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Dramatic increase in the numbers of function- ally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopula- tions identified olanzapine 10mg overnight delivery medications 7 rights. Altered peptide ligand vaccination with Flt3 lig- and expanded dendritic cells for tumor immunotherapy purchase 2.5 mg olanzapine otc medicine 10 day 2 times a day chart. A recombinant Listeria mono- cytogenes vaccine expressing a model tumor antigen protects mice against lethal tumor 116 Kundu-Raychaudhuri and Engleman challenge and causes regression of established tumors. Immunoregulation of murine myeloma cell growth and differentiation: a monoclonal model of B cell differ- entiation. Monoclonal anti- idiotype antibodies against the murine B cell lymphoma 38C13: characterization and use as probes for the biology of the tumor in vivo and in vitro. Systemic administration of interleukin 2 enhances the therapeutic efficacy of dendritic cell-based tumor vaccines. The molecu- lar weight of most cytokines ranges between 6 and 60 kD, and these proteins can be glycosylated or myristylated. Although their primary role is in the host-defense response, they can stimulate the growth and differentiation of a number of target cells, e. Because of the breadth of their activity, the cytokines have been characterized by investigators in different disciplines, with a resul- tant variety of names. The intent of this chapter is to provide some background on the biology of cytokines and to describe their role in the earlier stages of the immune response to infectious agents prior to the immune system s commitment to either a cellular or humoral response. Knowledge of their role in infections should help us understand the rationale for use of cytokines or cytokine antagonists as therapy for the specific infections dis- cussed in subsequent chapters. This grouping is based on some gross structural similarities in the receptors for the cytokines within the two groups. The last section provides a sketch of the activity of cytokines in the immune response to infections that are the focus of many of therapeutic interventions intended to modulate cytokine activity. Depending on the type of stimulation, a given cell can pro- duce different cytokines. Induction of cytokine production with measurable tissue or serum concentrations occurs rapidly when cells are stimulated by antigen or bacterial products. Because of the constant surveillance by the immune system, some unde- tectable to low concentrations of cytokine production is probably ongoing in order to maintain routine maintenance of immunity. They can affect both the cells that secrete them (autocrine signals) or cells in the nearby environment (paracrine signals). Cytokines function as a network in which produc- tion of one cytokine can affect the production or activity of several other cytokines, either positively or negatively. This cytokine network can become quite complex, not only because of the number of target cells whose function is altered by a given cytokine, but also because of the redundancy in the network, with several cytokines causing a given effect. The number of cytokines and their roles in different disease processes as identified to date continue to increase. There have been a number of reviews of the clinical role of individual cytokines (1 4). To give some idea of the number of cytokines identi- fied,18 interleukins, 20 different growth factors, and 4 types of interferons have been described. Table 1 presents characteristics of the interleukins, and the other cytokines that play a major role in the body s response to infection. Depending on the type of response to an infectious agent that is being described, cytokines are characterized as either pro-inflammatory or anti-inflammatory or described according to their production by activated T-cell subsets, Th1/Th2. Neither method classifies the cytokines distinctly since some cytokines could be considered either anti-inflammatory or pro-inflammatory in different disease settings. Cytokine Receptors The effect of a cytokine on the target cell follows the binding of its ligand to high- affinity receptors present on cells throughout the body. The type of signal transduced can depend on the type of cell and its state of development, i. The complexity of cytokine activity following receptor linkage is not only caused by the variation in the type of signal sent but also occurs because multiple cytokines can transduce the same biologic response. In addition to membrane-bound receptors, soluble receptors with similar ligand binding domains have been described for several cytokines, e. These soluble receptors can function as cytokine inhibitors whereby, binding of the Cytokines, Cytokine Antagonists, and Growth Factors 119 cytokine to its soluble receptor prevents the cytokine from effecting target cell func- tion. An analogous approach toward inhibiting cytokine effect by ligand binding may be used by some viruses that code for receptor-like molecules, e. Receptor Families Cytokine receptors are membrane glycoproteins with a single transmembrane domain and an external amino terminus. The functional receptor can consist of two or more subunits, and