* Your assessment is very important for improving the work of artificial intelligence, which forms the content of this project
103 Available Online at: www.ijrpp.com Print ISSN: 2278 - 2648 Online ISSN: 2278 - 2656 International Journal of Research in Pharmacology and Pharmacotherapeutics Research article LYCOZEN-GT: A SUPER ANTI-OXIDANT MULTIVITAMIN, MULTIMINERAL FORMULATION WITH GOODNESS OF LYCOPENE, GREEN TEA & GRAPE SEED EXTRACT FOR EXCELLENT PROTECTION. *1 Sumit Agarwal Director, Sain Medicaments Pvt. Ltd., Hyderabad, A.P. _________________________________________________________________________ ABSTRACT Damage to cells caused by free radicals is believed to play a central role in the aging process and in disease progression. Antioxidants are our first line of defense against free radical damage, and are critical for maintaining optimum health and well being. The need for antioxidants becomes even more critical with increased exposure to free radicals. Pollution, cigarette smoke, drugs, illness, stress, and even exercise can increase free radical exposure. As many factors can contribute to oxidative stress, individual assessment of susceptibility becomes important. Many experts believe that the Recommended Dietary Allowance (RDA) for specific antioxidants may be inadequate and, in some instances, the need may be several times the RDA. As part of a healthy lifestyle and a well-balanced, wholesome diet, antioxidant supplementation is now being recognized as an important means of improving free radical protection. Based on these facts a super antioxidant multivitamin, multimineral formulation LYCOZEN-GT of Lycopene, GreenTea Grape seed has been developed by R&D Centre, Sain Medicaments Pvt Ltd, Hyderabad. This paper Reviews the Role of LYCOZEN-GT in maintaining optimum health and well being. KEYWORDS: Lycozen-GT, Antioxidant, Multivitamin, Multimineral, Grape seed. ______________________________________________________________________________________________ INTRODUCTION The ability to utilize oxygen has provided humans with the benefit of metabolizing fats, proteins, and carbohydrates for energy; however, it does not come without cost. Oxygen is a highly reactive atom that is capable of becoming part of potentially damaging molecules commonly called “free radicals.” Free radicals are capable of attacking the healthy cells of the body, causing them to lose their structure and function. Cell damage caused by free _________________________________ * Corresponding author: Sumit Agarwal, M.Pharm., Sain Medicaments Pvt.Ltd, (MAKERS OF LYCOZEN-GT Tablets) Hyderabad. E-mail address: [email protected] radicals appears to be a major contributor to aging and to degenerative diseases of aging such as cancer, cardiovascular disease, cataracts, immune system decline, and brain dysfunction. Overall, free radicals have been implicated in the pathogenesis of at least 50 diseases. Fortunately, free radical formation is controlled naturally by various beneficial compounds known as antioxidants. It is when the availability of antioxidants is limited that this damage can become 104 Sumit Agarwal et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-1(2) 2012 [103-120] cumulative and debilitating. Free radicals are electrically charged molecules, i.e.; they have an unpaired electron, which causes them to seek out and capture electrons from other substances in order to neutralize themselves. Although the initial attack causes the free radical to become neutralized, another free radical is formed in the process, causing a chain reaction to occur. And until subsequent free radicals are deactivated, thousands of free radical reactions can occur within seconds of the initial reaction. Antioxidants are capable of stabilizing, or deactivating, free radicals before they attack cells. Antioxidants are absolutely critical for maintaining optimal cellular and systemic health and well-being. Fig: 1 REACTIVE OXYGEN SPECIES Reactive oxygen species (ROS) is a term which encompasses all highly reactive, oxygen-containing molecules, including free radicals. Types of ROS include the hydroxyl radical, the superoxide anion radical, hydrogen peroxide, singlet oxygen, nitric oxide radical, hypochlorite radical, and various lipid peroxides. All are capable of reacting with membrane lipids, nucleic acids, proteins and enzymes, and other small molecules, resulting in cellular damage. ROS are generated by a number of pathways. Most of the oxidants produced by cells occur as: • A consequence of normal aerobic metabolism: approximately 90% of the oxygen utilized by the cell is consumed by the mitochondrial electron transport system. • Oxidative burst from phagocytes (white blood cells) as part of the mechanism by which bacteria and viruses are killed, and by which foreign proteins (antigens) are denatured. • Xenobiotic metabolism, i.e., detoxification of toxic substances. Consequently, things like vigorous exercise, which accelerates cellular metabolism; chronic inflammation, infections, and other illnesses; exposure to allergens and the presence of “leaky gut” syndrome; and exposure to drugs or toxins such as cigarette smoke, pollution, pesticides, and insecticides may all contribute to an increase in the body’s oxidant load. Fig:2 ANTIOXIDANT PROTECTION www.ijrpp.com 105 Sumit Agarwal et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-1(2) 2012 [103-120] To protect the cells and organ systems of the body against reactive oxygen species, humans have evolved a highly sophisticated and complex antioxidant protection system. It involves a variety of components, both endogenous and exogenous in origin, that function interactively and synergistically to neutralize free radicals. These components include: • Nutrient-derived antioxidants like ascorbic acid (vitamin C), tocopherols and tocotrienols (vitamin E), carotenoids, and other low molecular weight compounds such as glutathione and lipoic acid. • Antioxidant enzymes, e.g., superoxide dismutase, glutathione peroxidase, and glutathione reductase, which catalyze free radical quenching reactions. • Metal binding proteins, such as ferritin, lactoferrin, albumin, and ceruloplasmin that sequester free iron and copper ions that are capable of catalyzing oxidative reactions. • Numerous other antioxidant phytonutrients present in a wide variety of plant foods Fig:3: How do antioxidants operate TABLE 1: VARIOUS ROS AND CORRESPONDING NEUTRALIZING ANTIOXIDANTS ROS Hydroxyl radical Superoxide radical Hydrogen peroxide Lipid peroxides NEUTRALIZING ANTIOXIDANTS Vitamin C, glutathione, flavonoids, lipoic acid Vitamin C, glutathione, flavonoids, SOD Vitamin C, glutathione, beta carotene, vitamin E, CoQ10, flavonoids, lipoic acid Beta carotene, vitamin E, ubiquinone, flavonoids, Glutathione peroxidase DIETARY ANTIOXIDANTS Vitamin C, vitamin E, and beta carotene are among the most widely studied dietary antioxidants. Vitamin C is considered the most important watersoluble antioxidant in extracellular fluids. It is capable of neutralizing ROS in the aqueous phase before lipid peroxidation is initiated. Vitamin E, a major lipid-soluble antioxidant, is the most effective chain-breaking antioxidant within the cell membrane where it protects membrane fatty acids from lipid peroxidation. Vitamin C has been cited as being capable of regenerating vitamin E. Beta carotene and other carotenoids are also believed to provide antioxidant protection to lipid-rich tissues. www.ijrpp.com 106 Sumit Agarwal et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-1(2) 2012 [103-120] Research suggests beta carotene may work synergistically with vitamin E. A diet that is excessively low in fat may negatively affect beta-carotene and vitamin E absorption, as well as other fat-soluble nutrients. Fruits and vegetables are major sources of vitamin C and carotenoids, while whole grains and high quality, properly extracted and protected vegetable oils are major sources of vitamin E. PHYTONUTRIENTS A number of other dietary antioxidant substances exist beyond the traditional vitamins discussed above. Many plant-derived substances, collectively termed “phyto nutrients,” or “phyto chemicals,” are becoming increasingly known for their antioxidant activity. Phenolic compounds such as flavonoids are ubiquitous within the plant kingdom: approximately, 3,000 flavonoid substances have been described. In plants, flavonoids serve as protectors against a wide variety of environmental stresses while, in humans, flavonoids appear to function as “biological response modifiers.” Flavonoids have been demonstrated