GALAXY NEUROCARE CAPSULES

Indications

• Vitamin B6 deficiency
• Isoniazid-induced neuropathy (prophylaxis and treatment)
• Idiopathic sideroblastic anaemia
• Prevention of penicillamine-induced neuropathy in Wilson's disease
• Metabolic diseases such as cystathioninuria and homocystinuria
• Premenstrual syndrome

Mechanism of action

Pyridoxine hydrochloride is converted in the body to pyridoxal phosphate, which is the active form of vitamin B6. It serves as a cofactor for more than 100 enzymatic reactions, particularly those involved in the metabolism of amino acids, the synthesis of neurotransmitters (such as serotonin, dopamine, and gamma-aminobutyric acid), and the production of hemoglobin. Its role in neurotransmitter synthesis makes it crucial for normal brain function and mood regulation.

Pharmacodynamics

Pyridoxine hydrochloride exerts its effects by facilitating the conversion of amino acids into neurotransmitters and is involved in the synthesis of heme. It impacts the metabolism of tryptophan to serotonin and is essential for the production of norepinephrine and gamma-aminobutyric acid, which are vital for proper neurological function. Deficiency of vitamin B6 can lead to neurological symptoms, including peripheral neuropathy and cognitive disturbances.

Pharmacokinetics

Pyridoxine hydrochloride is readily absorbed from the gastrointestinal tract. It is primarily metabolized in the liver, where it is converted to its active form, pyridoxal phosphate. The elimination half-life of pyridoxine is approximately 15-20 days, and it is excreted primarily through the urine. Renal impairment may affect the metabolism and excretion of pyridoxine, necessitating dose adjustments.

Contra-indications

• Hyperkalaemia
• Severe liver damage

Adverse effects

• Peripheral neuritis
• Hepatitis
• Hypoglycaemia
• Urine discolouration

Interactions

• Potassium aminobenzoate
• Isoniazid

Precautions

• Caution in renal impairment (increased risk of hyperkalaemia)
• Interrupt treatment during periods of low food intake (such as fasting, anorexia, and nausea) to reduce risk of hypoglycaemia
• Monitor liver function tests monthly during high-dose therapy

Pregnancy

Manufacturer advises avoiding use in pregnancy due to potential risk of birth defects; however, no adverse effects have been reported at normal dietary levels.

Breast-feeding

Theoretical risk of toxicity in infants if mothers take large doses.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Pyridoxine hydrochloride 10 mg tablets
• Pyridoxine hydrochloride 20 mg tablets
• Pyridoxine hydrochloride 50 mg tablets
• Pyridoxine hydrochloride oral solution 20 mg per 1 ml

Indications

• Isolated carboxylase defects
• Defects of biotin metabolism
• Prevention of deficiency in complete biliary obstruction

Dosage

Children: Neonate: Initially 10 mg once daily, adjusted according to response; maintenance 5–20 mg daily. Child: Initially 10 mg once daily, adjusted according to response; maintenance 5–20 mg daily, higher doses may be required.

Adults: For adults, the dosing may vary based on the condition being treated. General guidance is to refer to the BNF for specific dosing recommendations.

Mechanism of action

Biotin acts as a coenzyme for carboxylase enzymes, facilitating critical metabolic processes including gluconeogenesis, fatty acid synthesis, and amino acid catabolism.

Pharmacodynamics

Biotin is essential for the carboxylation of substrates in metabolic pathways, influencing energy metabolism and the synthesis of important biomolecules. It supports normal growth and development.

Pharmacokinetics

Biotin is absorbed in the intestine and is widely distributed in body tissues. It is not stored in large amounts, with excess being excreted in urine. The half-life and specific pharmacokinetic parameters can vary based on individual metabolism and dietary intake.

Adverse effects

• Rough skin
• Dry hair
• Enlarged liver
• Increases in erythrocyte sedimentation rate
• Increased serum calcium
• Increased serum alkaline phosphatase concentration

Precautions

• Excessive doses may be teratogenic
• High levels of vitamin A may cause birth defects

Pregnancy

No information available.

Breast-feeding

No information available.

Formulations

• Tablet
• Oral suspension
• Oral solution
• Solution for injection

Indications

• Hypertension
• Benign prostatic hyperplasia
• Urinary retention related to prostate enlargement

Dosage

Children: Refer to the BNF for Children for appropriate dosing guidelines in the paediatric population.