these subunits can be shared among different cytokines. This sharing of the receptor subunits among different cytokines may partially explain some of the func- tional redundancy and costimulation of their production and activity. Most cytokine receptors are members of the cytokine receptor superfamily which is characterized by a conserved amino acid motif in the extracellular portion and in a region proximal to the membrane (9, 10). This superfamily can be divided into three subfamilies according to a shared subunit, i. The receptors in the chain subfamily consist of three subunits (,, ): the, and subunits are members of the superfamily and are constitutively expressed on T-cells. Receptors in this subfamily have two subunits, with the chain distinct for each receptor. Both the and chains are members of the cytokine receptor superfamily, and signaling is mediated through lig- and interactions of the cytoplasmic regions on the shared chain. Formation of homodimers and heterodimers with gp 130 mediates signal transduction by these receptors. This dimerization (or oligomerization in cytokine receptors with more than two chains) increases the affinity of the dimers cytoplasmic domain that is proximal to the membrane to bind two Jaks. Both the Jaks and the cytoplasmic region of the receptor chain become phosphorylated simultaneously. This phosphorylation subsequently becomes a catalyst for the binding and phosphoryla- tion of two latent cytoplasmic transcription factors called Stats, i. The actual number of Stats is uncertain, but at least six have been characterized. Given the number of Jaks and Stats, it is understandable that different cytokine recep- tors associate with different Jaks, which then catalyze the binding and phosphorylation of different Stats (16). To add to the complexity, Stats can be phosphorylated by kinases other than Jaks, e. They share a high basic nature and can bind heparin through heparin binding domains. Chemokines are produced by nearly every cell type in response to inflammatory sig- nals, particularly signals that activate interactions between leukocytes and endothelial cells. Chemokines range between 68 to 100 amino acids in length and are defined by conserved motifs containing either two or four cysteine residues that form disulfide bonds in the protein tertiary structure. Genes encoding members of each group appear to cluster on the same chromosomes, i. The responsiveness to chemokine stimulation depends not only on the specific type of leukocytes but also on the condi- tions of stimulation, e.
The side antibiotics discount 10 mg olanzapine otc medications herpes, their mechanisms of action order olanzapine overnight medications for high blood pressure, and their major chain attached to the -lactam ring (R1) determines toxicities. The differences between the specic antibiotics many of the antibacterial characteristics of the specic in each class can be subtle, often requiring the expertise of antibiotic, and the structure of the side chain attached an infectious disease specialist to design the optimal to the dihydrothiazine ring (R2) determines the phar- anti-infective regimen. The specic indications for each wall transpeptidase and transglycolase causes rapid anti-infective are briey covered here. Inhibition of this transpeptidase discussion of specic regimens is included in the later prevents the cross-linking of the cell wall peptido- chapters that cover infections of specic anatomic sites. About -Lactam Antibiotics The activity of all -lactam antibiotics requires active bacterial growth and active cell wall synthesis. Penicillins, cephalosporins, and carbapenems killed, but those in an active log phase of growth are are all b-lactam antibiotics: quickly lysed. Hypersensitivity reactions are the most common side effects associated with the -lactam antibiotics. Penicillins are the agents that most commonly cause allergic reactions, at rates ranging from 0. Ceftriaxone is excreted in high con- allergies also prove to be allergic to cephalosporins and centrations in the bile and can crystallize, causing biliary carbapenems. Cefepime has been associated with antigens increase the probability of a host immune encephalopathy and myoclonus in elderly individuals. In combi- IgE-mediated hypersensitivity reaction that can result nation with aminoglycosides, cephalosporins demon- in anaphylaxis and urticaria. Because of the potential dan- Penicillins ger, patients with a history of an immediate hypersen- sitivity reaction to penicillin should never be given Tables 1. High levels of immunoglobulin G anti- Penicillins vary in their spectrum of activity. Natural penicillin antibodies can cause serum sickness, a syn- penicillins have a narrow spectrum. As a consequence, the penicillins must be dosed frequently, and dosing must be adjusted in patients with renal dysfunction. Allergic reactions are most common toxicity, and this agent can be used to sustain higher serum levels. Nephrotoxicity sometimes occurs when now frequent ( 30%)]; infections caused by cephalosporins are given in combination with mouth flora; Clostridium perfringens or spiro- aminoglycosides. Depending on the specic drug, penicillins can be given treatment of infections caused by mouth