to have antiinflammatory, antiallergenic, anti-viral, anti-aging, and anti-carcinogenic activity. The broad therapeutic effects of flavonoids can be largely attributed to their antioxidant properties. In addition to an antioxidant effect, flavonoid compounds may exert protection against heart disease through the inhibition of cyclooxygenase and lipoxygenase activities in platelets and macrophages. ENDOGENOUS ANTIOXIDANTS In addition to dietary antioxidants, the body relies on several endogenous defense mechanisms to help protect against free radical-induced cell damage. The antioxidant enzymes – glutathione peroxidase, catalase, and superoxide dismutase (SOD) – metabolize oxidative toxic intermediates and require micronutrient cofactors such as selenium, iron, copper, zinc, and manganese for optimum catalytic activity. It has been suggested that an inadequate dietary intake of these trace minerals may compromise the effectiveness of these antioxidant defense mechanisms. Research indicates that consumption and absorption of these important trace minerals may decrease with aging. Intensive agricultural methods have also resulted in significant depletion of these valuable trace minerals in our soils and the foods grown in them. Glutathione, an important water-soluble antioxidant, is synthesized from the amino acids glycine, glutamate, and cysteine. Glutathione directly quenches ROS such as lipid peroxides, and also plays a major role in xenobiotic metabolism. Exposure of the liver to xenobiotic substances induces oxidative reactions through the upregulation of detoxification enzymes, i.e., cytochrome P-450 mixed-function oxidase. When an individual is exposed to high levels of xenobiotics, more glutathione is utilized for conjugation (a key step in the body’s detoxification process) making it less available to serve as an antioxidant. Research suggests that glutathione and vitamin C work interactively to quench free radicals and that they have a sparing effect upon each other. Lipoic acid, yet another important endogenous antioxidant, categorized as a “thiol” or “biothiol,” is a sulfur-containing molecule that is known for its involvement in the reaction that catalyzes the oxidative decarboxylation of alpha-keto acids, such as pyruvate and alphaketoglutarate,in the Krebs cycle. Lipoic acid and its reduced form, dihydrolipoic acid (DHLA), are capable of quenching free radicals in both lipid and aqueous domains and as such has been called a “universal antioxidant.” Lipoic acid may also exert its antioxidant effect by chelating with pro-oxidant metals. Research further suggests that lipoic acid has a sparing effect on other antioxidants. Animal studies have demonstrated supplemental lipoic acid to protect against the symptoms of vitamin E or vitamin C deficiency. Additional physiological antioxidants are listed in Table: II. www.ijrpp.com 107 Sumit Agarwal et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-1(2) 2012 [103-120] TABLE II: ANTIOXIDANT PROTECTION SYSTEM Endogenous Antioxidants Dietary Antioxidants Metal Binding Proteins Enzymes: Bilirubin Vitamin C Albumin (copper) Thiols, e.g., glutathione, lipoic acid, N-acetyl cysteine NADPH and NADH Vitamin E Ceruloplasmin (copper) copper/zinc and manganesedependent superoxide dismutase (SOD) Iron-dependent catalase Beta carotene and other carotenoids and oxycarotenoids, e.g., lycopene and lutein Polyphenols, e.g., flavonoids, flavones, flavonols,and proanthocyanidins Vitamin C Vitamin E Beta carotene and other carotenoids and oxycarotenoids, e.g., lycopene and lutein Metallothionein (copper) Ubiquinone (coenzyme Q10) Uric acid Selenium-dependent glutathione peroxidase Ferritin (iron) Myoglobin (iron) Transferrin (iron) Albumin (copper) Ceruloplasmin (copper) Metallothionein (copper) OXIDATIVE STRESS As remarkable as our antioxidant defense system is, it may not always be adequate. The term “oxidative stress” has been coined to represent a shift towards the pro-oxidants in the prooxidant/antioxidant balance that can occur as a result of an increase in oxidative metabolism. Increased oxidative stress at the cellular level can come about as a consequence of many factors, including exposure to alcohol, medications, trauma, cold, infections, poor diet, toxins, radiation, or strenuous physical activity. Protection against all of these processes is dependent upon the adequacy of various antioxidant substances that are derived either directly or indirectly from the diet. Consequently, an inadequate intake of antioxidant nutrients may compromise antioxidant potential, thus compounding overall oxidative stress. OXIDATIVE STRESS AND HUMAN DISEASE Oxidative damage to DNA, proteins, and other macromolecules has been implicated in the pathogenesis of a wide variety of diseases, most notably heart disease and cancer. A growing body of animal and epidemiological studies as well as clinical intervention trials suggests that antioxidants may play a pivotal role in preventing or slowing the progression of both heart disease and some forms of cancer. CONDITIONS ASSOCIATED WITH OXIDATIVE DAMAGE • Atherosclerosis • Cancer • Pulmonary dysfunction www.ijrpp.com 108 Sumit Agarwal et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-1(2) 2012 [103-120] • Cataracts • Arthritis and inflammatory diseases • Diabetes • Shock, trauma, and ischemia • Renal disease and hemodialysis • Multiple sclerosis • Pancreatitis • Inflammatory bowel disease and colitis • Parkinson’s disease • Neonatal lipoprotein oxidation • Drug reactions • Skin lesion & Aging administration. The quantity of cobalamin detected following a small oral dose of methylcobalamin is similar to the amount following administration of cyanocobalamin. But significantly more cobalamin accumulates in liver tissue following administration of methylcobalamin. Human urinary excretion of methylcobalamin is about one-third that of a similar dose of cyanocobalamin, indicating substantially greater tissue retention.1 Clinical Indications Bell’s Palsy Evidence suggests methylcobalamin dramatically shortened the recovery time for facial nerve function in Bell’s palsy.2 Role of LYCOZEN-GT in Preventing Oxidative Damage caused by free radicals. LYCOZEN-GT, A SuperAntioxidant Multivitamin, Multimineral Formulation with goodness of Lycopene,GreenTea Extract,Grapeseed Extract Composition of LYCOZEN-GT Tablet Each Film Coated Tablet Contains: Methylcobalamine 500mcg Lycopene 5mg Grape Seed Extract 10mg GreenTeaExtract 25mg Folic acid 1mg Calcium Pantothenate 10mg Pyridoxine Hydrochloride 3mg Thiamine Mononitrate 10mg Riboflavine 3mg Vitamin A acetate 10 I.U. Vitamin E acetate 10 I.U. Vitamin C 25mg Niacinamide 10mg Biotin 100mcg Selenium 60mcg Zinc 10mg Cancer Cell culture and in vivo experimental results indicated methylcobalamin can inhibit the proliferation of malignant cells.3 Methylcobalamin enhanced survival time and reduced tumor growth following inoculation of mice with Ehrlich ascites tumor cells.4 Methylcobalamin has been shown to increase survival time of leukemic mice. Under the same experimental conditions, cyanocobalamin was inactive.5 Although more research is required to verify findings, experimental evidence suggested methylcobalamin might enhance the efficacy of methotrexate.6 Diabetic Neuropathy Oral administration of methylcobalamin (500 mcg three times daily for four months) resulted in subjective improvement in burning sensations, numbness, loss of sensation, and muscle cramps. An improvement in reflexes, vibration sense, lower motor neuron weakness, and sensitivity to pain was also observed.7 PHARMACOLOGY Role of Methylcobalamin in LYCOZEN-GT Methylcobalamin is one of the two coenzyme forms of vitamin B12 (the other being adenosylcobalamin). It is a cofactor in the enzyme methionine synthase, which functions to transfer methyl groups for the regeneration of methionine from homocysteine. Evidence indicates methylcobalamin is utilized more efficiently than cyanocobalamin to increase levels of one of the coenzyme forms of vitamin B12. Experiments have demonstrated similar absorption of methylcobalamin following oral Eye Function Experiments indicated chronic administration of methylcobalamin protected cultured retinal neurons against N-methyl-D-aspartate-receptor-mediated Deterioration of glutamate neurotoxicity.8 accommodation following visual work has also been shown to improve in individuals receiving methylcobalamin.9 Heart Rate Variability Heart rate variability is a means of detecting the relative activity and balance of the sympathetic/ parasympathetic nervous