Adults: Refer to the BNF for specific dosing recommendations based on individual clinical scenarios.

Mechanism of action

Alpha acts by selectively blocking alpha-1 adrenergic receptors, which are responsible for mediating vasoconstriction in blood vessels. By inhibiting these receptors, alpha promotes vasodilation, leading to a decrease in peripheral vascular resistance and subsequently lowering blood pressure. Additionally, this action can help alleviate urinary symptoms associated with an enlarged prostate.

Pharmacodynamics

The pharmacodynamics of alpha involve its competitive antagonism at alpha-1 adrenergic receptors, resulting in decreased vasoconstriction and increased blood flow. This mechanism is beneficial in conditions characterized by high blood pressure and urinary retention due to prostatic enlargement. The onset of action typically occurs within hours, with peak effects observed within a few days of consistent dosing.

Pharmacokinetics

Alpha is absorbed well from the gastrointestinal tract, with peak plasma concentrations achieved within 1-3 hours post-administration. The drug undergoes hepatic metabolism, primarily via cytochrome P450 enzymes, resulting in active and inactive metabolites. The elimination half-life varies, but it generally is around 6-12 hours, allowing for once-daily dosing in many cases. Renal excretion is a significant route for its metabolites, necessitating caution in patients with renal impairment.

Interactions

• maois, irreversible + alpha blockers: Severe (increases effects)
• ribociclib + alpha blockers: Severe (increases exposure)
• cobicistat + alpha blockers: Moderate (increases exposure)
• idelalisib + alpha blockers: Moderate (increases exposure)
• dronedarone + alpha blockers: Unknown (increases exposure)
• antifungals, azoles + alpha blockers: Unknown (increases exposure)
• crizotinib + alpha blockers: Unknown (increases exposure)
• imatinib + alpha blockers: Unknown (increases exposure)
• letermovir + alpha blockers: Unknown (increases exposure)
• clarithromycin + alpha blockers: Unknown (increases exposure)

Indications

• Type 2 diabetes mellitus
• Insulin resistance
• Impaired glucose tolerance
• Metabolic syndrome
• Hyperlipidemia

Dosage

Children: Refer to the BNF for Children for specific dosage recommendations suitable for pediatric patients.

Adults: Refer to the BNF for specific dosage recommendations based on the condition being treated.

Mechanism of action

Chromium enhances insulin signaling by upregulating insulin receptor-mediated pathways. It affects downstream effector molecules after insulin binds to its receptor, leading to the activation of phosphatidylinositol 2-kinase (PI3K) and protein kinase B (Akt). This process promotes the translocation of glucose transporter-4 (Glut4) to the cell membrane, facilitating increased glucose uptake. Additionally, chromium can promote GLUT-4 transporter translocation independently of insulin receptor activity under insulin-resistant conditions and aids in cholesterol efflux by increasing membrane fluidity.

Pharmacodynamics

Trivalent chromium is essential for the glucose tolerance factor, which activates insulin-mediated pathways. It enhances insulin binding to cells, increases the density of insulin receptors, and activates insulin receptor kinase, all of which contribute to improved insulin sensitivity. Chromium deficiency can lead to impaired glucose metabolism, and supplementation can normalize glucose tolerance in individuals exhibiting diabetic-like characteristics due to deficiency.

Pharmacokinetics

Chromium absorption occurs primarily in the intestines, but its bioavailability is influenced by various dietary factors, such as the presence of other minerals and vitamins. The mineral is transported in the bloodstream bound to transferrin and is predominantly stored in the liver, spleen, and bone. The elimination of chromium occurs mainly through urine, with small amounts excreted in feces. The half-life and exact metabolic pathways for chromium can vary based on its form and the individual's nutritional status.

Pregnancy

Chromium is generally considered safe during pregnancy when taken in appropriate amounts, but it is advisable to consult a healthcare provider.

