OVAZOA-M SOFT GELATIN CAPSULES

Adverse effects

• Arthralgia
• Infection
• Dizziness
• Dry mouth
• Gastrointestinal discomfort
• Headaches
• Nausea
• Altered mood
• Night sweats
• Skin reactions
• Aggression
• Depression
• Disorientation
• Weight gain
• Electrolyte imbalance

Interactions

• Fluvoxamine: Severe (increases exposure)
• Givosiran: Moderate (increases exposure)
• Phenytoin: Unknown (decreases exposure)
• Axitinib: Unknown (increases exposure)
• Ritonavir: Unknown (decreases exposure)
• Leflunomide: Unknown (decreases exposure)
• Mexiletine: Unknown (increases exposure)
• Osilodrostat: Unknown (increases exposure)
• Rucaparib: Unknown (increases exposure)
• Teriflunomide: Unknown (decreases exposure)

Precautions

• Use with caution in hepatic impairment
• Use with caution in renal impairment
• Drowsiness may persist into the next day, affecting performance of skilled tasks such as driving

Pregnancy

No information available-avoid.

Breast-feeding

Present in milk-avoid.

Storage

Store in a cool, dry place away from light.

Formulations

• Modified-release tablets (Circadin®, Slenyto®)
• Immediate-release tablets (Adaflex®, Ceyesto®, Syncrodin®)
• Hard capsules
• Oral solution

Indications

• Antioxidant support
• Reduction of oxidative stress
• Support for skin health
• Potential benefits in eye health
• Support for cardiovascular health
• Improvement of exercise performance

Dosage

Children: Refer to specific product recommendations and clinical guidelines as there is no established standard dose.

Adults: Refer to specific product recommendations and clinical guidelines as there is no established standard dose.

Mechanism of action

Astaxanthin acts primarily as an antioxidant, neutralizing free radicals and protecting cells from oxidative damage. It is believed to work through various mechanisms, including scavenging reactive oxygen species (ROS) and enhancing the body's natural antioxidant defenses. Astaxanthin may also modulate signaling pathways related to inflammation and immune response.

Pharmacodynamics

Astaxanthin exhibits a high degree of antioxidant activity, being significantly more effective than other carotenoids in quenching singlet oxygen and scavenging free radicals. Its lipophilic nature allows it to integrate into cell membranes, providing cellular protection and stability. This compound may also influence gene expression related to antioxidant enzymes and inflammatory markers, promoting overall cellular health.

Pharmacokinetics

Astaxanthin is absorbed primarily in the intestine, with bioavailability enhanced when taken with fats. Peak plasma concentrations are typically reached within 4 to 6 hours post-ingestion. It is metabolized in the liver and excreted mainly via bile. The elimination half-life of astaxanthin is variable but generally ranges from several hours to a few days, depending on individual metabolism and dosage.

Pregnancy

Astaxanthin is generally considered safe, but there is limited research on its effects during pregnancy. Consult a healthcare provider for guidance.

Breast-feeding

Safety during breastfeeding has not been well established. Consultation with a healthcare provider is recommended.

Storage

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

Indications

• Vitamin D deficiency
• Rickets
• Osteomalacia
• Osteoporosis
• Hypoparathyroidism

Dosage

Adults: The usual adult dose for vitamin D deficiency is 800 to 2000 IU daily, depending on the severity of deficiency and clinical condition. Higher doses may be used under medical supervision.

Mechanism of action

Cholecalciferol is converted to its active forms, 25-hydroxyvitamin D in the liver and 1,25-dihydroxyvitamin D in the kidneys. These metabolites enhance the intestinal absorption of calcium and phosphorus, increase serum calcium levels, and mobilize these minerals from bone. This process is regulated by parathyroid hormone, which influences calcium and phosphate metabolism, particularly in the kidneys.

Pharmacodynamics

The pharmacodynamics of cholecalciferol involve its conversion to active metabolites that play a significant role in calcium and phosphorus homeostasis. The metabolites facilitate intestinal absorption of these minerals, promote bone mineralization, and influence renal reabsorption. The onset of action occurs within 10 to 24 hours following administration, as metabolic activation is required for its biological effects.