systems. Methylcobalamin produces improvements in www.ijrpp.com 109 Sumit Agarwal et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-1(2) 2012 [103-120] several components of heart rate variability, suggesting a balancing effect on the nervous system.10 HIV Under experimental conditions, methylcobalamin inhibited HIV-1 infection of normal human blood monocytes and lymphocytes.11 Homocysteinemia Elevated levels of homocysteine can be a metabolic indication of decreased levels of the methylcobalamin form of vitamin B12. Therefore, it is not surprising that elevated homocysteine levels were reduced from a mean value of 14.7 to 10.2 nmol/ml following parenteral treatment with methylcobalamin.12 Male Infertility In one study, methylcobalamin, at a dose of 6 mg per day for 16 weeks, improved sperm count by 37.5 percent.13 In a separate investigation, methylcobalamin, given at a dose of 1,500 micrograms per day for 4-24 weeks, resulted in sperm concentration increases in 38 percent of cases, total sperm count increases in 54 percent of cases, and sperm motility increases in 50 percent of cases.14 Sleep Disturbances The use of methylcobalamin in the treatment of a variety of sleep-wake disorders is very promising. Although the exact mechanism of action is not yet elucidated, it is possible that methylcobalamin is needed for the synthesis of melatonin, since the biosynthetic formation of melatonin requires the donation of a methyl group. Supplementation appears to have a great deal of abilities to modulate melatonin secretion, enhance light-sensitivity, normalize circadian rhythms, and normalize sleepwake rhythm.15-20 Role of lycopene in LYCOZEN-GT Lycopene, a carotenoid without provitamin-A activity, is present in many fruits and vegetables. It is a red, fat-soluble pigment found in certain plants and microorganisms, where it serves as an accessory light-gathering pigment and protects these organisms against the toxic effects of oxygen and light. Tomato products, including ketchup, tomato juice, and pizza sauce, are the richest sources of lycopene in the U.S. diet, accounting for greater than 80 percent of the total lycopene intake of Americans.21 In addition to tomatoes (Lycopersicon esculentum) and tomato-based products, lycopene is also found in watermelon, papaya, pink grapefruit, and pink guava. Lycopene from both processed and cooked tomato products is more bioavailable than from fresh tomatoes.22 Dietary intakes of tomatoes and tomato products containing lycopene have been shown in cell culture, animal, and epidemiological investigations to be associated with a decreased risk of chronic diseases, such as cancer and cardiovascular disease.23-25 In addition, serum and tissue lycopene levels have been inversely correlated with risk of lung and prostate cancers.26 Biochemistry and Pharmacokinetics Lycopene, also known as psi-carotene, is a lipophilic compound, an acyclic isomer of betacarotene, and is insoluble in water. It is a C40, open-chain carotenoids with 11 conjugated double bonds. Because of the abundance of double bonds in its structure, there are potentially 1,056 different isomers of lycopene, but only a fraction is found in nature.27 Lycopene is converted to beta-carotene by the action of lycopene beta cyclase.28 Among the carotenoids, lycopene is found in the serum,25 testes, adrenal glands, and prostate.24 In contrast to other carotenoids, its serum values are not regularly reduced by smoking or alcohol consumption, although levels are reduced by increasing age.29. The linear all-trans configuration is the predominant form of lycopene, making up approximately 90 percent of its dietary sources.30 Stahl et al found that heating tomato juice resulted in trans-to-cis isomerization of lycopene, and on ingestion, the cis isomers of lycopene appeared to predominate in human serum over all-trans isomers.31 Gartner et al showed that more than half of total lycopene in human serum is in the cis form.32 The exact functions and relative activities of these different isomers are currently unknown. However, several research groups have suggested cis isomers of lycopene are better absorbed than the all-trans form.30 Investigations are meanwhile underway to determine whether there are biological differences between all-trans and various cis isomers of lycopene regarding its antioxidant properties and other biological functions. Mechanisms of Action Lycopene has the capacity to prevent free-radical damage to cells caused by reactive oxygen species. www.ijrpp.com 110 Sumit Agarwal et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-1(2) 2012 [103-120] It is a potent antioxidant in vitro and in human studies, reducing the susceptibility of lymphocyte DNA to oxidative damage,33 inactivating hydrogen peroxide and nitrogen dioxide,14 and protecting lymphocytes from nitrogen oxide induced membrane damage and cell death twice as efficiently as beta-carotene.34 Evidence is accumulating to suggest other mechanisms of action for lycopene, including modulation of intercellular gap junction communication, an anticancer mechanism.25,26 In addition, lycopene at physiological concentrations has been shown to inhibit human cancer cell growth by interfering with growth factor receptor signaling and cell cycle progression, specifically in prostate cancer cells.26 Clinical Indications Cardiovascular Disease Lycopene may reduce lipids by inhibiting the enzyme macrophage 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase (an important step in cholesterol synthesis)15 and by enhancing LDL degradation.21 In addition, available evidence suggests intimal wall thickness and risk of myocardial infarction (MI) are reduced in persons with higher adipose tissue concentrations of lycopene.21 Recent epidemiological studies have shown an inverse relationship between tissue and serum levels of lycopene and mortality from coronary heart disease (CHD), cerebrovascular disease, and MI.36-38 The strongest populationbased evidence on lycopene and MI comes from the European Community Multicenter Study on Antioxidants, Myocardial Infarction and Breast Cancer (EURAMIC) that evaluated the relationship between adipose tissue antioxidant status and acute MI.16 The study recruited 1,379 individuals (662 patients, 717 controls) from 10 European countries. Needle aspiration biopsy samples of adipose tissue were taken shortly after the infarction, and levels of alpha- and beta-carotenes, lycopene, and alphatocopherol were measured. After adjusting for age, body mass index, socioeconomic status, smoking, hypertension, and maternal and paternal history of heart disease, only lycopene levels were found to be protective. The protective potential of lycopene was maximal among individuals with the highest polyunsaturated fat stores, supporting the antioxidant theory. Results also showed a doseresponse relationship between each quintile of adipose tissue lycopene and the risk of MI. Similarly, lower blood lycopene levels were also found to be associated with increased risk and mortality from CHD in a concomitant crosssectional study comparing Lithuanian and Swedish populations.37 In a recent clinical trial, 60 healthy individuals (30 men/30 women) were randomized to examine the change in plasma lycopene and resistance of lipoproteins to oxidative stress. Fifteen days of tomato product consumption significantly enhanced the protection of lipoproteins to oxidative stress as measured by a significant increase (p< 0.05) in the lag period (a measure of antioxidant capacity) after consumption of lycopene.39 Increased thickness of the intimamedia has been shown to predict coronary events.40 Rissanen et al investigated the relationship between plasma concentrations of lycopene and intima- media thickness of the common carotid artery wall (CCA-IMT) in 520 males and females (age 45-69).41 The authors conclude that low plasma lycopene concentrations are associated with early atherosclerosis in men,but not women, as manifested by increased CCA-IMT. Cancer Oxidative stress is recognized as one of the major contributors to increased risk of cancer48, and in chemical assays, lycopene is the most potent antioxidant among various common carotenoids. 