Breast-feeding

Chromium is excreted in breast milk, and while it is deemed safe in moderate amounts, consultation with a healthcare provider is recommended.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Mechanism of action

Folic acid is biochemically inactive until it is converted into active forms, primarily tetrahydrofolic acid and methyltetrahydrofolate, by the enzyme dihydrofolate reductase (DHFR). These active forms are essential for maintaining normal erythropoiesis, synthesizing nucleic acids, interconverting amino acids, and generating formate. They participate in critical one-carbon transfer reactions necessary for DNA synthesis and methylation processes. Folic acid, in conjunction with vitamin B12, helps normalize elevated homocysteine levels by facilitating its remethylation to methionine, a process that is crucial for various metabolic pathways.

Pharmacodynamics

Folic acid is an essential cofactor for enzymes involved in nucleic acid synthesis and amino acid metabolism. It is particularly significant in preventing megaloblastic anemia, which arises from impaired DNA synthesis due to folate deficiency. The synthesis of thymidylate, necessary for DNA formation, is directly influenced by folate availability. Folic acid's role is especially crucial during periods of rapid cellular division, and it has protective effects against certain cancer developments. As humans cannot synthesize folic acid endogenously, adequate dietary intake is essential for maintaining normal physiological functions.

Pharmacokinetics

Folic acid is absorbed in the small intestine and is then converted into its active forms within the body. The bioavailability of folic acid is influenced by factors such as food composition and the presence of certain gastrointestinal conditions. Once absorbed, it is transported in the bloodstream, mainly as 5-methyltetrahydrofolate. The distribution of folate occurs within various tissues, with significant

Adverse effects

• Allergic reactions
• Gastrointestinal disturbances
• Skin rash
• Altered sleep patterns

Interactions

• Anticonvulsants may reduce the effectiveness of folic acid
• Methotrexate may interfere with folic acid metabolism
• Trimethoprim-sulfamethoxazole can enhance the effects of folic acid deficiency

Precautions

• Monitor for signs of anemia in patients with malabsorption syndromes
• Use cautiously in patients with a history of hypersensitivity to folic acid
• Assess for vitamin B12 deficiency before initiating treatment, as folic acid can mask symptoms

Pregnancy

Folic acid is essential during pregnancy to prevent neural tube defects and support fetal development. Supplementation is recommended before conception and during the first trimester.

Breast-feeding

Folic acid passes into breast milk, and adequate maternal intake is important to ensure sufficient levels for the nursing infant.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Tablets
• Oral solutions
• Injectable forms

Indications

• Atopic dermatitis
• Rheumatoid arthritis
• Premenstrual syndrome
• Eczema
• Other inflammatory skin conditions

Dosage

Children: Refer to clinical guidelines or a healthcare professional for appropriate dosing information.

Adults: Refer to clinical guidelines or a healthcare professional for appropriate dosing information.

Mechanism of action

Gamolenic acid is thought to exert its effects through several mechanisms, primarily related to the modulation of inflammatory pathways. It serves as a precursor to the synthesis of prostaglandin E1 (PGE1), an anti-inflammatory substance that can help decrease inflammatory responses and improve skin barrier function. By increasing the levels of PGE1, gamolenic acid may also help in regulating the immune response, reducing symptoms associated with inflammatory conditions.

Pharmacodynamics

The pharmacodynamics of gamolenic acid involve its role in the synthesis of biologically active metabolites, such as prostaglandins and leukotrienes, which have significant effects on inflammation and immune modulation. It may enhance skin hydration and decrease trans-epidermal water loss, contributing to its use in dermatological conditions. Additionally, gamolenic acid may influence the balance of pro-inflammatory and anti-inflammatory cytokines, further modulating immune responses in various conditions.

Pharmacokinetics

Gamolenic acid is absorbed from the gastrointestinal tract following oral administration, but the exact pharmacokinetic parameters, including the peak plasma concentration and half-life, are not well established. Once absorbed, it is incorporated into cellular membranes where it can be metabolized into its active forms. The distribution of gamolenic acid in body tissues and its elimination pathways remain to be fully elucidated, necessitating further research.

Adverse effects

• Nausea
• Diarrhea
• Abdominal discomfort
• Headache
• Dizziness

Precautions

• Use with caution in patients with known allergies to components of the formulation
• Monitor for gastrointestinal side effects
• Consider potential interactions with other medications

Pregnancy

Safety in pregnancy has not been established, consult healthcare provider before use.