Pharmacokinetics

Cholecalciferol is absorbed in the gastrointestinal tract, and its absorption is enhanced by the presence of dietary fats. It is transported in the bloodstream bound to vitamin D-binding protein. Once in the liver, it undergoes hydroxylation to form 25-hydroxyvitamin D, which is further converted in the kidneys to the active form, 1,25-dihydroxyvitamin D. The elimination half-life of cholecalciferol varies, typically spanning several days, and it is primarily excreted in bile and urine.

Adverse effects

• Hypercalcemia
• Hypercalciuria
• Nausea
• Vomiting
• Constipation
• Weakness
• Fatigue

Interactions

• May enhance the effects of thiazide diuretics, leading to increased risk of hypercalcemia
• Anticonvulsants may increase metabolism of vitamin D, leading to reduced effectiveness
• Cholestyramine may reduce absorption of vitamin D

Precautions

• Monitor serum calcium levels in patients with renal impairment
• Caution in patients with a history of hypercalcemia or hyperparathyroidism
• Use with caution in patients taking other medications that affect calcium metabolism

Pregnancy

Cholecalciferol can be used during pregnancy if indicated, as vitamin D is essential for fetal bone development.

Breast-feeding

Cholecalciferol is excreted in breast milk, but is generally considered safe during breastfeeding.

Storage

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

Formulations

• Capsules
• Tablets
• Liquid formulations

Indications

• Oxidative stress-related disorders
• Inflammation
• Cardiovascular diseases
• Neurodegenerative diseases
• Age-related conditions

Dosage

Children: Refer to specific product guidelines or clinical studies for dosing information, as no standard dose is established.

Adults: Refer to specific product guidelines or clinical studies for dosing information, as no standard dose is established.

Mechanism of action

Superoxide dismutase catalyzes the conversion of superoxide (O2-) radicals into molecular oxygen (O2) and hydrogen peroxide (H2O2). This reaction is vital for mitigating oxidative stress by reducing the concentration of harmful superoxide radicals in the body, thereby protecting cellular components from oxidative damage.

Pharmacodynamics

Dismutase exerts its pharmacological effects primarily through its antioxidant properties. By lowering the levels of superoxide radicals, it helps to maintain cellular redox balance and prevent oxidative damage to proteins, lipids, and DNA. This action contributes to reduced inflammation and may improve tissue repair and recovery in various diseases where oxidative stress is a contributing factor.

Pharmacokinetics

The pharmacokinetics of dismutase can vary based on its source (e.g., human, animal, or plant-derived). Generally, it exhibits a short half-life in circulation due to rapid clearance by the body. Its bioavailability may also be affected by factors such as administration route and formulation. After administration, dismutase is distributed to tissues where it exerts its protective effects against oxidative stress. However, specific pharmacokinetic parameters may not be well characterized due to variability in formulations and routes of administration.

Pregnancy

There is insufficient data on the safety of dismutase in pregnancy. Consult a healthcare provider before use.

Breast-feeding

Limited data is available on the excretion of dismutase in human milk. Consult a healthcare provider before use.

Storage

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

Indications

• Cardiovascular diseases
• Erectile dysfunction
• Peripheral arterial disease
• Wound healing
• Muscle growth and recovery
• Immune system support

Dosage

Children: For paediatric dosing, it is important to refer to the BNF for Children for appropriate guidelines based on the child's age, weight, and clinical condition.

Adults: The typical dosage for adults varies based on the condition being treated, but common oral doses range from 2 to 30 grams per day, divided into multiple doses. For specific dosing recommendations, please refer to the BNF.

Mechanism of action

L-arginine is converted to nitric oxide by nitric oxide synthase (NOS), which is crucial for vascular function and blood flow regulation. NO activates guanylate cyclase, leading to increased levels of cyclic GMP, a secondary messenger that mediates vasodilation and other cellular responses. This pathway is vital in both the cardiovascular and immune systems, with different isoforms of NOS (eNOS, nNOS, iNOS) contributing to various physiological effects.