42 Lycopene has been found to inhibit proliferation of several types of human cancer cells, including endometrial, breast, and lung.43-45 In addition, in vivo studies have shown lycopene has tumorsuppressive activity.46 Other studies support the hypothesis that carotenoid-containing plant products, such as lycopene, exert a cancer protective effect via a decrease in oxidative and other damage to DNA in humans.47 Lycopene has also recently been shown to elevate levels of hepatic reduced glutathione and biotransformation enzymes, potentially playing a key role in preventing cancer development at extrahepatic sites.48 In one epidemiological review regarding intake of tomatoes, tomato-based products, and blood lycopene levels in relation to the risk of various cancers, 72 studies were identified.49 Of those, 57 reported inverse associations between tomato intake or blood lycopene level and the risk of cancer at a defined anatomic site; 35 of these inverse associations were statistically significant. The evidence for a benefit was strongest for cancers of the prostate, lung, and stomach. Data were also suggestive of a benefit for cancers of the www.ijrpp.com 111 Sumit Agarwal et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-1(2) 2012 [103-120] pancreas, colon and rectum, esophagus, oral cavity, breast, and cervix.50-58 In a case-control study conducted between 1993 and 1999, examining the relationship between 17 micronutrients and breast cancer risk in 289 women with confirmed breast cancer and 442 controls, lycopene was significantly inversely associated with breast cancer risk.60 Median intake of lycopene in the “high intake” group was 6.2 mg/day. In a 1998 study, samples taken from the Breast Cancer Serum Bank in Columbia, Missouri, were analyzed to evaluate the relationship of levels of carotenoids (including lycopene), selenium, and retinol with breast cancer.61 Only lycopene was found to be associated with a reduced risk for developing breast cancer. In another study involving 32 women with cervical dysplasia (cervical intraepithelial neoplasia (CIN) I, CIN II, and CIN III/carcinoma in situ) and 113 controls with normal cervical cytology, women with higher levels of lycopene in the blood were found to have a 33- percent decreased risk of developing cervical cancer.64 Lycopene is one of the micronutrients currently being examined in National Cancer Institute- sponsored, phase I, II, or III chemoprevention trials for prostate, breast, and colon cancers.65 These studies suggest lycopene may have anti proliferatives and chemo preventive properties. Diabetes Data from phase I of the Third National Health and Nutrition Examination Survey (1988- 1991) were used to examine concentrations of lycopene and other carotenoids in 40- to 74-year old persons with normal glucose tolerance (n =1,010), impaired glucose tolerance (n = 277), newly diagnosed diabetes (n = 148), and previously diagnosed diabetes (n = 230), based on World Health Organization criteria.66 After adjustment for age, sex, race, education, serum cotinine (a metabolic byproduct of nicotine), serum cholesterol, body mass index, physical activity, alcohol consumption, vitamin use, and carotene and energy intake, lycopene was inversely related to fasting serum insulin after adjustment for confounders (p<0.05). These data suggest a possible role for lycopene in the pathogenesis of insulin resistance and diabetes. A study investigated the relationship between hyperglycemia and serum carotenoids, including lycopene, and intake of vegetables and fruits. Subjects were recruited with a history of diabetes mellitus (n=133) or with hyperglycemia diagnosed using a conservative 5.6-percent cutoff value for hemoglobin A1c (n=151).67 Serum levels of carotenoids and retinol were measured using highperformance liquid chromatography. The authors concluded that an intake of vegetables and fruits rich in carotenoids, including lycopene, might be a protective factor against hyperglycemia. Other Clinical Indications Studies have also investigated the relationship and/or use of lycopene for cataracts,68 longevity,69 malaria,70 digestive-tract cancers,71,72 immune modulation,73 Alzheimer’s disease, 74 and preeclampsia.75. Patients with HIV infection or inflammatory diseases may have depleted lycopene serum concentrations.76 Drug-Nutrient and Nutrient-Nutrient Interactions Cholesterol-lowering drugs (e.g.,probucol),77 78 mineral oil, fat substitutes, and pectin79 may decrease the absorption of lycopene; whereas, betacarotene,80 medium-chain triglycerides, and dietary oils such as olive oil may enhance the absorption of lycopene.81 Dosage Therapeutic dosages of lycopene range from 6-60 mg daily. Dosages include 6 mg for reducing the risk of prostate cancer; 83 6.5 mg for reducing the risk of lung cancer in non-smoking women;64 12 mg for reducing the risk of lung cancer in nonsmoking men;84 30 mg for decreasing the growth of prostate cancer38 and preventing exercise-induced asthma;85 and 60 mg for reducing LDL cholesterol.35 GRAPE SEED EXTRACT in LYCOZEN-GT Grape seed extract is a source of potent antioxidants called pro anthocyanidins, also known as oligomeric pro anthocyanidin complexes (OPCs), a type of flavonoid. Research supports benefits for chronic venous insufficiency, varicose veins, prevention of blood clots while flying, and reducing post-surgical edema. Preliminary research suggests benefits for ADHD, PMS, erectile dysfunction, asthma, allergies, hemorrhoids, and prevention of atherosclerosis. It is very well tolerated, but may cause minor upset stomach. It may enhance the effect of blood-thinning drugs. www.ijrpp.com 112 Sumit Agarwal et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-1(2) 2012 [103-120] Mechanisms of Action OPCs possess antioxidant, antimutagenic, anticarcinogenic, anti-inflammatory, and antiviral properties. Antioxidant The potent antioxidative properties of OPCs account for their therapeutic benefit in disease states characterized by oxidative stress. OPCs also demonstrate potent, concentration-dependent, free radical scavenging ability. Studies in mice show OPCs inhibit chemically-induced lipid peroxidation, DNA fragmentation, and subsequent apoptosis (indicators of oxidative tissue damage) in a dose-dependent manner in hepatic and brain tissue. Human studies also demonstrate an antioxidative mechanism as evidenced by decreased lipid peroxidation of LDL cholesterol and increased free-radical trapping capacity after consumption of red wine containing OPCs. OPCs appear to have an affinity for vascular tissue and strongly inhibit several enzymes involved in degradation of collagen, elastin, and hyaluronic acid, the main structural components of the extravascular matrix. These effects are perhaps attributable to trapping reactive oxygen species and preventing oxidative injury to vascular endothelium. In vitro studies have also found OPCs increase resistance of cell membranes to injury and degradation. Proanthocyanidins possess endothelium dependent relaxing (EDR) activity in blood vessels by increasing nitric oxide production,16 and stimulate vascular endothelial growth factor, a signaling factor involved in initiation of wound healing. OPCs may also protect the microvasculature of the retina and increase visual acuity, possibly by increasing the rate of rhodopsin regeneration. In a rabbit model of ischemia/ reperfusion, OPCs’ beneficial effects were attributed to binding of copper and iron liberated from myocardial tissue, thereby reducing their oxidative effects. The positive effects of OPCs on microcirculation are also attributed to their inhibition of LDL oxidation and decreased incidence of foam cells, markers of early stage atherosclerosis. Grape seed proanthocyanidins may have a vitamin E-sparing effect. A clinical study of 10 healthy volunteers examining the effect of OPC supplementation on markers of oxidative stress showed significantly increased levels of alphatocopherol in red cell membranes. Anti-inflammatory OPCs from pine bark decrease symptoms of chronic inflammation. In vitro, studies demonstrate anti-inflammatory effects may be due to inhibition of peroxide generation by macrophages. In addition, animal studies demonstrate OPCs from grape seed significantly inhibit the formation of pro-inflammatory cytokines, interleukin 1-beta, and tumor necrosis factor-alpha. Antimutagenic/Anticarcinogenic OPCs possess natural antimutagenic properties when exposed to certain strains of bacteria. Although the exact mechanism is not known, an in vitro study found OPCs exhibit selective cytotoxicity for certain cancerous cell lines, while remaining non-toxic to normal human gastric mucosal cells and macrophages. An in vitro study in a mouse skin tumor model demonstrated OPCs’ inhibition of two markers of tumor promotion. Antimicrobial Effects Flavonoids and associated polyphenol, particularly OPCs, elicit an inhibitory effect on human immunodeficiency virus (HIV). A possible