ora. Some penicillins have G is also primarily recommended for Clostridium perfrin- been formulated to withstand the acidity of the stomach gens, C. Penicillins are well distributed in multocida, and spirochetes including syphilis and Lep- the body and are able to penetrate most inamed body tospira. However, in many areas of the ence of inammation, therapeutic levels are generally United States, more than 30% of strains are moderately achievable in the cerebrospinal uid. In these Spectrum of Activity and Treatment Recommenda- cases, ceftriaxone, cefotaxime, or high-dose penicillin tions Pencillin G (Table 1. Capnocytophaga canimorsus, clavulanate adds Citrobacter freundii Fusobacterium nucleatum, susceptibility to: Serratia spp. Infections with high- effective against Shigella exneri and sensitive strains of level penicillin-resistant S. Amoxicillin can be used to 2 g/mL) require treatment with vancomycin or another treat otitis media and air sinus infections. However, the superiority of Amoxicillin has excellent oral absorption: 75% as com- amoxicillin clavulanate over amoxicillin for middle ear pared with 40% for ampicillin. As observed with the natural penicillins, the half-life cillins have the same half-life as penicillin (30 minutes) is short (1 hour) and these drugs are primarily excreted and require dosing at 4-hour intervals or constant unmodied in the urine. Unlike the natural Spectrum of Activity and Treatment Recommenda- penicillins, these agents are cleared hepatically, and tions The spectrum of activity in the aminopenicillins doses of nafcillin and oxacillin usually do not need to is slightly broader than in the natural penicillins be adjusted for renal dysfunction. Intravenous ampicillin is recommended for hepatic excretion of nafcillin means that the dose treatment of Listeri monocytogenes, sensitive enterococci, needs to be adjusted in patients with significant Proteus mirabilis, and non -lactamase-producing hepatic dysfunction. These oral agents are used primarily for mild soft-tissue infections or to complete therapy of a resolv- About the Aminopenicillins ing cellulitis. Short half-life (1 hour), and clearance similar to Pharmacokinetics The half-lives of ticarcillin and natural penicillins. Parenteral ampicillin indicated for Listeria been discontinued in favor of ticarcillin clavulanate and monocytogenes, sensitive enterococci, Proteus piperacillin tazobactam. Whenever possi- of piperacillin tazobactam should be increased from ble, vancomycin should be avoided. In combination with an the initial drug of choice for otitis media and aminoglycoside, piperacillin tazobactam often demon- bacterial sinusitis. Amoxicillin clavulanate has improved cover- administration of the piperacillin tazobactam needs to age of Staphylococcus, H. Increased efcacy Spectrum of Activity and Treatment Recommenda- compared with amoxicillin is not proven in tions Ticarcillin and piperacillin are able to resist otitis media. However, covers amoxicillin- -lactamases produced by Pseudomonas, Enterobacter, resistant H. These antibiotics can be used for empiric coverage of moderate to severe intra-abdominal infections. They efficiently, and so dose adjustment is usually not have been combined with a -lactamase inhibitor (clavu- required in liver disease. Spectrum of Activity and Treatment Recommenda- These agents are reasonable alternatives to nafcillin tions The synthetic modication of penicillin to ren- or oxacillin when gram-negative coverage is also der it resistant to the -lactamases produced by S. Because oral preparations result in consid- About Carboxypenicillins and Ureidopenicillins erably lower serum concentration levels, cloxacillin or 1. Ticarcillin clavulanate and piperacillin tazobac- tam have excellent broad-spectrum coverage, including methicillin-sensitive Staphylococcus 1. Primarily indicated for methicillin-sensitive hospital aspiration pneumonia, and mixed soft- Staphylococcus aureus and cellulitis. They have been used for skin and bone infec- tions thought to be caused by a combination of gram- Pharmacokinetics Cefazolin, the preferred parenteral negative and gram-positive organisms. The rst-generation cephalosporins Cephalosporins penetrate most body cavities, but they fail to cross the Tables 1. First- generation cephalosporins are predominantly effective against gram-positive cocci. The third-genera- About First-Generation Cephalosporins tion cephalosporins demonstrate even greater activity against gram-negative bacilli, but only limited activity 1. Useful for treating soft-tissue infections and for urally leads to the assumption that newer, later- surgical prophylaxis. Can often be used as an generation cephalosporins are better than the older alternative to oxacillin or nafcillin. The half-lives of cephalexin and cephradine are the newer penicillins, second-generation cephalosporins short, requiring frequent administration. Because cefoxitin and cefotetan demonstrate increased Spectrum of Activity and Treatment Recommenda- anaerobic coverage, including many strains of B. They intra-abdominal infections and mixed aerobic anaerobic are active against oral cavity anaerobes, but are soft-tissue infections, including diabetic foot infections.