Pharmacodynamics

L-arginine has been shown to enhance immune responses, improve wound healing, stimulate growth hormone release, and support muscle hypertrophy and tissue repair. Its role in nitric oxide production aids in vasodilation, improving blood circulation and oxygen delivery to tissues, which is essential for recovery and regeneration.

Pharmacokinetics

L-arginine is absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1-2 hours after oral administration. It is metabolized primarily in the liver and kidneys, with a half-life of approximately 1-2 hours. The bioavailability of L-arginine can be influenced by dietary intake and metabolic conditions.

Adverse effects

• Gastrointestinal disturbances
• Nausea
• Diarrhea
• Abdominal pain
• Hypotension
• Allergic reactions

Interactions

• Antihypertensive agents may have additive effects leading to increased hypotension
• Sildenafil and other medications for erectile dysfunction may have enhanced effects when used with L-arginine

Precautions

• Caution in patients with a history of asthma or allergies
• Use with caution in patients with hypotension
• Monitor blood pressure in patients taking antihypertensive medications

Pregnancy

The safety of L-arginine in pregnancy has not been established. Consult a healthcare provider before use.

Breast-feeding

L-arginine is excreted in breast milk, and its safety during breastfeeding is not well established. Consult a healthcare provider.

Storage

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

Formulations

• Oral tablets
• Powder for oral solution
• Capsules

Indications

• Dietary supplement for antioxidant support
• Potential risk reduction for prostate cancer
• Potential risk reduction for lung cancer

Dosage

Children: Refer to specific guidelines as dosing can vary based on the formulation and purpose of use.

Adults: Refer to specific guidelines as dosing can vary based on the formulation and purpose of use.

Mechanism of action

Lycopene functions as a very potent antioxidant, trapping singlet oxygen and reducing mutagenesis. It inhibits cancer cell growth by disrupting growth factor receptor signaling and cell cycle progression. Lycopene upregulates connexin 43, enhancing gap junctional communication which is often deficient in tumors. Furthermore, it exhibits synergistic effects on cell proliferation and differentiation when combined with 1,25-dihydroxyvitamin D3, indicating interactions at a nuclear or subcellular level.

Pharmacodynamics

Lycopene's antioxidant properties play a critical role in protecting cells from oxidative stress. By trapping reactive oxygen species, it lessens cellular damage and may help to prevent the initiation and progression of cancer. Its ability to modulate cell signaling pathways and improve gap junction communication contributes to its anticancer effects. The interactions with vitamin D3 suggest a complex role in regulating cellular functions.

Pharmacokinetics

Lycopene is absorbed in the intestine and can be detected in the serum and various tissues. Its bioavailability can be influenced by dietary factors, including fat intake, which enhances absorption. Once in the body, lycopene is stored in adipose tissue and the liver. The elimination half-life and exact metabolic pathways are not well defined, but it is believed to undergo some conversion into other metabolites before excretion.

Pregnancy

There is insufficient reliable information regarding the safety of lycopene during pregnancy. Caution is advised.

Breast-feeding

Lycopene is considered safe during breastfeeding, but data on its excretion in human milk is limited.

Storage

Store in a cool, dry place, away from light.

Indications

• Cancer chemoprevention
• Selenium deficiency

Dosage

Children: Refer to the BNF for Children for appropriate dosing information.

Adults: Refer to the BNF for appropriate dosing information.

Mechanism of action

Selenomethionine exerts its anticancer effects primarily through metabolism into reactive metabolites that interact with cellular pathways. Specifically, when combined with methioninase, its anticancer activity is enhanced, leading to increased levels of superoxide and apoptosis in cancer cells expressing wild-type p53. This process involves translocation of p53 to mitochondria, activation of caspase pathways, and modulation of apoptosis-related proteins.