Breast-feeding

Consult healthcare provider as safety during breastfeeding is not established.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Capsules
• Softgel capsules
• Liquid formulations

Indications

• Diabetic neuropathy
• Oxidative stress-related disorders
• Metabolic syndrome
• Weight management
• Liver health

Dosage

Children: Refer to specific product guidelines, as safety and efficacy in children have not been established.

Adults: Refer to specific product guidelines, as dosages may vary based on the formulation and indication.

Mechanism of action

Lipoic acid acts as a cofactor for mitochondrial enzyme complexes, particularly those involved in the Krebs cycle, enhancing energy production. It also possesses antioxidant properties, neutralizing free radicals and regenerating other antioxidants such as vitamins C and E. Additionally, lipoic acid can modulate various signaling pathways, including those related to insulin sensitivity and inflammation.

Pharmacodynamics

Lipoic acid has a dual role as a coenzyme and an antioxidant. By participating in the decarboxylation of alpha-keto acids, it aids in energy production. Its antioxidant properties contribute to the protection of cells from oxidative stress, which is implicated in various chronic diseases. Lipoic acid can improve insulin sensitivity, making it beneficial in managing glucose metabolism disorders.

Pharmacokinetics

After oral administration, lipoic acid is absorbed in the gastrointestinal tract, with peak plasma concentrations occurring within 30 to 60 minutes. It undergoes hepatic metabolism, primarily via reduction and conjugation, resulting in various metabolites. The elimination half-life is approximately 30 minutes to 2 hours, and it is excreted primarily in urine. The bioavailability of lipoic acid can be affected by food intake.

Adverse effects

• Nausea
• Vomiting
• Abdominal pain
• Skin rash
• Hypoglycemia

Interactions

• May enhance the effects of insulin and other antidiabetic medications
• May interact with heavy metal chelators

Precautions

• Use with caution in patients with diabetes due to the risk of hypoglycemia
• Monitor blood sugar levels in diabetic patients

Pregnancy

Safety during pregnancy has not been established; use only if clearly needed.

Breast-feeding

It is not known whether lipoic acid is excreted in human breast milk; caution is advised.

Storage

Store in a cool, dry place away from light.

Formulations

• Capsules
• Tablets
• Injectable solutions

Indications

• Vitamin B12 deficiency
• Peripheral neuropathy
• Diabetic neuropathy
• Neurological disorders
• Anemia related to vitamin B12 deficiency

Dosage

Children: For children, consult the BNF for Children for appropriate dosing guidelines based on age and clinical condition.

Adults: The usual adult dose for vitamin B12 deficiency is 500 to 1500 micrograms daily, administered intramuscularly or orally, as per clinical need.

Mechanism of action

Mecobalamin acts as a cofactor in the conversion of homocysteine to methionine, thereby playing a significant role in the methylation process necessary for DNA synthesis and repair. It also aids in the maintenance of myelin sheaths in nerve cells, which is vital for proper nerve function and regeneration.

Pharmacodynamics

Mecobalamin enhances cellular energy metabolism and promotes the regeneration of nerve fibers. It influences the synthesis of neurotransmitters and the overall function of the nervous system, reducing symptoms of neuropathy and improving nerve conduction velocities.

Pharmacokinetics

Mecobalamin is rapidly absorbed following intramuscular injection, with peak plasma concentrations occurring within a few hours. It is primarily distributed in tissues, including the liver and kidneys. The drug is metabolized in the liver, and its elimination occurs primarily through urine, with a half-life of several hours.

Adverse effects

• Nausea
• Diarrhea
• Headache
• Dizziness
• Rash
• Pruritus

Precautions

• Use with caution in patients with known hypersensitivity to mecobalamin or any component of the formulation.
• Monitor patients with renal impairment.

Pregnancy

Mecobalamin is generally considered safe during pregnancy, but consult a healthcare provider for individual assessment.

Breast-feeding

Mecobalamin is excreted in breast milk; caution is advised when administered to nursing mothers.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Tablets
• Injections

Dosage

Children: Refer to specific guidelines or consult a healthcare professional for appropriate dosing information, as current literature does not provide standardized dosing recommendations.

Adults: Refer to specific guidelines or consult a healthcare professional for appropriate dosing information, as current literature does not provide standardized dosing recommendations.