Elevated cho- lesterol and lower levels of high-density lipoproteins are associated with stroke in aging and lipid-lowering drugs reduce the incidence of myocardial infarction [6 order olanzapine 5 mg online medicine urology, 237] best purchase for olanzapine symptoms ketosis. While major trials have indicated that statins are well tolerated in the elderly, the association between hyperlipidemia and stroke is not strong in this group. However, this may also result from other protective actions of statins on the endothelium, including anti-oxidant, anti-inammatory effects and stabilization of plaques . After age 65, blood lipid levels are less prominent risk factors for cardiovascular diseases and by age 75, blood lipids have little predictive value . In fact, specic lipids may be associ- ated with longevity in the elderly population, for example sphingomyelin in women [103, 238]. Thus among the elderly the risk imposed by hypertension is likely more severe than hyperlipidemia. In current smokers this risk is elevated irrespective of the pack-years of smoking exposure . Remarkably, prior to 75 years of age, hypertension and diabetes are much less important risk factors as compared to heavy (>2 drinks/day) alcohol consumption at midlife [129 ]. Altered glucose metabolism is not necessarily a component of aging, and may represent a sub population that is generally at higher risk for other adverse geriatric processes . Some support for this idea comes from the fact that vascular disease increases before the elevation of glucose levels and more than 25 % of newly diagnosed diabetic patients already have cardiovascular disease [281 ]. The convergence of comorbid disease and sociocultural stressors during aging as risk factors for stroke ts well with the concept of an allostatic load . Allostatic load refers to the cumulative lifespan exposure to adverse circumstances, The Impact of Aging on Ischemic Stroke 167 and integrates with the 3-hit hypothesis where disease susceptibility is thought to result from genetic predisposition, early life events and later-life events . In contrast, age was an inde- pendent predictor of hemorrhage in the European Acute Stroke Study . In a small retrospective study of 22 stroke patients who were 90 years or older, most patients had poor outcomes at 30 days post stroke and many died [180 ]. While several reasons may explain why the preclinical promise of these drugs was not borne out in clinical trials, an important consideration is the lack of aging animals used in the preclinical studies . Most preclinical studies used healthy young animals as test subjects, which clearly does not approximate the human population . Preclinical studies with these drugs routinely failed to use clinically relevant animal models, such as the aged and those with comorbid diseases. A comprehen- sive review of preclinical studies that lay the groundwork for these failed drugs found that virtually all studies (43/45) used only younger animals . The use of cell therapies and grafts in stroke has focused on adult stem cells or induced pluripotent stem cells [23, 110]. Both human and animal stroke brains show signs of proliferation, including the aging human . Intra-parenchymal [158 ] and intra-arterial  delivery of bone marrow derived mesenchymal cells is reported to improve neurological outcomes and functional performance when The Impact of Aging on Ischemic Stroke 169 delivered post stroke. Interestingly, grafts of human umbilical tissue-derived cells have also been shown effective for neural recovery in aged animals . Environmental enrichment appears to improve neurologic function in both young and old animals , and further enhances functional recovery when combined with stem cell therapy . Although the mechanism of action is not well under- stood, several end points are improved including release of trophic factors, anti- inammatory effects, angiogenesis and cell survival (reviewed in [47 ]). Angiogenesis is considered critical to long term stroke recovery , and the low rate of vessel formation in the elderly is thought to be associated with low rates of functional recovery. Formation of new blood vessels is a desired therapeutic out- come, and ischemic events provide important signals for new vessel formation, such as secretion of angiogenic and matrix remodeling factors. These studies, while promising, underscore the need for preclinical studies to mimic clinically valid aspects of the patient population, including old age and comorbidities. Age differences in stroke outcomes in preclinical models tend to mirror the ndings of the clinical studies. In a study of neonates (10 day), and adult animals at 2 and 6 months, functional recovery was best in the neonate and was impaired in the older age groups, suggesting that the plastic environment of the immature brain is better suited for stroke recovery . Similarly, post stroke epi- lepsy, a common complication in this disease, was more common in older animals 170 F. Sex differences also modulate stroke outcome in the context of aging in animal models. Adult females have a smaller infarct and better cerebral blood ow than age-matched males both in normoglycemic  and diabetic  animals. However, although female mice sustain a much smaller