Pharmacodynamics

Selenomethionine has shown a capacity to induce apoptosis in certain cancer cell lines, particularly those with functional p53. The compound appears to increase superoxide production, mitochondrial dysfunction, and activation of apoptotic markers. While it has been investigated for its chemopreventive properties, its weaker efficacy compared to other selenium compounds limits its role as a primary agent in cancer therapy.

Pharmacokinetics

Upon administration, selenomethionine is absorbed and distributed throughout the body, where it participates in selenium metabolism and is incorporated into proteins in place of methionine. The metabolism involves conversion to various selenoamino acids and metabolites, which are then excreted primarily via renal pathways. The pharmacokinetics can be influenced by dietary selenium intake and individual metabolic variations.

Pregnancy

Selenomethionine should only be used in pregnancy if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Caution should be exercised when administering selenomethionine to nursing mothers.

Storage

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

Formulations

• Selenomethionine capsules
• Selenomethionine tablets

Mechanism of action

Superoxide functions primarily as a signaling molecule, influencing various biological pathways. It participates in redox signaling by modulating the activity of proteins through reversible oxidation. Notably, superoxide is involved in pathways such as protein S-nitrosylation and denitrosylation, which affect protein function and signaling. Additionally, it is implicated in the superpathway of glycolysis and the Entner-Doudoroff pathway, linking energy metabolism to oxidative stress responses.

Pharmacodynamics

The pharmacodynamics of superoxide are complex, as it can exert both beneficial and harmful effects depending on its concentration and context. At low concentrations, superoxide can promote cell survival and proliferation through signaling pathways. Conversely, at high concentrations, it contributes to oxidative damage, lipid peroxidation, and DNA damage, potentially leading to conditions such as inflammation, cancer, and neurodegenerative diseases.

Pharmacokinetics

Superoxide is generated endogenously and does not have a traditional pharmacokinetic profile like drugs. Its lifespan is extremely short, with a half-life measured in microseconds to milliseconds, as it rapidly dismutates to hydrogen peroxide through the action of superoxide dismutase. Due to its reactive nature, superoxide does not circulate in the body but rather acts locally at the site of production.

Pregnancy

Not applicable. Superoxide is a reactive oxygen species and does not have a defined use in pregnancy.

Breast-feeding

Not applicable. Superoxide is a reactive oxygen species and does not have a defined use in breastfeeding.

Storage

Not applicable. Superoxide is a reactive oxygen species and is not stored as a medicinal product.

Indications

• Supplementation in individuals with coenzyme Q10 deficiency
• Support for cardiovascular health
• Management of certain neurodegenerative diseases
• Enhancement of energy levels and exercise performance

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations.

Adults: Refer to the BNF for specific dosing recommendations.

Mechanism of action

Ubiquinol participates in the mitochondrial electron transport chain, where it acts as an electron carrier, transferring electrons between complexes I and III. This process is essential for the generation of ATP through oxidative phosphorylation. Additionally, as an antioxidant, ubiquinol helps to neutralize free radicals, thereby protecting cellular components from oxidative damage. It is involved in several metabolic pathways, including the TCA cycle and aerobic respiration.

Pharmacodynamics

Ubiquinol enhances mitochondrial energy production and improves cellular bioenergetics. Its antioxidant properties contribute to the stabilization of cellular membranes and the protection of lipids, proteins, and DNA from oxidative damage. The effect of ubiquinol on mitochondrial function can lead to improved exercise capacity, enhanced cardiovascular function, and potential neuroprotective benefits.

Pharmacokinetics

Ubiquinol is absorbed from the gastrointestinal tract and is distributed throughout the body, particularly in organs with high energy demands, such as the heart, liver, and kidneys. Its bioavailability can be influenced by factors such as formulation, food intake, and individual metabolic variations. The half-life of ubiquinol is variable, but it is generally estimated to be several hours. It is metabolized in the liver and excreted primarily through the bile.

Pregnancy

There is insufficient data on the safety of ubiquinol during pregnancy. Consult healthcare professionals before use.

