTP. 50. 376-99. 10.1016/j.yrtph.2008.01.004.

Tri-Amino injection is a combination of three conditional, non-essential amino acids: L-Arginine, L-Citrulline, and L-Ornithine that can play a critical role in:

• Cardiovascular health
• Vasodilation (blood flow)
• Erectile function
• General health and longevity

Amino acids are separated into three categories: essential, nonessential, and conditional. 

Essential Amino Acids: Essential amino acids are the amino acids that are present in foods - since the body cannot produce them endogenously.

Nine out of the twenty amino acids necessary for health are essential, but adults need get only eight of them from dietary sources: valine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine and tryptophan. The 9^th amino acid is histidine and it is only essential in infants. The body cannot store amino acids, so a regular daily supply of these essential building blocks of protein is needed. 

Non-essential and Conditional Amino Acids: Nonessential is a misnomer because these amino acids do fill essential roles. They are considered non-essential because the body can synthesize them, not because they are not essential to health. 

Of these eleven non-essential amino acids, eight are referred to as conditional amino acids because when the body is ill or under stress, it may not be capable of producing enough of these amino acids to meet its needs. 

The conditional amino acids include; arginine, ornithine, glutamine, tyrosine, cysteine, glycine, proline, and serine.

Amino acids can be used by the body to produce energy, but their primary function is to build proteins. Certain amino acids may also fill non-protein-building functions; such as in the formation of neurotransmitters or hormones. 

Each of the body’s twenty amino acids has a unique chemical structure that dictates how they’ll be utilized. A protein will consist of fifty to two-thousand different amino acids that are linked together in a particular sequence according to specific (genetic) instructions.

Tri-amino Injection can be used to supplement the body with two conditional amino acids: l-arginine and l-ornithine, plus citrulline – which in a study published in the Journal Critical Care was identified as a possibly critical biomarker and pharmaconutrient.  These amino acids have been shown by various research studies to play a potentially vital role in supporting cardiovascular health, healthy blood flow, and consequently, erectile dysfunction caused by vascular issues and poor circulation.

L-Arginine: L-arginine is an amino acid that can be obtained from the diet and is necessary for the body to synthesize proteins. Arginine is converted by the body into another important substance - nitric oxide. 

Nitric oxide relaxes blood vessels which is vital for healthy blood flow to the heart and organs throughout the body (including genitals). Nitric oxide aids blood vessels to maintain the flexibility needed for unrestricted blood flow.  This improved blood flow helps maintain both optimal blood pressure and a proper sexual function.

L-arginine has been studied in clinical researched aimed at improving heart and blood vessel conditions that include: 

Congestive heart failure Angina pectoris (chest pain) Hypertension Erectile dysfunction (ED) Coronary artery disease

Ornithine is reduced to arginine in the body, but this will usually occur very slowly, making the combination of arginine and ornithine potentially synergistic. 

Preliminary research shows that supplements containing l-ornithine may improve athletic performance, such as; speed, strength, and power. Studies have also shown that l-ornithine may help to support healthy wound recovery; this benefit is attributed to the role of l-ornithine in producing collagen. There is evidence that l-ornithine may act to decrease anxiety levels when combined with caffeine, possibly because l-ornithine has the ability to cross the blood-brain barrier. 

L-Citrulline: L-citrulline is an amino acid that boosts the production of nitric oxide in the body. Nitric oxide acts to relax the arteries for improved blood flow throughout the body.

Some studies indicate that l-citrulline may help people with diabetes that have circulatory issues such as slow wound healing.  Because of its effects in increasing nitric oxide production, l-citrulline supplementation may improve dilation of blood vessels and blood flow that can improve the symptoms of mild to moderate degrees of erectile dysfunction. 

L-arginine has been used in several studies including recurring pain in the legs from blocked arteries, decreased mental capacity due to age (dementia), and male infertility. 

L-arginine has been used in combination with various over-the-counter (OTC) and prescription medications for several conditions. For example: L-arginine has been used with ibuprofen to treat the symptoms of migraine headaches and combined with conventional chemotherapy drugs in the treatment of breast cancer. 

In addition to other amino acids, arginine has been used to treat cachexia (wasting) in people with cancer and with fish oil and certain supplements to help reduce infections, improve healing, and shorten recovery times after surgery.  It has also been used in protocols used to diagnose growth hormone deficiency since it may stimulate the release of that hormone.