infarct , they showed signi- cantly more mortality and poorer stroke outcomes as compared to older males. These sex differences prompted several studies addressing the contribution of hor- mones to stroke outcomes, specically estrogen. Using natural variations in circu- lating estrogen levels, Liao and colleagues  showed that the extent of ischemic damage was inversely related to circulating levels of estrogen . In fact, replace- ment with 17 estradiol [77, 234, 243] and its inactive stereoisomer 17 estradiol  as well as the conjugate equine estrogen preparation  all reduce infarct volume in female animals. Exogenous estrogen replacement is neuroprotective when given prior  or subsequent to the injury [167, 286]. However, it should be noted that all these studies were done in young female animals that were ovariecto- mized to mimic a surgical menopause. In contrast, as mentioned earlier, elevated levels of sex hormones may have a negative effect on stroke in the aged. Hormone treatment in studies using older female animals does not reliably result in stroke neuroprotection and may in fact exacerbate stroke recovery. Besides gonadal ste- roids, other endocrine systems are also affected by aging and disease, and it has been proposed that these changes may impact the overall effectiveness of estrogen in an aging model . Cell death occurs not only in those areas directly affected by the ischemia, but also in neighboring cells as a result of an ischemic cascade initiated in proximal cells. A feed forward process then ensues, whereby calcium-induced release of the excitatory amino acid glutamate, further increases Ca+2 accumulation. Consequently, stimulation of calcium dependent enzymes initi- ate a wide variety of cellular reactions resulting in free radical formation and oxida- tive stress. Death of ischemic neurons causes toxicity in the local microenvironment, and activates local immune and inammatory cells, thus amplifying the possibility of cell death (reviewed in ). At the cellular level, aged animals are able to mount a cytoprotective response to stroke but the timing of proliferation and activation of key support cells such as glia and endothelial cells is accelerated, resulting in rapid infarct development and poor prognosis in aged animals . Endothelial cells, astrocytes and microglia are the major support cells of the brain and play a critical role in preserving neurons follow- ing ischemic injury. A critical way in which these cells interact is the neurovascular unit, where blood brain barrier components (endothelial cells, astrocytes and peri- cytes) form a functional unit with neighboring neurons.
From 18 to 22% of the population of 35 to 64 years were more 2 mm deep in the probing of the periodontal bags in 11 to 13% of tooth surfaces 7.5mg olanzapine amex medications for fibromyalgia. Periodontitis occurs when tissue destruction due to the direct effect of bacterial toxins and removal prod ucts generic 2.5 mg olanzapine overnight delivery medicine 93 2264, in addition, the effects caused indirectly by the harmful organic defense mechanisms. Bacteria causes tissue destruction with its deletion, this is a feature of marginal periodontitis products. The hydrolysis of the connective tis sue associated with the inflammation is due to the reactive oxygen species and the elastase/ lysosomic-like enzymes. Prostaglandin E, Interleukin 1-/ J and the lipopolysaccharide activates osteoclasts and induce a resorption of alveolar bone. Cellular and humoral components of the immune system, mainly involved in the periodontal immune response are leukocytes, immunoglobulins, complement system and lysozyme. If the immune defenses are working properly, the periodontium is pro tected from the harmful effect of pathogenic substances secreted by the microorganisms. The immunocompetent host is able to defend itself against microbial attacks that occur every day. We can say that the periodontal inflammation is a local reaction to a tissue injury whose purpose is the destruction of the causal factor, dilution or its encapsulation. The human immune system can be classified according to their function within the perio dontium, follows: Secretory system Neutrophils, antibodies and complement system Leukocytes and macrophages Immune regulation system. The system formed by neutrophils, antibodies and complement is crucial to the immune de fense against periodontal infections. When functional defects of neutrophils occur, it increas es the frequency of serious marginal periodontitis . Oxidative stress A phenomenon that occurs within the periodontal disease is called oxidative stress. A fundamental characteristic of the reactions of free radicals is that act of chain reactions, where a radical reaction generates another consecutively. The tetravalent reduction of oxygen to produce water through the electron transport chain in mitochondria is relatively safe. The most important function is serving as a10 suppressor of primary free radicals, located in the membranes in the vicinity of unsaturated lipid chains. There are less established functions that include the oxidation/reduction of the control of the origin and transmission of signals in cells that induce the expression of gender, the control