Breast-feeding

Limited data available. Caution is advised when using ubiquinol while breastfeeding.

Storage

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

Formulations

• Capsules
• Softgels
• Tablets

Mechanism of action

Melatonin is a derivative of tryptophan. It binds to melatonin receptor type 1A, which then acts on adenylate cylcase and the inhibition of a cAMP signal transduction pathway. Melatonin not only inhibits adenylate cyclase, but it also activates phosphilpase C. This potentiates the release of arachidonate. By binding to melatonin receptors 1 and 2, the downstream signallling cascades have various effects in the body. The melatonin receptors are G protein-coupled receptors and are expressed in various tissues of the body. There are two subtypes of the receptor in humans, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). Melatonin and melatonin receptor agonists, on market or in clinical trials, all bind to and activate both receptor types.The binding of the agonists to the receptors has been investigated for over two decades or since 1986. It is somewhat known, but still not fully understood. When melatonin receptor agonists bind to and activate their receptors it causes numerous physiological processes. MT1 receptors are expressed in many regions of the central nervous system (CNS): suprachiasmatic nucleus of the hypothalamus (SNC), hippocampus, substantia nigra, cerebellum, central dopaminergic pathways, ventral tegmental area and nucleus accumbens. MT1 is also expressed in the retina, ovary, testis, mammary gland, coronary circulation and aorta, gallbladder, liver, kidney, skin and the immune system. MT2 receptors are expressed mainly in the CNS, also in the lung, cardiac, coronary and aortic tissue, myometrium and granulosa cells, immune cells, duodenum and adipocytes. The binding of melatonin to melatonin receptors activates a few signaling pathways. MT1 receptor activation inhibits the adenylyl cyclase and its inhibition causes a rippling effect of non activation; starting with decreasing formation of cyclic adenosine monophosphate (cAMP), and then progressing to less protein kinase A (PKA) activity, which in turn hinders the phosphorilation of cAMP responsive element-binding protein (CREB binding protein) into P-CREB. MT1 receptors also activate phospholipase C (PLC), affect ion channels and regulate ion flux inside the cell. The binding of melatonin to MT2 receptors inhibits adenylyl cyclase which decreases the formation of cAMP.[4] As well it hinders guanylyl cyclase and therefore the forming of cyclic guanosine monophosphate (cGMP). Binding to MT2 receptors probably affects PLC which increases protein kinase C (PKC) activity. Activation of the receptor can lead to ion flux inside the cell. Melatonin is implicated in numerous physiological processes, including circadian rhythms, stress, and reproduction, many of which are mediated by the hypothalamus and pituitary. The physiological actions of melatonin are mainly mediated by melatonin receptors. /The authors/ describe the distribution of the melatonin receptor MT1 in the human hypothalamus and pituitary by immunocytochemistry. MT1 immunoreactivity showed a widespread pattern in the hypothalamus. In addition to the area of the suprachiasmatic nucleus (SCN), a number of novel sites, including the paraventricular nucleus (PVN), periventricular nucleus, supraoptic nucleus (SON), sexually dimorphic nucleus, the diagonal band of Broca, the nucleus basalis of Meynert, infundibular nucleus, ventromedial and dorsomedial nucleus, tuberomamillary nucleus, mamillary body, and paraventricular thalamic nucleus were observed to have neuronal MT1 receptor expression. No staining was observed in the nucleus tuberalis lateralis and bed nucleus of the stria terminalis. The MT1 receptor was colocalized with some vasopressin (AVP) neurons in the SCN, colocalized with some parvocellular and magnocellular AVP and oxytocine (OXT) neurons in the PVN and SON, and colocalized with some parvocellular corticotropin-releasing hormone (CRH) neurons in the PVN. In the pituitary, strong MT1 expression was observed in the pars tuberalis, while a weak staining was found in the posterior and ant