L-Ornithine: L-ornithine is another nitrogen precursor like arginine. It is also the amino acid used in the body’s urea cycle, which makes it possible to eliminate excess nitrogen (ammonia) from the body. 

Ammonia is the waste product of normal cellular metabolism. It becomes toxic when it accumulates in the body. L-ornithine is the catalyst in a process that changes ammonia into urea, which is eliminated by urination. The highest concentration of l-ornithine is found in connective tissues like the skin. 

• Peter J. Reeds. Dispensable and Indispensable Amino Acids for Humans. J Nutr. 2000 Jul;130(7):1835S-40S.
• Yarandi, Shadi S. et al. “Amino Acid Composition in Parenteral Nutrition: What Is the Evidence?” Current opinion in clinical nutrition and metabolic care 14.1 (2011): 75–82. PMC. Web. 29 Sept. 2017.
• Wu G. Amino acids: metabolism, functions, and nutrition. Amino Acids. 2009 May;37(1):1-17. doi: 10.1007/s00726-009-0269-0. Epub 2009 Mar 20.
• Critical Care201519:204.https://doi.org/10.1186/s13054-015-0881-1. Piton and Capellier; licensee BioMed Central. 2015. Published: 1 May 2015.
• Elam RP, Hardin DH, Sutton RA, Hagen L. Effects of arginine and ornithine on strength, lean body mass and urinary hydroxyproline in adult males. J Sports Med Phys Fitness. 1989 Mar;29(1):52-6.
• Cynober, L. “Can Arginine and Ornithine Support Gut Functions?” Gut 35.1 Suppl (1994): S42–S45. Print.
• M.W.Radomski, R.M.J.Palmer, S.Moncada. Characterization of the L-arginine: nitric oxide pathway in human platelets. Br.J.Pharmacol.(1990),101,325-328.
• Cardiology Research and Practice. Volume 2012 (2012), Article ID 656247, 7 pages. http://dx.doi.org/10.1155/2012/656247
• Effects of arginine and ornithine on strength, lean body mass and urinary hydroxyproline in adult males. (PMID:2770269)
• Misaizu, Akane et al. “The Combined Effect of Caffeine and Ornithine on the Mood of Healthy Office Workers.” Preventive Nutrition and Food Science 19.4 (2014): 367–372. PMC. Web. 29 Sept. 2017.
• Luiking, Yvette C., Mariëlle P.K.J. Engelen, and Nicolaas E.P. Deutz. “REGULATION OF NITRIC OXIDE PRODUCTION IN HEALTH AND DISEASE.” Current opinion in clinical nutrition and metabolic care 13.1 (2010): 97–104. PMC. Web. 29 Sept. 2017.
• Baumgardt, Shelley L. et al. “Chronic Co-Administration of Sepiapterin and L-Citrulline Ameliorates Diabetic Cardiomyopathy and Myocardial Ischemia/Reperfusion Injury in Obese Type 2 Diabetic Mice.” Circulation. Heart failure 9.1 (2016): e002424. PMC. Web. 29 Sept. 2017.
• Oral L-Citrulline Supplementation Improves Erection Hardness in Men With Mild Erectile Dysfunction. Cormio, Luigi et al. Urology , Volume 77 , Issue 1 , 119 – 122
• Yi, Jing et al. “L-Arginine and Alzheimer’s Disease.” International Journal of Clinical and Experimental Pathology 2.3 (2009): 211–238. Print.
• Jahangir, Eiman et al. “The Effect of L-Arginine and Creatine on Vascular Function and Homocysteine Metabolism.” Vascular medicine (London, England) 14.3 (2009): 239–248. PMC. Web. 29 Sept. 2017.
• Scibona M, Meschini P, Capparelli S, Pecori C, Rossi P, Menchini Fabris GF. L-arginine and male infertility. Minerva Urol Nefrol. 1994 Dec;46(4):251-3.
• Sandrini G, Franchini S, Lanfranchi S, Granella F, Manzoni GC, Nappi G. Effectiveness of ibuprofen-arginine in the treatment of acute migraine attacks. Int J Clin Pharmacol Res. 1998;18(3):145-50.
• Yu Cao, Yonghui Feng, Yanjun Zhang, Xiaotong Zhu and Feng Jin. L-Arginine supplementation inhibits the growth of breast cancer by enhancing innate and adaptive immune responses mediated by suppression of MDSCs in vivo. BMC Cancer201616:343
• Gullett, Norleena P. et al. “Nutritional Interventions for Cancer-Induced Cachexia.” Current problems in cancer 35.2 (2011): 58–90. PMC. Web. 29 Sept. 2017.
• Bower RH1, Cerra FB, Bershadsky B, Licari JJ, Hoyt DB, Jensen GL, Van Buren CT, Rothkopf MM, Daly JM, Adelsberg BR. Early enteral administration of a formula (Impact) supplemented with arginine, nucleotides, and fish oil in intensive care unit patients: results of a multicenter, prospective, randomized, clinical trial. Crit Care Med. 1995 Mar;23(3):436-49.
• Höche F, Klapperstück T, Wohlrab J. Effects of L-Ornithine on metabolic processes of the urea cycle in human keratinocytes. Skin Pharmacol Physiol. 2004 Nov-Dec;17(6):283-8.
• National Center for Biotechnology Information. PubChem Compound Database; CID=6262, https://pubchem.ncbi.nlm.nih.gov/compound/6262 (accessed Sept. 29, 2017).
• http://www.mayoclinic.org/drugs-supplements/arginine/interactions/hrb-20058733
• http://www.mayoclinic.org/drugs-supplements/arginine/interactions/hrb-20058733