of membrane channels, the structure and solubility in lipids . The living organism has adapted to an existence under a continuous output of radi cal free flow. Between the different antioxidant defense mechanism adaptation mechanism is of great importance. Antioxidants are "those substances that when they are present in lower concentrations compared to the substrate of an oxidizable, significantly delay or in hibit the oxidation of the substrate". The various possible mechanisms that antioxidants can offer protection against damage from free radicals are: The prevention of the formation of radical free. Antioxidant defense system is very dynamic and responsive to any disturbance that occurs in the body redox balance. Antioxidants can be regulated and neutralize the formation of radical free that can occur due to oxidative stress, such as the factor transcription factors Ac tivator protein 1 and nuclear-kb are redox sensitive. The presence of inflammatory infiltrate is a constant feature in periodontal disease. It is known that these cells release lots of free radicals; it is suspected that these metabolites are involved in the pathogenesis of the disease. The presence of a dense inflammatory infiltrate in periodontal disease leads to the suspicion that the relationship of periodontal leukocyte- tissue has a double aspect. This increase is related to clinical periodontal status and is reversed by therapy. Its activity has been increased in the crevicular fluid of sites with gingivitis and perio dontitis with respect to healthy sites. There is a close relationship between free radical production by leukocytes and activation of proteases. Altogether these actions could have profound effects on the function and integri ty of the gingival epithelium. The above evidence leads to consider that in the inflammatory periodontal disease, the gen eral etiological factors causing the breakup of physiological systems of inhibition of lipid peroxidation, creates a low level of antioxidant protection of periodontal tissues. In these cir cumstances, the local factors lead to the migration of neutrophils to the gingiva and gingival fluid. This lipid peroxidation is the mechanism that triggers the develop ment of morphofunctionalchangesin periodontium and their vessels, which results in de struction of collagen and bone resorption. These concepts empha size the utility of antioxidants in the prophylaxis and treatment of periodontal disease and therefore justify the search of new antioxidant preparations for this purpose. In some cases, however, the inflammation occurs regardless of these fac tors, suggesting the existence of other stimulating immune. Although its magnitude is relatively low, its impact on affected patients and their costs in health systems is high. There is a considerable variation in the incidence and mortality rates around the world. Squamous cell cancer of the posterior lateral border of the tongue in a 28-year-old woman. In a very general overview, the balance between tu mor suppressor genes and those genes that induce cell cycle is altered. Allowing cells to es cape cell cycle control and developing an unpredictable biological behavior. Subsequently, the cells express molecules that allow them to acquire an invasive phenotype, a phenomen on known as epithelial-mesenchymal transition. Free radicals are products of the oxidation-reduction systems of the cell and its participation in cellular metabolic functions is essential for cell survival. The involvement of free radicals in cancer development has been studied for 3 decades, and there is sufficient evidence that implicates theirs in the multistage theory of carcinogenesis. It should be added that oxidative protein damage participates in facilitating the development of cancer. The results agree that there is an imbalance between the high amount of free radicals and insufficient antioxidant system activity. Added to this, some researchers have observed that high levels of lipid-peroxidation combined with low levels of thiols and anti oxidant status, correlate with poor survival rate in patients with oral cancer . It is considered that the smoke from cigarettes have 4000 chemicals, 40 of which have carcinogenic potential. It has been shown that ciga rette smoke contains pro-oxidants that are capable of initiating the process of lipid-peroxida tion and deplete levels of antioxidants from the diet [17,18]. In contrast, there is epidemiological evidence that demonstrates the protective effect of diet on some populations [19-21]. For example in Greece, which has the lowest rates of oral can cer among European countries,its population is exposed to latent risk factors such as alcohol intake and smoking; micronutrients consume such as riboflavin, magnesium and iron corre lated inversely with oral cancer . Consequently, several authors have proposed the ingestion of diverse exogenous antioxi dants; supporting in those epidemiological studies, where the diet offers protection for the development of cancer, and taking into account that the endogenous antioxidant systems have been overwhelmed by oxidative stress. For example, vitamin C is one of the most extensively evaluated antioxidants in oral cancer alternative co-therapies.