Pharmacodynamics

Melatonin is a hormone normally produced in the pineal gland and released into the blood. The essential amino acid L-tryptophan is a precursor in the synthesis of melatonin. It helps regulate sleep-wake cycles or the circadian rhythm. Production of melatonin is stimulated by darkness and inhibited by light. High levels of melatonin induce sleep and so consumption of the drug can be used to combat insomnia and jet lag. MT1 and MT2 receptors may be a target for the treatment of circadian and non circadian sleep disorders because of their differences in pharmacology and function within the SCN. SCN is responsible for maintaining the 24 hour cycle which regulates many different body functions ranging from sleep to immune functions

Mechanism of action

Most individuals naturally generate adequate amounts of vitamin D through ordinary dietary intake of vitamin D (in some foods like eggs, fish, and cheese) and natural photochemical conversion of the vitamin D3 precursor 7-dehydrocholesterol in the skin via exposure to sunlight. Conversely, vitamin D deficiency can often occur from a combination of insufficient exposure to sunlight, inadequate dietary intake of vitamin D, genetic defects with endogenous vitamin D receptor, or even severe liver or kidney disease. Such deficiency is known for resulting in conditions like rickets or osteomalacia, all of which reflect inadequate mineralization of bone, enhanced compensatory skeletal demineralization, resultant decreased calcium ion blood concentrations, and increases in the production and secretion of parathyroid hormone. Increases in parathyroid hormone stimulate the mobilization of skeletal calcium and the renal excretion of phosphorus. This enhanced mobilization of skeletal calcium leads towards porotic bone conditions. Ordinarily, while vitamin D3 is made naturally via photochemical processes in the skin, both itself and vitamin D2 can be found in various food and pharmaceutical sources as dietary supplements. The principal biological function of vitamin D is the maintenance of normal levels of serum calcium and phosphorus in the bloodstream by enhancing the efficacy of the small intestine to absorb these minerals from the diet. At the liver, vitamin D3 or D2 is hydroxylated to 25-hydroxyvitamin D and then finally to the primary active metabolite 1,25-dihydroxyvitamin D in the kidney via further hydroxylation. This final metabolite binds to endogenous vitamin d receptors, which results in a variety of regulatory roles - including maintaining calcium balance, the regulation of parathyroid hormone, the promotion of the renal reabsorption of calcium, increased intestinal absorption of calcium and phosphorus, and increased calcium and phosphorus mobilization of calcium and phosphorus from bone to plasma to maintain balanced levels of each in bone and the plasma. In particular, calcitriol interacts with vitamin D receptors in the small intestine to enhance the efficiency of intestinal calcium and phosphorous absorption from about 10-15% to 30-40% and 60% increased to 80%, respectively. Furthermore, calcitriol binds with vitamin D receptors in osteoblasts to stimulate a receptor activator of nuclear factor kB ligand (or RANKL) which subsequently interacts with receptor activator of nuclear factor kB (NFkB) on immature preosteoclasts, causing them to become mature bone-resorbing osteoclasts. Such mature osteoclasts ultimately function in removing calcium and phosphorus from bone to maintain blood calcium and phosphorus levels. Moreover, calcitriol also stimulates calcium reabsorption from the glomerular filtrate in the kidneys. Additionally, it is believed that when calcitriol binds with nuclear vitamin D receptors, that this bound complex itself binds to retinoic acid X receptor (RXR) to generate a heterodimeric complex that consequently binds to specific nucleotide sequences in the DNA called vitamin D response elements. When bound, various transcription factors attach to this complex, resulting in either up or down-regulation of the associated gene's activity. It is thought that there may be as much as 200 to 2000 genes that possess vitamin D response elements or that are influenced indirectly to control a multitude of genes across the genome. It is in this way that cholecalciferol is believed to function in regulating gene transcription associated with cancer risk, autoimmune disorders, and cardiovascular disease linked to vitamin D deficiency. In fact, there has been some research to suggest calcitriol may also be able to prevent malignancies by inducing cellular maturation and inducing apoptosis and inhibiting angiogenesis, exhibit anti-inflammatory effects by inhibiting foam cell formation and promoting angiogenesis in en