Vitamin B complex is essential for a wide variety of functions in the human body, Its deficiency can also lead to several disorders including chronic neurological ones. Biochemically, different structures are grouped together under B complex on the basis of their natural occurrence in same type of food and solubility in water. Since humans are not able to synthesize vitamins in B complex on their own and these vitamins are easily excreted from the body through urine, their regular intake is essential to maintain energy production, DNA/RNA synthesis/repair, genomic and non-genomic methylation as well as synthesis of numerous neurochemicals and signaling molecules. B complex deficiency is normally caused due to four possible reasons; high consumption of processed and refined food, with lack of dairy and meat-based food in diet, excessive consumption of alcohol, impaired absorption from the gastrointestinal tract or impaired storage and use by liver. 

According to clinical research parenteral administration (intramuscular or intravenous) is preferred over other drug administration routes as it provides first-pass metabolism avoidance, reliable therapeutic concentrations and better bioavailability of dosage.  It can also be used in situations when oral route is not feasible.

B vitamins are necessary for the proper functioning of the methylation cycle, DNA synthesis, repair and maintenance of phospholipids and generally essential for healthy skin, muscles, brain, and nerve functionality.  The individual functions are described below but more often than not they work together to achieve the required effect.

Vitamin B1 (Thiamine):  It plays an important role in energy metabolism, immunity boosting and functioning of nervous system. It can help avoid type 2 diabetes, several cardiovascular diseases, some vision and kidney disorders and neurodegenerative diseases like Alzheimer’s disease.

Vitamin B2 (Riboflavin):  It is a powerful antioxidant and plays a vital role in maintaining healthy blood cells and boosts metabolism.

Vitamin B3 (Niacin):  Niacin plays a critical role in proper functioning of the nervous and digestive systems. Like other vitamins from the family it is necessary for energy production and metabolism of fatty acids. It also provides healthy skin, nails, and hair.

Vitamin B5 (Pantothenic Acid):  Pantothenic acid is essential for healthy development of the central nervous system. It is involved in energy production and through different metabolic and anabolic cycles in development of amino acids, blood cells, vitamin D3 and other fatty acids.

Vitamin B6 (Pyridoxine):  Vitamin B6 has a very influential role in synthesis of neurotransmitters and is essential for good mental health. It also has a direct effect on immune function. It plays a role in metabolism of amino acids and is a necessary co-factor in the folate cycle, lack of which can lead to anemia.

Epidemiological evidence in some cases hints that the accepted dosages of vitamin B helps only to avoid their marginal deficiency and further benefits could accrue from higher dosages than those provided by RDA. 