mechanism may be inhibition of gene expression regulating virus binding to cell receptors on normal lymphocytes, thus preventing infection. Role of GREEN TEA EXTRACT in LYCOZEN-GT Green tea is derived from the plant Camellia sinensis. Unlike black and oolong tea, it is not fermented, which preserves the active constituents. It provides a high level of antioxidants called polyphenol, particularly the catechin called epigallocatechin gallate (EGCG). It is used for heart health, cancer prevention, cervical dysplasia, weight loss, liver disease, and gum health. Green tea contains caffeine, but less so than black tea and coffee. Side effects are rare; large amounts may cause insomnia and nervousness. Clinical Summary Tea polyphenol are powerful antioxidants that may reduce LDL oxidation and the formation of oxidized DNA metabolites, thus contributing to lower risks of CVD and cancer. They may also promote oral health and help with weight control. Catechins have been found to be anti-oxidant, antimutagenic, antibacterial, anti-inflammatory, and antiviral. www.ijrpp.com 113 Sumit Agarwal et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-1(2) 2012 [103-120] Green tea can reduce food intake4, lipid absorption and blood triglyceride, cholesterol, and leptin levels, as well as stimulating energy expenditure, fat oxidation, HDL levels, and faecal lipid excretion. Both tea catechins and heat-treated tea catechins suppress postprandial hyper triglyceridaemia. Ikeda suggests that this, along with the properties of lowering cholesterol and preventing LDL oxidation, makes green tea a suitable substance for prevention of coronary heart disease. Liu lists additional properties of green tea such as reducing body weight, body fat, and blood levels of glucose and lipid in leptin receptordefective obese rats. EGCG protects pancreatic cells, enhances insulin activity, represses hepatic glucose production, reduces food uptake and absorption, stimulates thermogenesis and lipid excretion, and modulates insulin-leptin endocrine systems. It also inhibits the sodium-dependent glucose transporter and represses various enzymes related to lipid metabolism, such as acetyl-CoA carboxylase, fatty acid synthase, pancreatic lipase, gastric lipase, and lipoxygenase. Green tea extract may prevent the development of hepatic steatosis and reduces liver injury without altering hepatic alpha-tocopherol and ascorbic acid. Role of Folic Acid in LYCOZEN-GT Folic acid, also known generically as folate or folacin, is a member of the B-complex family of vitamins, and works in concert with vitamin B12. Folic acid functions primarily as a methyl-group donor involved in many important body processes, including DNA synthesis. Therapeutically, folic acid is instrumental in reducing homocysteine levels and the occurrence of neural tube defects. It may play a key role in preventing cervical dysplasia and protecting against neoplasia in ulcerative colitis. Folic acid also shows promise as part of a nutritional protocol to treat vitiligo, and may reduce inflammation of the gingiva. Furthermore, certain neurological, cognitive, and psychiatric presentations may be secondary to folate deficiency. Such presentations include peripheral neuropathy, myelopathy, restless legs syndrome, insomnia, dementia, forgetfulness, irritability, endogenous depression, organic psychosis, and schizophrenia-like syndromes. Folic acid is required for cell division, growth, amino acid metabolism, enzyme reactions, and production of RNA, DNA, and red blood cells. Folic Acid is used for heart health (lowers homocysteine) and prevention of cancer (colon and cervical) and birth defects (neural tube). Folic Acid Deficiency occurs in alcoholics and those with poor diets, and causes anemia, fatigue, weakness, headache, hair loss, diarrhea, and poor immune function. Pregnancy or cancer results in increased rates of cell division and metabolism, increasing the need for folate. Drugs that deplete folate: nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and aspirin, phenytoin, methotrexate phenobarbital, cholestyramine, colestipol, trimethoprim, and sulfasalazine. Folic Acid Supplements are recommended for most adults for heart and cancer protection, and especially for pregnant women; multivitamins typically provide the recommended amount of 400 mcg per day. Folic acid is composed of three primary structures, a hetero-bicyclic pteridine ring, para-aminobenzoic acid (PABA), and glutamic acid. Because humans cannot synthesize this compound, it is a dietary requirement. Although folic acid is the primary form of folate used in dietary supplements or fortified foods, it comprises only 10 percent or less of folates in the diet. Dietary folic acid, or the form naturally found in foods, is actually a complex and variable mixture of folate compounds, such as poly glutamate (multiple glutamate molecules attached) conjugate compounds, reduced folates, and tetra hydro folates. Although folates are abundant in the diet, cooking or processing destroys these compounds. The best folate sources in foods are green, leafy vegetables; sprouts, fruits, brewer’s yeast, liver, and kidney also contain high amounts of folates. Role of Calcium Pentothenate in LYCOZENGT Pantothenic acid (vitamin B5) is a water-soluble Bcomplex vitamin that was identified in 1933, isolated and extracted from liver in 1938, and first synthesized in 1940.1 R. J. Williams is credited with coining the name from the Greek word panthos, which translates as “from everywhere.” It was given this name because of its widespread presence in food. Most vitamin B5, and its derivatives or precursors, added to foods and beverages, or used in dietary supplements, is made by chemical synthesis. Only the Dextrorotatory (D) isomer of pantothenic acid – D-pantothenic acid – possesses biologic activity. Pure D-pantothenic acid can be used as a dietary supplement: it is www.ijrpp.com 114 Sumit Agarwal et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-1(2) 2012 [103-120] water-soluble, viscous, and yellow in color. Because D-pantothenic acid is relatively unstable – it can be destroyed by heat and acid and alkaline conditions – the more stable calcium pantothenate is the form of vitamin B5 usually found in dietary supplements. It is water-soluble, crystalline, and white in color. Ten mg of calcium pantothenate is approximately equivalent to 9.2 mg of pure Dpantothenic acid. Calcium Pantothenate is required for carbohydrate metabolism, adrenal function, enzyme reactions, and production of fats, cholesterol, bile acids, hormones, neurotransmitters, and red blood cells. Deficiency of calcium pantothenate is rare, except in malnutrition, and causes burning/tingling in hands and feet, fatigue, and headache. Drugs that deplete Calcium Pantothenate is, oral contraceptives, amitriptyline, imipramine, and desipramine. Most people get adequate niacin from diet and/or a multivitamin. Role of Vitamin B6 (Pyridoxine) in LYCOZENGT Pyridoxine is necessary for protein and fat metabolism, hormone function (estrogen and testosterone), and the production of red blood cells, niacin, and neurotransmitters (serotonin, dopamine, and norepinephrine). Pyridoxine is also used therapeutically for PMS, depression, morning sickness, carpal tunnel syndrome and heart health (lowers homocysteine, an amino acid that, at high levels, can cause arteriosclerosis and build up arterial plaque). Deficiency of pyridoxine is uncommon, except in alcoholics and the elderly, and causes seizures, irritability, depression, confusion, mouth sores, and impaired immune function. Drugs that deplete vitamin B6(Pyridoxine): antibiotics, oral contraceptives, isoniazid, penicillamine, and Parkinson’s drugs. Supplementation of Pyridoxine is recommended for the elderly, alcoholics, and those with poor diets. Role of Thiamine Mononitrate in LYCOZENGT Thiamine or thiamin or vitamin B1 named as the "thio-vitamine" ("sulfur-containing vitamin") is a water-soluble vitamin of the B complex. First named aneurin for the detrimental neurological effects if not present in the diet, it was eventually assigned the generic descriptor name vitamin B1. Its phosphates derivatives are involved in many cellular processes. The best-characterized form is thiamine pyrophosphate (TPP), a coenzyme in the catabolism of sugars and amino acids. Thiamine is used in the biosynthesis of the neurotransmitter acetylcholine and Gamma-Amino Butyric Acid (GABA). Thiamine derivatives and thiamine-dependent enzymes are present in all cells of the body, thus a thiamine deficiency would seem