Pharmacodynamics

The in vivo synthesis of the predominant two biologically active metabolites of vitamin D occurs in two steps. The first hydroxylation of vitamin D3 cholecalciferol (or D2) occurs in the liver to yield 25-hydroxyvitamin D while the second hydroxylation happens in the kidneys to give 1, 25-dihydroxyvitamin D. These vitamin D metabolites subsequently facilitate the active absorption of calcium and phosphorus in the small intestine, serving to increase serum calcium and phosphate levels sufficiently to allow bone mineralization. Conversely, these vitamin D metabolites also assist in mobilizing calcium and phosphate from bone and likely increase the reabsorption of calcium and perhaps also of phosphate via the renal tubules. There exists a period of 10 to 24 hours between the administration of cholecalciferol and the initiation of its action in the body due to the necessity of synthesis of the active vitamin D metabolites in the liver and kidneys. It is parathyroid hormone that is responsible for the regulation of such metabolism at the level of the kidneys.

Mechanism of action

Many of supplemental L-arginine's activities, including its possible anti-atherogenic actions, may be accounted for by its role as the precursor to nitric oxide or NO. NO is produced by all tissues of the body and plays very important roles in the cardiovascular system, immune system and nervous system. NO is formed from L-arginine via the enzyme nitric oxide synthase or synthetase (NOS), and the effects of NO are mainly mediated by 3,'5' -cyclic guanylate or cyclic GMP. NO activates the enzyme guanylate cyclase, which catalyzes the synthesis of cyclic GMP from guanosine triphosphate or GTP. Cyclic GMP is converted to guanylic acid via the enzyme cyclic GMP phosphodiesterase. NOS is a heme-containing enzyme with some sequences similar to cytochrome P-450 reductase. Several isoforms of NOS exist, two of which are constitutive and one of which is inducible by immunological stimuli. The constitutive NOS found in the vascular endothelium is designated eNOS and that present in the brain, spinal cord and peripheral nervous system is designated nNOS. The form of NOS induced by immunological or inflammatory stimuli is known as iNOS. iNOS may be expressed constitutively in select tissues such as lung epithelium. All the nitric oxide synthases use NADPH (reduced nicotinamide adenine dinucleotide phosphate) and oxygen (O2) as cosubstrates, as well as the cofactors FAD (flavin adenine dinucleotide), FMN (flavin mononucleotide), tetrahydrobiopterin and heme. Interestingly, ascorbic acid appears to enhance NOS activity by increasing intracellular tetrahydrobiopterin. eNOS and nNOS synthesize NO in response to an increased concentration of calcium ions or in some cases in response to calcium-independent stimuli, such as shear stress. In vitro studies of NOS indicate that the Km of the enzyme for L-arginine is in the micromolar range. The concentration of L-arginine in endothelial cells, as well as in other cells, and in plasma is in the millimolar range. What this means is that, under physiological conditions, NOS is saturated with its L-arginine substrate. In other words, L-arginine would not be expected to be rate-limiting for the enzyme, and it would not appear that supraphysiological levels of L-arginine which could occur with oral supplementation of the amino acid^would make any difference with regard to NO production. The reaction would appear to have reached its maximum level. However, in vivo studies have demonstrated that, under certain conditions, e.g. hypercholesterolemia, supplemental L-arginine could enhance endothelial-dependent vasodilation and NO production.

Pharmacodynamics

Studies have shown that is has improved immune responses to bacteria, viruses and tumor cells; promotes wound healing and regeneration of the liver; causes the release of growth hormones; considered crucial for optimal muscle growth and tissue repair.