• Vitamin B complex 1.D. Kennedy, “B Vitamins and the Brain: Mechanisms, Dose and Efficacy—A Review,” Nutrients, vol. 8, no. 2, p. 68, Jan. 2016.
• J. Zhang, Z. Xie, N. Zhang, and J. Zhong, “Nanosuspension drug delivery system: preparation, characterization, postproduction processing, dosage form, and application,” in Nanostructures for Drug Delivery, Elsevier, 2017, pp. 413–443.
• K. Mikkelsen and V. Apostolopoulos, “Vitamin B1, B2, B3, B5, and B6 and the Immune System,” in Nutrition and Immunity, Cham: Springer International Publishing, 2019, pp. 115–125.
• M. S. Morris, “The Role of B Vitamins in Preventing and Treating Cognitive Impairment and Decline,” Adv. Nutr., vol. 3, no. 6, pp. 801–812, Nov. 2012.
• M. S. Morris, M. F. Picciano, P. F. Jacques, and J. Selhub, “Plasma pyridoxal 5′-phosphate in the US population: the National Health and Nutrition Examination Survey, 2003–2004,” Am. J. Clin. Nutr., vol. 87, no. 5, pp. 1446–1454, May 2008.

Methylcobalamin (Vitamin B-12) aides in the growth of healthy blood cells, nerve cells, and bodily proteins; assist with the metabolism of fats and carbohydrates to release energy; help regulate appetite and mood (key factors in overeating); and are a great treatment for people who cannot absorb vitamin B-12. Vitamin B-12 is an essential water-soluble vitamin that is commonly found in a variety of foods such as fish, shellfish, meat, eggs, and dairy products. Important in DNA synthesis, vitamin B-12 is frequently used in combination with other B vitamins in what is known as a vitamin B-complex formulation. Vitamin B-12 is bound to the protein in food, and released by stomach acids during digestion. Once released, B-12 combines with a substance called intrinsic factor (IF) before it is absorbed into the bloodstream.

Decreases in vitamin B-12 levels are more common in the elderly, HIV-infected persons, and vegetarians. Vitamin B-12 deficiency is often defined by low levels of within the body stores of this vitamin, which can result in anemia – a lower-than-normal number of red blood cells wherein some of the symptoms include fever, excessive sweating, and soreness or weakness in the arms and legs. The inability to absorb vitamin B-12 from the intestinal tract can lead to various types of anemia, the most prominent of which is a type of megaloblastic anemia called pernicious anemia. However, this form of anemia is quickly remedied through vitamin B-12 supplementation.

Vitamin B-12 has a fascinating history, which rounds out over a decade of vitamin research as one of the last vitamins to be discovered. An essential daily nutrient, vitamin B-12 is needed to maintain healthy red blood cells, healthy nerve cells, and to make DNA. However, it was discovered as a cure to a condition known as pernicious anemia, which is directly related to a vitamin B-12 deficiency.

Pernicious anemia is a blood disorder in which red blood cells fail to develop normally, resulting in the steady decline of red blood corpuscles that was fatal until the 1920s. The disease was first described completely in 1849 by English physician Thomas Addison (1793-1860), who noted that the typical symptoms included increasing weakness and pallor, accompanied by obesity or weight gain rather than weight loss. 

Numerous scientists played roles in helping to discover and isolate the causes and cure for anemia: 

• Dr. Newcastle was never looking for a vitamin supplement, but rather a simple cure for pernicious anemia. He discovered that administering regurgitated gastric juices to his patients caused disease improvement.
• Dr. George Whipple's (1878-1976) studies showed that beef liver could improve the formation of red corpuscles in anemic dogs. He bled dogs to induce anemia and then set about to find out which foods would cause the dogs to recover the quickest. He discovered that feeding the dogs raw liver essentially cured anemia. Thus, raw liver, or raw liver juice became the treatment of choice for pernicious anemia. He recommended patients eat at least a 1/2 pound per day.
• George Minot and William Murphy were two researchers who set about to try to isolate the curative property of raw liver. They were successful in showing that the curative property was in the liver tissue. For their respective roles in the discovery of a cure of pernicious anemia Whipple, Minot, and Murphy all won the 1934 Nobel Prize in Medicine.
• Edwin Cohn created a liver extract that was substantially more potent than simply eating raw liver.
• American and British researchers Karl A. Folkers and Alexander R. Todd respectively, simultaneously discovered, isolated, and named cobalamin (vitamin B-12) in 1948.
• Dorothy Crowfoot Hodgkin with more sophisticated technology, using crystallographic data, was able to determine the molecular structure of vitamin B-12. This made it possible in the 1950s to produce large quantities from bacteria cultures leading to the modern form of treatment for the disease. She also won a Nobel Prize for her work.