Mechanism of action

Picolinate acts as a metabolic intermediate, particularly in the catabolism of tryptophan. It participates in several biochemical pathways such as amino acid and derivative metabolism, and its presence is crucial for the degradation of tryptophan into various metabolites. This process includes its involvement in the production of important coenzymes and other bioactive compounds, thus influencing metabolic pathways and cellular functions.

Pharmacodynamics

Picolinate is involved in the metabolism of tryptophan, leading to the generation of kynurenine and other metabolites. The compound plays a role in the biosynthesis of NAD, which is essential for cellular respiration and energy production. Its effects may include modulation of metabolic pathways and potential influence on cognitive and metabolic health, although specific pharmacodynamic effects can vary based on the context of use.

Pharmacokinetics

The pharmacokinetics of picolinate, including absorption, distribution, metabolism, and excretion, are not extensively documented. It is generally understood that compounds involved in amino acid metabolism are absorbed and utilized by the body in a manner that supports metabolic functions. However, specific parameters such as bioavailability, half-life, and excretion pathways are not well-characterized.

Pregnancy

There is insufficient data on the safety of picolinate in pregnancy. Consult healthcare providers for advice.

Breast-feeding

Limited data is available on the excretion of picolinate in human milk. Caution is advised.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Indications

• Vitamin B6 deficiency
• Peripheral neuropathy associated with isoniazid therapy
• Supplementation in specific dietary deficiencies

Dosage

Children: Refer to the BNF for Children for specific paediatric dosing guidance.

Adults: Refer to the BNF for specific dosing details, typically 10-50 mg daily for deficiency.

Mechanism of action

Pyridoxine, mainly in its active form pyridoxal 5'-phosphate, is involved in numerous biochemical reactions, including amino acid metabolism, glycogen breakdown, nucleic acid synthesis, and the production of key neurotransmitters. It aids in the synthesis of hemoglobin and sphingolipids, and its deficiency can impair several physiological processes, including immune response and vascular health.

Pharmacodynamics

Pyridoxine is utilized for the prevention and treatment of vitamin B6 deficiency, particularly in individuals undergoing treatment with isoniazid, which can deplete vitamin B6 levels. It may also have beneficial effects on blood pressure and lipid profiles, as studies have shown it can lower both systolic and diastolic blood pressure, inhibit platelet aggregation, and improve cholesterol levels. Additionally, it plays a role in enhancing immune function and protecting endothelial cells from injury.

Pharmacokinetics

Pyridoxine is rapidly absorbed from the gastrointestinal tract. It is transported to tissues where it is phosphorylated to its active form, pyridoxal 5'-phosphate. The vitamin is primarily excreted in urine as pyridoxine and its metabolites. Its half-life varies depending on the individual’s nutritional status and other factors. Adequate dietary intake is essential for maintaining optimal levels in the body.

Pregnancy

Pyridoxine is generally considered safe during pregnancy. However, high doses should be avoided unless specifically prescribed.

Breast-feeding

Pyridoxine is excreted in breast milk, but at normal dietary levels it is considered safe for breastfeeding mothers.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets
• Oral solution
• Injectable form