Mechanism of action

Serum and tissue lycopene levels have been inversely related to the risk of lung and prostate cancers. Lycopene functions as a very potent antioxidant, and it can trap singlet oxygen and reduce mutagenesis in the Ames test. Lycopene at physiological concentrations can inhibit human cancer cell growth by interfering with growth factor receptor signaling and cell cycle progression. Studies using human and animal cells identified connexin 43, a gene whose expression is upregulated by lycopene and which allows direct intercellular gap junctional communication (GJC). GJC is deficient in many human tumors and its restoration or upregulation is associated with decreased proliferation. The combination of low concentrations of lycopene with 1,25-dihydroxyvitamin D3 exhibits a synergistic effect on cell proliferation and differentiation, and an additive effect on cell cycle progression in the HL-60 promyelocytic leukemia cell line, suggesting some interaction at a nuclear or subcellular level.

Mechanism of action

Selenomethionine (SeMet) is the chemical form or major component of selenium used for cancer chemoprevention in several clinical trials. However, evidence from experimental studies indicates that SeMet has weaker anticancer effects than most other forms of selenium. ... The anticancer activity of SeMet can be enhanced by methioninase (METase), indicating that SeMet metabolites are responsible for its anticancer activity. ... Wild-type p53-expressing LNCaP human prostate cancer cells were more sensitive to cotreatment with SeMet and METase than p53-null PC3 human prostate cancer cells. SeMet and METase cotreatment significantly increased levels of superoxide and apoptosis in LNCaP cells. Cotreatment with SeMet and METase resulted in increased levels of phosphorylated p53 (Ser15), total p53, Bax, and p21(Waf1) proteins. LNCaP cells treated with SeMet and METase also showed p53 translocation to mitochondria, decreased mitochondrial membrane potential, cytochrome c release into the cytosol, and activation of caspase-9. The effects of SeMet and METase were suppressed by pretreatment with a synthetic superoxide dismutase mimic or by knockdown of p53 via RNA interference. Reexpression of wild-type p53 in PC3 cells resulted in increases in superoxide production, apoptosis, and caspase-9 activity and a decrease in mitochondrial membrane potential following cotreatment with SeMet and METase. /The/ study shows that apoptosis induced by SeMet plus METase is superoxide mediated and p53 dependent via mitochondrial pathway(s). These results suggest that superoxide and p53 may play a role in cancer chemoprevention by selenium. ... The toxicity of Se is thought to arise from its ability to substitute for sulfur during the assembly of proteins. .../More/ recent studies also indicate that some forms of selenium are capable of generating oxidative stress in an in vitro test system that includes glutathione. L-Selenomethionine, the predominant form of selenium in the eggs of oviparous vertebrates, does not generate oxidative radicals in this system, but lesions consistent with oxidative stress have been identified in fish and birds with high concentrations of Se. /This study reports/ on the ability of rainbow trout embryos to transform L-selenomethionine to a form capable of producing a superoxide radical. Oxidative stress appears to be generated by methioninase enzyme activity in the embryos that liberates methylselenol from l-selenomethionine. Methylselenol redox cycles in the presence of glutathione producing superoxide and likely accounts for oxidative lesions present in fish and birds environmentally exposed to excessive loads of selenomethionine. /L-Selenomethionine/ Primary cultures of porcine aortic endothelial cells were used to test the potential protective effect ... against several types of oxidative stress. The stressors included exposure to hyperoxia, treatment with paraquat, and incubation in the presence of the hypoxanthine/xanthine oxidase system. This protective effect ... of selenomethionine ... is known to increase glutathione peroxidase activity. ... High-selenium containing yeast is being evaluated in clinical trials against colon polyp recurrence. However, the molecular targets for the anticancer effects of selenium remain unclear. Previous studies by our group demonstrated that selenomethionine-induced growth arrest appears to be mediated by activation of ERK and subsequent phosphorylation of RSK and histone H3. These results suggest that selenomethionine can alter gene expression. In the present study, we have used cDNA microarrays to determine whether gene expression differences exist in HCT116 colon cancer cells treated with selenomethionine. These experiments reveal statistically significant expression changes for 50 genes. Genes we found to increase with selenomethionine treatment include KLK6, ATOX1, SGK, GJB2, DAP-1, PLAU, VIM, DPYSL2, STC2 and PXN. Conversely, genes downregulated by selenomethionine include PRKACB,