to adversely affect all of the organ systems. However, the nervous system and the heart are particularly sensitive to thiamine deficiency, because of their high oxidative metabolism. Thiamine deficiency commonly presents sub acutely and can lead to metabolic coma and death. A lack of thiamine can be caused by malnutrition, a diet high in thiaminase-rich foods (raw freshwater fish, raw shellfish, ferns) and/or foods high in antithiamine factors (tea, coffee, betel nuts) and by grossly impaired nutritional status associated with chronic diseases, such as alcoholism, gastrointestinal diseases, HIV-AIDS, and persistent vomiting. It is thought that many people with diabetes have a deficiency of thiamine and that this may be linked to some of the complications that can occur. Well-known syndromes caused by thiamine deficiency include beriberi, Wernicke Korsakoff syndrome, and optic neuropathy. Role of Riboflavine in LYCOZEN-GT Riboflavin, also known as vitamin B2 is an easily absorbed colored micronutrient with a key role in maintaining health in humans and animals. It is the central component of the cofactors FAD and FMN, and is therefore required by all flavoproteins. As such, vitamin B2 is required for a wide variety of cellular processes. It plays a key role in energy metabolism, and for the metabolism of fats, ketone bodies, carbohydrates, and proteins. Riboflavin is continuously excreted in the urine of healthy individuals, making deficiency relatively common when dietary intake is insufficient. However, riboflavin deficiency is always accompanied by deficiency of other vitamins. A deficiency of riboflavin can be primary - poor vitamin sources in one's daily diet - or secondary, which may be a result of conditions that affect absorption in the intestine, the body not being able to use the vitamin, or an increase in the excretion of the vitamin from the body. In humans, signs and symptoms of riboflavin deficiency (ariboflavinosis) include cracked and red lips, inflammation of the lining of mouth and tongue, mouth ulcers, cracks at the corners of the www.ijrpp.com 115 Sumit Agarwal et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-1(2) 2012 [103-120] mouth (angular cheilitis), and a sore throat. A deficiency may also cause dry and scaling skin, fluid in the mucous membranes, and irondeficiency anemia. The eyes may also become bloodshot, itchy, watery and sensitive to bright light. Riboflavin deficiency is classically associated with the oral-ocular-genital syndrome. Angular cheilitis, photophobia, and scrotal dermatitis are the classic remembered signs. Role of Vitamin A in LYCOZEN-GT Vitamin A is a fat-soluble vitamin that is derived from two sources: preformed retinoids and provitamin carotenoids. Retinoids, such as retinal and retinoic acid, are found in animal sources like liver, kidney, eggs, and dairy produce. Carotenoids like beta-carotene (which has the highest vitamin A activity) are found in plants such as dark or yellow vegetables and carrots. Natural retinoids are present in all living organisms, either as preformed vitamin A or as carotenoids, and are required for a vast number of biological processes like vision and cellular growth. A major biologic function of vitamin A (as the metabolite retinal) is in the visual cycle.Research also suggests that vitamin A may reduce the mortality rate from measles, prevent some types of cancer, aid in growth and development, and improve immune function. Recommended daily allowance (RDA) levels for vitamin A oral intake have been established by the U.S. Institute for Medicine of the National Academy of Sciences to prevent deficiencies in vitamin A. At recommended doses, vitamin A is generally considered non-toxic. Excess dosing may lead to acute or chronic toxicity. Vitamin A deficiency is rare in industrialized nations but remains a concern in developing countries, particularly in areas where malnutrition is common. Prolonged deficiency can lead to xerophthalmia (dry eye) and ultimately to night blindness or total blindness, as well as to skin disorders, infections (such as measles), diarrhea, and respiratory disorders. Role of Vitamin C (Ascorbic Acid) in LYCOZEN-GT Vitamin C is required for synthesis of collagen (structural component of blood vessels, tendons, and bone), norepinephrine (neurotransmitter), and carnitine (amino acid involved in energy production); It promotes wound healing; It supports immune function and gum health; and has antioxidant properties. It used to prevent cataracts, macular degeneration, heart disease, stroke, cancer, and colds; improve wound healing and response to stress; reduce bronchial spasms in asthmatics; and prevent lead toxicity. Severe deficiency causes scurvy (bleeding, bruising, hair and tooth loss, joint pain, and swelling), which is rare today. Marginal deficiencies are common among the elderly, alcoholics, and those with cancer, chronic illness, or stress. Symptoms include fatigue, easy bruising, poor wound healing and appetite, anemia, and sore joints. Drugs that deplete vitamin C: oral contraceptives, aspirin, corticosteroids, and furosemide. Large doses of vitamin C (greater than 1,000 mg/day) may reduce the effect of warfarin (blood-thinning drug). The Linus Pauling Institute recommends 400 mg of vitamin C daily, which is higher than the RDA, yet much lower than the UL. Most multivitamin supplements provide 60 mg of vitamin C. Natural and synthetic forms are chemically identical and have the same effects on the body. Mineral salts of ascorbic acid (i.e., calcium ascorbate) are buffered and therefore, less acidic and less likely to cause upset stomach. Role of Niacinamide in LYCOZEN-GT Numerous studies have shown that niacin can lower LDL, triglyceride, and lipoprotein-A levels and raise HDL. Niacin can cause liver inflammation at higher dosages (more than 500 mg daily) Niacin is required for energy metabolism, enzyme reactions, skin and nerve health, and digestion. High doses of nicotinic acid (3 g daily) can lower cholesterol (reduce LDL and triglycerides and increase HDL) and reduce the risk of heart attack and stroke. Deficiency causes pellagra, the symptoms of which are skin rash, diarrhea, dementia, and death. Deficiency may be caused by poor diet, mal absorption diseases, dialysis, and HIV. Drugs that deplete vitamin B3: antibiotics, isoniazid, and 5-Fluorouracil (chemotherapy). High-dose niacin, taken along with statin drugs (i.e., lovastatin), may increase the risk of rhabdomyolysis (muscle degeneration and kidney disease). Most people get adequate niacin from diet and/or a multivitamin; supplements may be recommended for those with high cholesterol. Role of Biotin in LYCOZEN-GT Biotin is a Part of the B-vitamin family; involved in the synthesis of fat, glycogen, and amino acids and www.ijrpp.com 116 Sumit Agarwal et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-1(2) 2012 [103-120] enzyme reactions; required for DNA replication; important for healthy hair and nails. It used therapeutically to strengthen fingernails. Deficiency is rare except in those with hereditary disorders of biotin metabolism, liver disease, and during pregnancy (due to increased needs). It can also occur in those who consume raw egg white for prolonged periods (weeks to years) because a protein found in egg white (avidin) binds biotin and prevents its absorption or in those given intravenous feeding without biotin supplementation. Deficiency symptoms include hair loss; scaly red rash around the eyes, nose, mouth, and genital area; depression; lethargy; hallucination; numbness and tingling of the extremities; and impaired glucose utilization and immune system function. Drugs that deplete biotin: primidone, carbamazepine, phenobarbital, phenytoin, valproic acid, and antibiotics. Most people get adequate biotin from diet and/or supplements. Role of Selenium in LYCOZEN-GT Selenium is an essential component of enzymes that function as antioxidants; involved in detoxification; selenium converts thyroid hormone to its active form; It supports immune function; It enhances the antioxidant activity of vitamin E. Selenium is used to strengthen immune function and prevent infection, to protect against colon and prostate cancer, and to prevent oxidative stress and support immune system function in those with HIV/AIDS. Deficiency of selenium is uncommon, but may occur in those with poor diets, those who live in areas where the soil is depleted in selenium, Crohn’s disease, and mal absorption syndromes (celiac disease). Symptoms disease).Symptoms Symptoms of deficiency of selenium is