Mechanism of action

Biotin is necessary for the proper functioning of enzymes that transport carboxyl units and fix carbon dioxide, and is required for various metabolic functions, including gluconeogenesis, lipogenesis, fatty acid biosynthesis, propionate metabolism, and catabolism of branched-chain amino acids. In human tissues biotin is a cofactor for the enzymatic carboxylation of four substrates: pyruvate, acetyl coenzyme A (CoA), propionyl CoA, and beta-methylcrotonyl CoA. As such, it plays an important role in both carbohydrate and fat metabolism. Carbon dioxide fixation occurs in a two-step reaction, the first involving binding of carbon dioxide to the biotin moiety of the holoenzyme, and the second involving transfer of the biotin-bound carbon dioxide to an appropriate acceptor. Biotin functions in carbon dioxide fixation reactions in intermediate metabolism, transferring the carboxyl group to acceptor molecules. It acts similarly in decarboxylation reactions. Biotin is essential in human metabolism for its part in the previously described enzymatic steps, in catalyzing deamination of amino acids, and in oleic acid synthesis. Biotin is a cofactor for the enzymatic carboxylation of pyruvate, acetyl coenzyme A (CoA), propionyl CoA, and beta-methylcrotonyl CoA, and, therefore, plays an important role in carbohydrate and fat metabolism. Protein folding in the endoplasmic reticulum (ER) depends on Ca2+; uptake of Ca2+ into the ER is mediated by sarco/endoplasmic reticulum Ca2+-ATPase 3 (SERCA3). The 5'-flanking region of the SERCA3 gene (ATP2A3) contains numerous binding sites for the transcription factors Sp1 and Sp3. Biotin affects the nuclear abundance of Sp1 and Sp3, which may act as transcriptional activators or repressors. Here we determined whether biotin affects the expression of the SERCA3 gene and, thus, protein folding in human lymphoid cells. Jurkat cells were cultured in media containing 0.025 nmol/L biotin (denoted "deficient") or 10 nmol/L biotin ("supplemented"). The transcriptional activity of the full-length human SERCA3 promoter was 50% lower in biotin-supplemented cells compared to biotin-deficient cells. Biotin-dependent repressors bind to elements located 731 to 1312 bp upstream from the transcription start site in the SERCA3 gene. The following suggest that low expression of SERCA3 in biotin-supplemented cells impaired folding of secretory proteins in the ER, triggering unfolded protein response: (i) sequestration of Ca2+ in the ER decreased by 14 to 24% in response to biotin supplementation; (ii) secretion of interleukin-2 into the extracellular space decreased by 75% in response to biotin supplementation; (iii) the nuclear abundance of stress-induced transcription factors increased in response to biotin supplementation; and (iv) the abundance of stress-related proteins such ubiquitin activating enzyme 1, growth arrest and DNA damage 153 gene, X-box binding protein 1 and phosphorylated eukaryotic translation initiation factor 2alpha increased in response to biotin supplementation. Collectively, this study suggests that supplements containing pharmacological doses of biotin may cause cell stress by impairing protein folding in the ER. Evidence is emerging that biotin participates in processes other than classical carboxylation reactions. Specifically, novel roles for biotin in cell signaling, gene expression, and chromatin structure have been identified in recent years. Human cells accumulate biotin by using both the sodium-dependent multivitamin transporter and monocarboxylate transporter 1. These transporters and other biotin-binding proteins partition biotin to compartments involved in biotin signaling: cytoplasm, mitochondria, and nuclei. The activity of cell signals such as biotinyl-AMP, Sp1 and Sp3, nuclear factor (NF)-kappaB, and receptor tyrosine kinases depends on biotin supply. Consistent with a role for biotin and its catabolites in modulating these cell signals, greater than 2000 biotin-dependent genes have

Pharmacodynamics

Biotin is a water-soluble B-complex vitamin which is composed of an ureido ring fused with a tetrahydrothiophene ring, which attaches a valeric acid substituent at one of its carbon atoms. Biotin is used in cell growth, the production of fatty acids, metabolism of fats, and amino acids. It plays a role in the Kreb cycle, which is the process in which energy is released from food. Biotin not only assists in various metabolic chemical conversions, but also helps with the transfer of carbon dioxide. Biotin is also helpful in maintaining a steady blood sugar level. Biotin is often recommended for strengthening hair and nails. Consequenty, it is found in many cosmetic and health products for the hair and skin. Biotin deficiency is a rare nutritional disorder caused by a deficiency of biotin. Initial symptoms of biotin deficiency include: Dry skin, Seborrheic dermatitis, Fungal infections, rashes including erythematous periorofacial macular rash, fine and brittle hair, and hair loss or total alopecia. If left untreated, neurological symptoms can develop, including mild depression, which may progress to profound lassitude and, eventually, to somnolence; changes in mental status, generalized muscular pains (myalgias), hyperesthesias and paresthesias. The treatment for biotin deficiency is to simply start taking some biotin supplements. A lack of biotin in infants will lead to a condition called seborrheic dermatitis or "cradle cap". Biotin deficiencies are extremely rare in adults but if it does occur, it will lead to anemia, depression, hair loss, high blood sugar levels, muscle pain, nausea, loss of appetite and inflamed mucous membranes.