Vitamin B-12 Deficiency

Pernicious anemia is a decrease in red blood cells that occurs when your intestines cannot properly absorb vitamin B-12, and presents a host of complications and symptoms. However, studies have shown that a deficiency of vitamin B-12 can also lead to abnormal symptoms. These symptoms may include ataxia (shaky movements and unsteady gait), muscle weakness, spasticity (stiff or rigid muscles), incontinence (lack of bladder and/or bowel control), hypotension (low blood pressure), vision problems, dementia, psychoses (abnormal condition of the mind), and mood disturbances. Giving vitamin B-12 by mouth, by injection, or by nasal inhalation is effective for preventing and treating dietary vitamin B-12 deficiency.

There exists a long list of other conditions, disorders, and complications related to vitamin B-12 deficiency, and on which the research remains unclear/inconclusive, but has shown some improvement during vitamin B-12 supplementation including: 

Alzheimer's disease​, Angioplasty (opening narrowed/blocked arteries), Breast cancer, Canker sores, Cardiovascular disease/hyperhomocysteinemia, Cervical cancer, Claudication (leg pain from clogged arteries), Depression, Diabetic neuropathy (nerve damage), Diagnostic procedure, Facial spasm, Fatigue, Fractures (prevention), High cholesterol, Imerslund-Grasbeck disease, Joint pain (elbow), Mental performance, Poisoning (cyanide), Shaky-leg syndrome, Sickle cell disease, Sleep disorders (circadian rhythm)

Vitamin B-12 Sources and Treatments

Vitamin B-12 is necessary to produce an adequate amount of healthy red blood cells in the bone marrow, is available only in animal foods (meat and dairy products) or yeast extracts (such as brewer’s yeast). Vitamin B-12 is a water-soluble vitamin, which means it easily dissolves in water and is paradoxically stored in the liver (making it a good source). It is eliminated from the body through the urine, typically between 24 and 72 hours after consumption, depending on how active a person is and the amount of fluids they take in. Due to the rapid rate with which the body processes Vitamin B-12 frequent supplementation is needed to address deficiencies.

The stomach acids that aid in the natural breakdown of food also breakdown vitamin B-12 pill supplements, the body will only absorb a small amount when ingested orally. In addition, as a person gets older the body’s ability to absorb B-12 through digestion continually decreases. In fact, many adults are completely unable to absorb B-12. Injections provide a direct and concentrated method of supplying the body with the vitamin B-12, and are of particular value to older populations when normal absorption rates decrease, even in the absence of pernicious anemia. The conventional way of fixing a vitamin B-12 deficiency has been through intramuscular injections. 

Research findings show ample evidence to reveal that injections of 1 to 2 milligrams per day can quickly correct deficiencies. It is not apparent whether smaller amounts, such as the 25 micrograms or so found in multivitamins, are sufficient to cure deficiencies. Such a claim is substantiated by the fact that although oral supplementation with vitamin B-12 is safe, efficient, and inexpensive most multi-vitamin pills contain 100-200 micrograms of the cyanocobalamin or methylcobalamin forms of B-12. Furthermore, many multivitamins cannot be chewed, which is important for their thorough absorption.

Routine B-12 injections at a dosage of 1 milligram per month also helps to lower homocysteine levels in the blood, thereby reducing the probability of heart diseases and strokes. A vitamin B-12 injection acts as a stimulant for energizing the body, through cobalamin, which transmits its “anti-stress” elements to the human body. For example, the recommended effective cure for chronic fatigue syndrome (CFS) is 6 to 7 milligram dose of vitamin B-12 intramuscular injection per week for 3 weeks.

The replenishment with parenteral (IV) cyanocobalamin causes a rapid and complete improvement of megaloblastic anemia and gastrointestinal symptoms caused by vitamin B12 deficiency. The parenteral administration also halts the progression of neurological damage associated with B12 deficiency, but the complete improvement of the condition may depend on the severity and extent of the deficiency. 