muscular weakness and wasting, cardio myopathy (inflammation of the heart), pancreatic damage, and impaired immune function. Drugs that deplete selenium are valproic acid and corticosteroids (prednisone). Role of Zinc in LYCOZEN-GT Zinc is involved in numerous enzyme reactions; required for growth and development, immune and neurological function, reproduction and regulation of gene expression stabilize the structure of proteins and cell membranes. Zinc is used to support immune function, reduce severity and duration of the common cold, and delay the progression of macular degeneration. Severe deficiency of Zinc is rare, except in those with a genetic disorder, severe malnutrition or mal absorption, severe burns, or chronic diarrhea. Marginal deficiency of Zinc is common in malnourished people, vegetarians, pregnant women, the elderly, and those with celiac disease, Crohn’s disease, colitis, and sickle-cell anemia. Symptoms of deficiency include impaired growth and development, skin rashes, severe diarrhea, immune system deficiencies, impaired wound healing, poor appetite, impaired taste sensation, night blindness, clouding of the corneas, and behavioral disturbances. Drugs that deplete zinc are diuretics, anticonvulsants, iron supplements, penicillamine, ACE-inhibitor drugs, acid-reducing drugs, and oral contraceptives. Zinc supplements can reduce absorption of antibiotics (tetracycline and quinolones), so separate intake of zinc supplements from these products by two hours. Since the average zinc intake is below the RDA and many conditions and drugs deplete zinc levels, a supplement should be considered. Functional Use: It helps to prevent high blood pressure, hyperhomocysteinemia, atherosclerosis, diabetes, skin disorders, cancer, etc. Safety Details: Methylcobalamin: It is used as a safe agent in the treatment of diabetic neuropathies. EGCG from Green tea extract: is safe & does not cause any toxic effect. Proanthocyanidins (Grape seeds extract): The results of our studies indicate a lack of toxicity and support the use of proanthocyanidin-rich extract from grape seeds for various foods. Lycopene: In humans, there is a very long history of use with respect to dietary exposure, and even in the case of very high exposures from dietary sources, there is no indication of any significant adverse effects. Vitamins and Minerals: The results of our studies indicate a lack of toxicity and support the use of Vitamins and Minerals in above quantity & dosage in this formulation. Dosage and Administration: 1-2 tablets daily with meals or as directed by the health care practitioner. www.ijrpp.com 117 Sumit Agarwal et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-1(2) 2012 [103-120] Storage: Store in a cool, dry place below temperature 25 oC, protected from light. Keep out of reach of children Presentation: 30’s in Bottle pack and 2x15’s Alu/PVC blister pack. References 1. 2. 3. 4. 5. 6. 7. 8. 9. Okuda K, Yashima K, Kitazaki T, Takara I. Intestinal absorption and concurrent chemical changes of methylcobalamin. J Lab Clin Med 1973; 81:557-567. Jalaludin MA. Methylcobalamin treatment of Bell’s palsy. Methods Find Exp Clin Pharmacol 1995; 17:539-544. Nishizawa Y, Yamamoto T, Terada N, et al. Effects of methylcobalamin on the proliferation of androgen-sensitive or estrogen-sensitive malignant cells in culture and in vivo. Int J Vitam Nutr Res 1997;67:164-170. Shimizu N, Hamazoe R, Kanayama H, et al. Experimental study of antitumor effect of methyl-B12. Oncology 1987;44:169173. Tsao CS, Myashita K. Influence of cobalamin on the survival of mice bearing ascites tumor. Pathology 1993;61:104108. Miasishcheva NV, Gerasimova GK, Il’ina NS, Sof’ina ZP. Effect of methylcobalamin on methotrexate transport in normal and tumorous tissues. Biull Eksp Biol Med 1985;99:736-738. [Article in Russian] Yaqub BA, Siddique A, Sulimani R. Effects of methylcobalamin on diabetic neuropathy. Clin Neurol Neurosurg 1992; 94:105-111. Kikuchi M, Kashii S, Honda Y, et al. Protective effects of methylcobalamin, a vitamin B12 analog, against glutamateinduced neurotoxicity in retinal cell culture. Invest Ophthalmol Vis Sci 1997;38:848-854. Iwasaki T, Kurimoto S. Effect of methylcobalamin in accommodative dysfunction of eye by visual load. Sangyo Ika Daigaku Zasshi 1987;9:127-132. www.ijrpp.com 10. Yoshioka K, Tanaka K. Effect of methylcobalamin on diabetic autonomic neuropathy as assessed by power spectral analysis of heart rate variations. Horm Metab Res 1995;27:43-44. 11. Weinberg JB, Sauls DL, Misukonis MA, Shugars DC. Inhibition of productive human immunodeficiency virus-1 infection by cobalamins. Blood 1995; 86:1281-1287. 12. Araki A, Sako Y, Ito H. Plasma homocysteine concentrations in Japanese patients with non-insulin-dependent diabetes mellitus: effect of parenteral methylcobalamin treatment. Atherosclerosis 1993; 103:149-157. 13. Moriyama H, Nakamura K, Sanda N, et al. Studies on the usefulness of a long-term, high-dose treatment of methylcobalamin in patients with oligozoospermia. Hinyokika Kiyo 1987;33:151-156. 14. Isoyama R, Kawai S, Shimizu Y, et al. Clinical experience with methylcobalamin (CH3-B12) for male infertility. Hinyokika Kiyo 1984; 30:581-586. 15. Uchiyama M, Mayer G, Okawa M, MeierEwert K. Effects of vitamin B12 on human circadian body temperature rhythm. Neurosci Lett 1995;192:1-4. 16. Tomoda A, Miike T, Matsukura M. Circadian rhythm abnormalities in adrenoleukodystrophy and methyl B12 treatment. Brain Dev 1995; 17:428-431. 17. Yamada N. Treatment of recurrent hypersomnia with methylcobalamin (vitamin B12): a case report. Psychiatry Clin Neurosci 1995; 49:305-307. 18. Ohta T, Ando K, Iwata T, et al. Treatment of persistent sleep-wake schedule disorders in adolescents with methylcobalamin (vitamin B12). Sleep 1991; 14:414-418. 19. Mayer G, Kroger M, Meier-Ewert K. Effects of vitamin B12 on performance and circadian rhythm in normal subjects. Neuropsychopharmacology 1996;15:456464. 20. Hashimoto S, Kohsaka M, Morita N, et al. Vitamin B12 enhances the phase-response of circadian melatonin rhythm to a single bright light exposure in humans. Neurosci Lett 1996; 220:129-132. 118 Sumit Agarwal et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-1(2) 2012 [103-120] 21. Arab L, Steck S. Lycopene and cardiovascular disease. Am J Clin Nutr 2000;71:1691S- 1695S; discussion 1696S1697S. 22. Gartner C, Stahl W, Sies H. Lycopene is more bioavailable from tomato paste than from fresh tomatoes. Am J Clin Nutr 1997; 66:116-122. 23. Johnson EJ. The role of carotenoids in human health. Nutr Clin Care 2002; 5:5665. 24. Singh DK, Lippman SM. Cancer chemoprevention. Part 1: Retinoids and carotenoids and other classic antioxidants. Oncology (Huntingt) 1998;12:1643-1653, 1657-1658; discussion 1659-1660. 25. Rao AV, Agarwal S. Role of antioxidant lycopene in cancer and heart disease. J Am Coll Nutr 2000;19:563-569. 26. Heber D, Lu QY. Overview of mechanisms of action of lycopene. Exp Biol Med (Maywood) 2002;227:920-923. 27. Britton G. Structure and properties of carotenoids in relation to function. FASEB J 1995;9:1551-1558. 28. Rosati C, Aquilani R, Dharmapuri S, et al. Metabolic engineering of beta-carotene and lycopene content in tomato fruit. Plant J 2000;24:413-419. 29. Gerster H. The potential role of lycopene for human health. J Am Coll Nutr 1997; 16:109- 126. 30. Boileau TW, Boileau AC, Erdman JW Jr. Bioavailability of the all-trans and cisisomers of lycopene. Exp Biol Med (Maywood) 2002; 227:914-919. 31. Stahl W, Schwarz W, Sundquist AR, Sies H. Cis-trans isomers of lycopene and beta carotene in human serum and tissues. Arch Biochem Biophys 1992; 294:173-177. 32. Agarwal S, Rao AV. Tomato lycopene and its role in human health and chronic diseases. CMAJ 2000; 163:739-744. 33. Porrini M, Riso P. Lymphocyte lycopene concentration and DNA protection from oxidative damage is increased in women after a short period of tomato consumption. J Nutr 2000; 130:189-192. 34. Bohm F, Tinkler JH, Truscott TG. Carotenoids protect against cell membrane damage by the nitrogen dioxide radical. Nat Med 1995;1:98-99. www.ijrpp.com 35. Fuhrman B, Elis A, Aviram M. Hypocholesterolemic effect of lycopene and beta-carotene is related to suppression of cholesterol synthesis and augmentation of LDL receptor activity in macrophages. Biochem Biophys Res Commun 1997;233:658-662. 36. Kohlmeier L, Kark JD, Gomez-Gracia E, et al. Lycopene and myocardial infarction risk in the EURAMIC study. Am J Epidemiol 1997;146:618-626. 