Mechanism of action

Chromium is an essential nutrient involved in the metabolism of glucose, insulin and blood lipids. Its role in potentiating insulin signalling cascades has been implicated in several studies. Chromium upregulates insulin-stimulated insulin signal transduction via affecting effector molecules downstream of the insulin receptor (IR). IR-mediated signalling pathway involves phoshorylation of multiple intracellular domains and protein kinases, and downstream effector molecules. Upon activation by ligands, intracellular β-subunit of IR autophosphorylates and activates tyrosine kinase domain of the IR, followed by activation and phosphorylation of regulatory proteins and downstream signalling effectors including phosphatidylinositol 2-kinase (PI3K). PI3K activates further downstream reaction cascades to activate protein kinase B (Akt) to ultimately promote translocation of glucose transporter-4 (Glut4)-vesicles from the cytoplasm to the cell surface and regulate glucose uptake. Chromium enhances the kinase activity of insulin receptor β and increases the activity of downstream effectors, pI3-kinase and Akt. Under insulin-resistant conditions, chromium also promotes GLUT-4 transporter translocation that is independent of activity of IR, IRS-1, PI3-kinase, or Akt; chromium mediates cholesterol efflux from the membranes via increasing fluidity of the membrane by decreasing the membrane cholesterol and upregulation of sterol regulatory element-binding protein. As a result, intracellular GLUT-4 transporters are stimulated to translocate from intracellular to the plasma membrane, leading to enhanced glucose uptake in muscle cells. Chromium attenuates the activity of PTP-1B _in vitro,_ which is a negative regulator of insulin signaling. It also alleviates ER stress that is observed to be elevated the suppression of insulin signaling. ER stress is thought to activate c-Jun N-terminal kinase (JNK), which subsequently induces serine phosphorylation of IRS and aberration of insulin signalling. Transient upregulation of AMPK by chromium also leads to increased glucose uptake. While the toxicity of metals and metalloids, like arsenic, cadmium, mercury, lead and chromium, is undisputed, the underlying molecular mechanisms are not entirely clear. General consensus holds that proteins are the prime targets; heavy metals interfere with the physiological activity of specific, particularly susceptible proteins, either by forming a complex with functional side chain groups or by displacing essential metal ions in metalloproteins. Recent studies have revealed an additional mode of metal action targeted at proteins in a non-native state; certain heavy metals and metalloids have been found to inhibit the in vitro refolding of chemically denatured proteins, to interfere with protein folding in vivo and to cause aggregation of nascent proteins in living cells. Apparently, unfolded proteins with motile backbone and side chains are considerably more prone to engage in stable, pluridentate metal complexes than native proteins with their well-defined 3D structure. By interfering with the folding process, heavy metal ions and metalloids profoundly affect protein homeostasis and cell viability. This review describes how heavy metals impede protein folding and promote protein aggregation, how cells regulate quality control systems to protect themselves from metal toxicity and how metals might contribute to protein misfolding disorders.

Pharmacodynamics

Trivalent chromium is part of glucose tolerance factor, an essential activator of insulin-mediated reactions. Chromium helps to maintain normal glucose metabolism and peripheral nerve function. Chromium increases insulin binding to cells, increases insulin receptor density and activates insulin receptor kinase leading to enhanced insulin sensitivity. In chromium deficiency, intravenous administration of chromium resulted in normalization of the glucose tolerance curve from the diabetic-like curve typical of chromium deficiency.

Mechanism of action

Folic acid, as it is biochemically inactive, is converted to tetrahydrofolic acid and methyltetrahydrofolate by dihydrofolate reductase (DHFR). These folic acid congeners are transported across cells by receptor-mediated endocytosis where they are needed to maintain normal erythropoiesis, synthesize purine and thymidylate nucleic acids, interconvert amino acids, methylate tRNA, and generate and use formate. Using vitamin B12 as a cofactor, folic acid can normalize high homocysteine levels by remethylation of homocysteine to methionine via methionine synthetase. Folic acid, after conversion to tetrahydrofolic acid, is necessary for normal erythropoiesis, synthesis of purine and thymidylates, metabolism of amino acids such as glycine and methionine, and the metabolism of histidine. The principal biochemical function of folates is the mediation of one-carbon transfer reactions. 5-Methyltetrahydrofolate donates a methyl group to homocystine, in the conversion of homocystine to L-methionine. ... 5,10-Methyltetrahydrofolate is regenerated from tetrahydrofolate via the enzyme serine hydroxymethyltransferase, a reaction, which in addition to producing 5,10-methyltetrahydrofolate, yields glycine. ... 5,10-methyltetrahydrofolate, supplies the one carbon group for the methylation of deoxyuridylic acid to form the DNA precursor thymidylic acid. This reaction is catalyzed by thymidylate synthase and the folate product of the reaction is dihydrofolate. Dihydrofolate is converted to tetrahydrofolate via the enzyme dihydrofolate reductase ...