• System of Medicine (London, 1909), V, 728–757. Clifford Allbutt and Humphrey Davy Rolleston, eds. Pernicious Anemia. French Herbert.
• Annals of Medical History, 7 (1935), 130-132. Addison and His Discovery of Idiopathic Anemia. Long E. R.
• Modern Medical Monographs (New York and London, 1959), p. 63. The Megaloblastic Anemias. Herbert Victor.
• Orv Hetil. 2013 Nov 3;154(44):1754-8. History of the therapy of pernicious anemia. Jeney A.
• N Engl J Med. 2014 Feb 20;370(8):773-6. Vitamin B-12 and pernicious anemia--the dawn of molecular medicine. Bunn HF.
• Ann Nutr Metab. 2012;61(3):239-45. The discovery of vitamin B(12). Scott JM, Molloy AM.
• Turk J Haematol. 2013 Jun;30(2):226. Huge dose vitamin B-12 (vit B-12) treatment for pernicious anemia. Ozsoylu S.
• Pediatric Blood Cancer. 2014 Apr;61(4):753-5. Vitamin B-12 deficiency: The great masquerader. Dobrozsi S, Flood VH, Panepinto J, Scott JP, Brandow A.
• Semergen. 2013 Jul-Aug;39(5):e8-e11. Neurological signs due to isolated vitamin B-12 deficiency. Martinez Estrada KM1, Cadabal Rodriguez T, Miguens Blanco I, García Méndez L.
• Vasavada A, Sanghavi D. Cyanocobalamin. In: StatPearls [Internet] 2020. StatPearls Publishing.
• Sanz-Cuesta T, González-Escobar P, Riesgo-Fuertes R, Garrido-Elustondo S, del Cura-González I, Martín-Fernández J, Escortell-Mayor E, Rodríguez-Salvanés F, García-Solano M, González-González R, Martín-de la Sierra MÁ. Oral versus intramuscular administration of vitamin B12 for the treatment of patients with vitamin B12 deficiency: a pragmatic, randomized, multicentre, non-inferiority clinical trial undertaken in the primary healthcare setting (Project OB12). BMC Public Health. 2012; 12:1-1.

After iron, zinc it the second most abundant trace element in the human body. It is a divalent cation and the 30th element as well as the first element in group 12 of the periodic table. It is an essential micronutrient that plays a key role in the catalysis of over 100 enzymes such as alkaline phosphatase, lactic dehydrogenase, and RNA and DNA polymerase. It assists in the synthesis of RNA and DNA, cell proliferation and differentiation, and the stabilization of cell membranes and cell structures. Zinc exerts its gene regulatory and expressive effects through the formation of zinc finger proteins (ZnF).

The Role of Zinc in the Human Body:  Zinc also plays a role in the regulation of the immune system. Being an essential element, it is not synthesized by the human body but must be ingested through food or mineral supplements. Some of the common food sources of zinc include beef, poultry, seafood, and grains, among others. In adults, normal serum zinc levels are between 70 and 250 ug/dl. After oral ingestion, zinc absorption occurs mainly in the ileum and duodenum and its binds to plasma proteins such as albumin in the blood. Following its metabolism, it is excreted mainly in the stool; some metabolites are also excreted in the urine and sweat, but to a significantly lower extent. 

With zinc playing a significant role in many of the body's key processes, zinc deficiency can result in a variety of illnesses and medical disorders. Some of the clinical manifestations include, but are not limited to, the following:

• Hair and weight loss.
• Delayed wound healing and skin lesions such as oral lichen planus, pemphigus vulgaris, bullous pemphigoid, and epidermodysplasia verruciformis, among others.
• Decreased taste sensation and loss of appetite.
• Altered cognitive and motor performance in neonates and infants.
• Increased susceptibility to infections due to decreased functionality in monocytes, neutrophils, granulocytes, and phagocytosis.
• Exacerbation of hypertension as well as other cardiovascular diseases.
• Delayed puberty and growth retardation in adolescents.
• Osteoporosis as well as other abnormalities in bone mineralization and development.
• Decreased folate absorption which may result in macrocytic megaloblastic anemia.
• Mental lethargy and mood disorders. 
• With zinc playing a prominent role in many major processes within the human body, its mechanism of action varies depending on the organ system as well as the relevant process involved.
• Immune System and Anti-Inflammation
• In the immune system, zinc functions as a second messenger for immune cells; intracellular zinc participates in signaling events in immunity. It is involved in the development of monocytes and macrophages and regulates macrophagic functions such as phagocytosis and the production of proinflammatory cytokines. Zinc also inhibits phosphodiesterase, resulting in increased levels of guanosine-3' 5'- cyclic monophosphate which leads to the suppression of Tumor Necrosis Factor alpha (TNF-a), interleukin-1 beta (IL-1B), as well as other inflammatory cytokines. Additionally, zinc increases the expression of peroxisome proliferator-activated receptor- alpha; this results in the downregulation of inflammatory cytokines and adhesion molecules. Due to these and several other actions in the immune system, zinc is considered to be a key anti-inflammatory agent in the human body. 
• In the skin, zinc exerts its effects through several means in the development and maintenance of the skin cells. Zinc is most concentrated in the stratum spinosum layer of the skin compared to the other three layers namely basal layer, stratum granulosum, and stratum corneum. Studies have shown that zinc facilitates the proliferation as well as the survival of keratinocytes in the stratum spinosum; it also suppressed the activation of interferon-gamma and tumor necrosis factor-alpha by these keratinocytes. Additionally, zinc plays an active role in the development of Langerhans cells, a type of antigen-presenting cells, within the skin. Furthermore, the expression of melanocytes in the human skin is facilitated by zinc through mechanisms that are not yet fully understood. 
• In the central nervous system, zinc is essential in the formation and development of the growth factors, hormones, enzymes, and proteins during neurodevelopment; mild zinc deficiency during pregnancy has been shown to result in learning and memory abnormalities. Zinc helps in the development of the neural tube, the first brain structure that develops during pregnancy, the neural crest, and the process of stem cell proliferation during neurogenesis. Furthermore, free zinc is found in synaptic vesicles where it acts to modulate a variety of postsynaptic receptors; in the synaptic cleft it reduces the inhibitory actions of GABA receptors. Free zinc also exerts inhibitory actions on the release of glutamate, an excitatory neurotransmitter.

 

• "Zinc sulfate". Available: https://go.drugbank.com/drugs/DB09322
• Maxfield, L., Crane, J.S., "Zinc Deficiency", StatPearls. 2020. Available: https://www.ncbi.nlm.nih.gov/books/NBK493231/
• Saper, R.B., Rash, R., "Zinc: An Essential Micronutrient", American Family Physician, vol.79 issue 9, pp.768 – 772. 2009. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820120/#
• Mocchegiani, E., Romeo, J., Malavolta, M., Costarelli, L., Giacconi, R., Diaz, L., Marcos, A., "Zinc: Dietary intake and intake of supplementation on immune function in elderly", Age, vol.35 issue 3, pp.839 – 860. June 2013. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636409/
• Prasad, A.S., "Discovery of Human Zinc Deficiency: Its impact on Human Health and Disease", Advances in Nutrition, vol.4 issue 2, pp.176 – 190. March 2013. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3649098/
• Gammoh, N.Z., Rink, L., "Zinc in Infection and Inflammation", Nutrients, vol.9 issue 6. June 2017. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490603/
• Ogawa, Y., Kinoshita, M., Shimada, S., Kawamura, M., "Zinc and skin disorders", Nutrients, vol.10 issue 2. February 2018. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852775/
• Gower-Winter, S.D., Levenson, C.W., "Zinc in the central nervous system: From molecules to behavior", Biofactors, vol.38 issue 3, pp.186-193. May 2012. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757551/#:~:text=Zinc%20has%20also%20been%20implicated,these%20and%20other%20neurological%20disorders
• Roohani, N., Hurrell, R., Kelishadi, R., Schulin, R., "Zinc and its importance for human health: An integrative review", Journal of Research in Medical Sciences, vol.18 issue 2, pp.144-157. February 2013. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724376/
• "Zinc sulfate", Drug Bank. Available: https://go.drugbank.com/drugs/DB09322
• "Zinc – Fact Sheet for Health Professionals", National Institutes of Health, Office of Dietary Supplements. Available: https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/
• "Zinc sulfate Pregnancy and Breastfeeding Warnings", Drugs. Available: https://www.drugs.com/pregnancy/zinc-sulfate.html#:~:text=Zinc%20sulfate%20has%20been%20assigned,age)%20is%20recommended%20during%20pregnancy.
• Agnew, U.M., Slesinger, T.L., "Zinc Toxicity", StatPearls. Available: https://www.ncbi.nlm.nih.gov/books/NBK554548/