37. Kristenson M, Zieden B, Kucinskiene Z, et al. Antioxidant state and mortality from coronary heart disease in Lithuanian and Swedish men: concomitant cross-sectional study of men aged 50. BMJ 1997;314:629633. 38. Rissanen TH, Voutilainen S, Nyyssonen K, et al. Low serum lycopene concentration is associated with an excess incidence of acute coronary events and stroke: the Kuopio Ischaemic Heart Disease Risk Factor Study. Br J Nutr 2001;85:749-754. 39. Hadley CW, Clinton SK, Schwartz SJ. The consumption of processed tomato products enhances plasma lycopene concentrations in association with a reduced lipoprotein sensitivity to oxidative damage. J Nutr 2003; 133:727- 732. 40. Rissanen TH, Voutilainen S, Nyyssonen K, et al. Serum lycopene concentrations and carotid atherosclerosis: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr 2003; 77:133-138. 41. Rissanen T, Voutilainen S, Nyyssonen K, et al. Low plasma lycopene concentration is associated with increased intimamediathickness of the carotid artery wall. Arterioscler Thromb Vasc Biol 2000;20:2677- 2681. 42. Di Mascio P, Kaiser S, Sies H. Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch Biochem Biophys 1989;274:532-538. 43. Levy J, Bosin E, Feldman B, et al. Lycopene is a more potent inhibitor of human cancer cell proliferation than either alpha-carotene or beta-carotene. Nutr Cancer 1995;24:257-266. 44. Amir H, Karas M, Giat J, et al. Lycopene and 1, 25-dihydroxyvitamin D3 cooperate 119 Sumit Agarwal et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-1(2) 2012 [103-120] 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. in the inhibition of cell cycle progression and induction of differentiation in HL-60 leukemic cells. Nutr Cancer 1999; 33:105112. Ito Y, Suzuki K, Suzuki S, et al. Serum antioxidants and subsequent mortality rates of all causes or cancer among rural Japanese inhabitants. Int J Vitam Nutr Res 2002;72:237- 250. Sharoni Y, Giron E, Rise M, Levy J. Effects of lycopene-enriched tomato oleoresin on 7,12dimethylbenz[a]anthracene-induced rat mammary tumors. Cancer Detect Prev 1997;21:118123. Pool-Zobel BL, Bub A, Muller H, et al. Consumption of vegetables reduces genetic damage in humans: first results of a humanintervention trial with carotenoidrich foods. Carcinogenesis 1997;18:18471850. Bhuvaneswari V, Velmurugan B, Nagini S. Induction of glutathione-dependent hepatic biotransformation enzymes by lycopene in the hamster cheek pouch carcinogenesis model. J Biochem Mol Biol Biophys 2002;6:257-260. Giovannucci E. Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J Natl Cancer Inst 1999; 91:317-331. Pathak SK, Sharma RA, Mellon JK. Chemoprevention of prostate cancer by diet derived antioxidant agents and hormonal manipulation (Review). Int J Oncol 2003;22:5-13. Mucci LA, Tamimi R, Lagiou P, et al. Are dietary influences on the risk of prostate cancer mediated through the insulin-like growth factor system? BJU Int 2001; 87:814- 820. Gann PH, Ma J, Giovannucci E, et al. Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res 1999; 59:1225-1230. Norrish AE, Jackson RT, Sharpe SJ, Skeaff CM. Prostate cancer and dietary carotenoids. Am J Epidemiol 2000; 151:119-123. Giovannucci E, Rimm EB, Liu Y, et al. A prospective study of tomato products, www.ijrpp.com 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. lycopene, and prostate cancer risk. J Natl Cancer Inst 2002; 94:391-398. Lu QY, Hung JC, Heber D, et al. Inverse associations between plasma lycopene and other carotenoids and prostate cancer. Cancer Epidemiol Biomarkers Prev 2001;10:749-756. Stattin P, Bylund A, Rinaldi S, et al. Plasma insulin-like growth factor-I, insulin-like growth factor-binding proteins, and prostate cancer risk: a prospective study. J Natl Cancer Inst 2000;92:1910-1917. Willis MS, Wians FH. The role of nutrition in preventing prostate cancer: a review of the proposed mechanism of action of various dietary substances. Clin Chim Acta 2003; 330:57-83. Kucuk O, Sarkar FH, Sakr W, et al. Phase II randomized clinical trial of lycopene supplementation before radical Cancer Epidemiol prostatectomy. Biomarkers Prev 2001;10:861-868. Zhang S, Tang G, Russell RM, et al. Measurement of retinoids and carotenoids in breast adipose tissue and a comparison of concentrations in breast cancer cases and control subjects. Am J Clin Nutr 1997; 66:626-632. Levi F, Pasche C, Lucchini F, La Vecchia C. Dietary intake of selected micronutrients and breast-cancer risk. Int J Cancer 2001;91:260-263. Dorgan JF, Sowell A, Swanson CA, et al. Relationships of serum carotenoids, retinal, alpha-tocopherol and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States). Cancer Causes Control 1998;9:89-97. Cramer DW, Kuper H, Harlow BL, TitusErnstoff L. Carotenoids, antioxidants and ovarian cancer risk in pre- and postmenopausal women. Int J Cancer 2001;94:128-134. Goodman MT, Kiviat N, McDuffie K, et al. The association of plasma micronutrients with the risk of cervical dysplasia in Hawaii. Cancer Epidemiol Biomarkers Prev 1998;7:537-544. Kanetsky PA, Gammon MD, Mandelblatt J, et al. Dietary intake and blood levels of 120 Sumit Agarwal et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-1(2) 2012 [103-120] 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. lycopene: association with cervical dysplasia among non-Hispanic, black women. Nutr Cancer 1998; 31:31-40. Greenwald P, Milner JA, Anderson DE, McDonald SS. Micronutrients in cancer chemoprevention. Cancer Metastasis Rev 2002;21:217-230. Ford ES, Will JC, Bowman BA, Narayan KM. Diabetes mellitus and serum carotenoids findings from the Third National Health and Nutrition Examination Survey. Am J Epidemiol 1999;149:168-176. Suzuki K, Ito Y, Nakamura S, et al. Relationship between serum carotenoids and hyperglycemia: a population-based cross-sectional study. J Epidemiol 2002;12:357-366. Gale CR, Hall NF, Phillips DI, Martyn CN. Plasma antioxidant vitamins and carotenoids and age-related cataract. Ophthalmology 2001;108:1992-1998. Gross MD, Snowdon DA. Plasma lycopene and longevity: findings from the Nun Study. FASEB J 2001;15:A400. Metzger A, Mukasa G, Shankar AH, et al. Antioxidant status and acute malaria in children in Kampala, Uganda. Am J Trop Med Hyg 2001;65:115-119. Franceschi S, Bidoli E, La Vecchia C, et al. Tomatoes and risk of digestive-tract cancers. Int J Cancer 1994;59:181-184. De Stefani E, Oreggia F, Boffetta P, et al. Tomatoes, tomato-rich foods, lycopene and cancer of the upper aerodigestive tract: a case control in Uraguay. Oral Oncol 2000;36:47-53. Watzl B, Bub A, Brandstetter BR, Rechkemmer G. Modulation of human Tlymphocyte functions by the consumption of carotenoid-rich vegetables. Br J Nutr 1999;82:383-389. Mecocci P, Polidori MC, Cherubini A, et al. Lymphocyte oxidative DNA damage and plasma antioxidants in Alzheimer disease. Arch Neurol 2002;59:794-798. Palan PR, Mikhail MS, Romney SL. Placental and serum levels of carotenoids Obstet Gynecol in preeclampsia. 2001;98:459-462. Polidori MC, Mecocci P. Plasma susceptibility to free radical-induced www.ijrpp.com 77. 78. 79. 80. 81. 82. 83. 84. 85. antioxidant consumption and lipid peroxidation is increased in very old subjects with Alzheimer disease. J Alzheimers Dis 2002;4:517-522. Elinder LS, Hadell K, Johansson J, et al. Probucol treatment decreases serum concentrations of diet-derived antioxidants. Arteriosclerosis Thromb Vasc Biol 1995;15:1057-1063. Weststrate JA, Meijer GW. Plant sterol enriched margarines and reduction of plasma total- and LDL-cholesterol concentrations in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr 1998;52:334343. Riedl J, Linseisen J, Hoffmann J, Wolfram G. Some dietary fibers reduce the absorption of carotenoids in women. J Nutr 1999;129:2170- 2176. Johnson EJ, Qin J, Krinsky NI, Russell RM. Ingestion by men of a combined dose of betacarotene and lycopene does not affect the absorption of beta-carotene but improves that of lycopene. J Nutr 1997;127:1833-1837. Clark RM, Yao L, She L, Furr HC. A comparison of lycopene and astaxanthin absorption from corn oil and olive oil emulsions. Lipids 2000;35:803-806. Experimental Toxicology and Ecology, BASF Aktiengesellschaft, Product SafetyRegulations, Toxicology and Ecology, Ludwigshafen/ Rhein, Germany. Giovannucci E, Ascherio A, Rimm EB, et al. Intake of carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst 1995; 87:1767-1776. Michaud DS, Feskanich D, Rimm EB, et al. Intake of specific carotenoids and risk of lung cancer in 2 prospective US cohorts. Am J ClinNutr 2000; 72:990-997. Neuman I, Nahum H, Ben-Amotz A. Reductionof exercise-induced asthma oxidative stress by lycopene, a natural antioxidant. Allergy 2000; 55:1184-1189.