Pharmacodynamics

Folic acid is a water-soluble B-complex vitamin found in foods such as liver, kidney, yeast, and leafy, green vegetables. Also known as folate or Vitamin B9, folic acid is an essential cofactor for enzymes involved in DNA and RNA synthesis. More specifically, folic acid is required by the body for the synthesis of purines, pyrimidines, and methionine before incorporation into DNA or protein. Folic acid is the precursor of tetrahydrofolic acid, which is involved as a cofactor for transformylation reactions in the biosynthesis of purines and thymidylates of nucleic acids. Impairment of thymidylate synthesis in patients with folic acid deficiency is thought to account for the defective deoxyribonucleic acid (DNA) synthesis that leads to megaloblast formation and megaloblastic and macrocytic anemias. Folic acid is particularly important during phases of rapid cell division, such as infancy, pregnancy, and erythropoiesis, and plays a protective factor in the development of cancer. As humans are unable to synthesize folic acid endogenously, diet and supplementation is necessary to prevent deficiencies. In order to function properly within the body, folic acid must first be reduced by the enzyme dihydrofolate reductase (DHFR) into the cofactors dihydrofolate (DHF) and tetrahydrofolate (THF). This important pathway, which is required for de novo synthesis of nucleic acids and amino acids, is disrupted by anti-metabolite therapies such as [DB00563] as they function as DHFR inhibitors to prevent DNA synthesis in rapidly dividing cells, and therefore prevent the formation of DHF and THF. In general, folate serum levels below 5 ng/mL indicate folate deficiency, and levels below 2 ng/mL usually result in megaloblastic anemia.

Mechanism of action

Vitamin B6 is the collective term for a group of three related compounds, pyridoxine (PN), pyridoxal (PL) and pyridoxamine (PM), and their phosphorylated derivatives, pyridoxine 5'-phosphate (PNP), pyridoxal 5'-phosphate (PLP) and pyridoxamine 5'-phosphate (PMP). Although all six of these compounds should technically be referred to as vitamin B6, the term vitamin B6 is commonly used interchangeably with just one of them, pyridoxine. Vitamin B6, principally in its biologically active coenzyme form pyridoxal 5'-phosphate, is involved in a wide range of biochemical reactions, including the metabolism of amino acids and glycogen, the synthesis of nucleic acids, hemogloblin, sphingomyelin and other sphingolipids, and the synthesis of the neurotransmitters serotonin, dopamine, norepinephrine and gamma-aminobutyric acid (GABA).

Pharmacodynamics

Vitamin B6 (pyridoxine) is a water-soluble vitamin used in the prophylaxis and treatment of vitamin B6 deficiency and peripheral neuropathy in those receiving isoniazid (isonicotinic acid hydrazide, INH). Vitamin B6 has been found to lower systolic and diastolic blood pressure in a small group of subjects with essential hypertension. Hypertension is another risk factor for atherosclerosis and coronary heart disease. Another study showed pyridoxine hydrochloride to inhibit ADP- or epinephrine-induced platelet aggregation and to lower total cholesterol levels and increase HDL-cholesterol levels, again in a small group of subjects. Vitamin B6, in the form of pyridoxal 5'-phosphate, was found to protect vascular endothelial cells in culture from injury by activated platelets. Endothelial injury and dysfunction are critical initiating events in the pathogenesis of atherosclerosis. Human studies have demonstrated that vitamin B6 deficiency affects cellular and humoral responses of the immune system. Vitamin B6 deficiency results in altered lymphocyte differentiation and maturation, reduced delayed-type hypersensitivity (DTH) responses, impaired antibody production, decreased lymphocyte proliferation and decreased interleukin (IL)-2 production, among other immunologic activities.