Ledda
/
djledda-web

<html>
    <head><title>Aspirin, brain, and cancer</title></head>
    <body>
        <h1>
            Aspirin, brain, and cancer
        </h1>

        <p>
            When a drug such as caffeine or aspirin turns out to have a great variety of protective effects, it's
            important to understand what it's doing.
        </p>
        <p>
            Because aspirin has been abused by pharmaceutical companies that have competing products to sell, as well as
            by the original efforts to promote aspirin itself, people can easily find reasons why they shouldn't take
            it.
        </p>
        <p>
            Early in the 20th century, people were told that fevers were very bad, and that aspirin should be used
            whenever there is a fever.
        </p>
        <p>
            In the 1980s, there was a big publicity campaign warning parents that giving aspirin to a child with the flu
            could cause the potentially deadly Reye syndrome. Aspirin sales declined sharply, as sales of acetaminophen
            (Tylenol, etc.) increased tremendously. But in Australia, a study of Reye syndrome cases found that six
            times as many of them had been using acetaminophen as had used aspirin. (Orlowski, et al., 1987)
        </p>
        <p>
            Until the 1950s and 1960s, when new products were being promoted, little was said about the possibility of
            stomach ulceration from aspirin. Lately, there has been more publicity about the damage it can do to the
            stomach and intestine, much of it in connection with the sale of the new "COX-2 inhibitors." (These new
            drugs, rather than protecting the circulatory system as aspirin does, damage it.) Aspirin rapidly breaks
            down into acetic acid and salicylic acid (which is found in many fruits), and salicylic acid is protective
            to the stomach and intestine, and other organs. When aspirin was compared with the other common
            antiinflammatory drugs, it was found that the salicylic acid it releases protects against the damage done by
            another drug. (Takeuchi, et al, 2001; Ligumsky, et al., 1985.) Repeated use of aspirin protects the stomach
            against very strong irritants. The experiments in which aspirin produces stomach ulcers are designed to
            produce ulcers, not to realistically model the way aspirin is used.
        </p>

        <p>
            Recently, the public has been led to believe that drugs are being designed to fit certain cellular
            "receptors." The history of the "COX-2 inhibitors" is instructive, in a perverse way. The structures of DES
            and other synthetic estrogens were said to relate to "the estrogen receptor." Making these estrogenic
            molecules more soluble in water made them somewhat anti-estrogenic, leading to products such as Tamoxifen.
            But some of the molecules in this group were found to be antiinflammatory. The structure of Celecoxib and
            other "COX-2 inhibitors" is remarkably similar to the "designer estrogens." Considering this, it's a little
            odd that so few in the U.S. are openly discussing the possibility that estrogen's function is directly
            related to inflammation, and involves the production of many inflammatory mediators, including COX-2. (See
            Lerner, et al., 1975; Luo, et al., 2001; Cushman, et al, 2001; Wu, et al., 2000; Herrington, et al., 2001.)
        </p>

        <p>
            Soot and smoke contain many chemicals that produce inflammation (Brune, et al., 1978). In the 1930s, soot
            was known to be both carcinogenic and estrogenic, and analysis of its components led to the production of
            the early commercial estrogens. Any intelligent person reading the chemical and biological publications of
            that time will see how closely associated cancer, inflammation, and estrogen are.
        </p>
        <p>
            Soon after vitamin E was discovered, tocopherol was defined as a brain-protective, pregnancy protective,
            male fertility protective, antithrombotic, antiestrogenic agent. But very soon, the estrogen industry made
            it impossible to present ideas that explained vitamin E, progesterone, vitamin A, or thyroid hormone in
            terms of the protection they provide against estrogenic substances. Since the polyunsaturated fats caused
            the same conditions that were caused by unopposed estrogen, vitamin E came to be known as an "antioxidant,"
            because it reduced their toxicity. (Vitamin E is now known to suppress COX-2, synergizing with aspirin and
            opposing estrogen.)
        </p>
        <p>
            In 1970, when I was beginning to see the ways in which unopposed estrogen and accumulated polyunsaturated
            fats interacted with a vitamin E deficiency during aging and in infertility, I got some prostaglandins to
            experiment with, since they are products of the oxidation of linoleic acid. The prostaglandins are an
            interesting link between estrogens and inflammation, in normal physiology as well as in disease.
        </p>
        <p>
            I wanted to test their effects on the uterus, especially the sites where the embryos implant. There was a
            theory that the electrical charge of the surface of the uterus was decreased at the implantation sites, to
            reduce the repulsion between two negatively charged things. Although there were regions of lower surface
            charge along the lining of the uterus, the charge changed as waves of muscle contraction moved along the
            uterus, and the prostaglandins affected the contractions.
        </p>
        <p>
            To understand the differences between the different types of prostaglandin, I tested them on my arm, and
            those with the most hydroxyl groups produced regions with an increased negative charge. For comparison, I
            exposed another spot to sunlight for an hour, and found that there was a similar increase in the negative
            charge in that spot. Apparently the prostaglandins were causing an injury or excitation, a mild
            inflammation, in the skin cells.
        </p>

        <p>
            A few years later, aspirin was found to inactivate the enzyme that forms prostaglandins, by the transfer of
            the acetyl radical to the enzyme. This became the orthodox "explanation" for what aspirin does, though it
            neglected to explain that salicylic acid (lacking the acetyl radical) had been widely known in the previous
            century for its very useful antiinflammatory actions. The new theory did explain (at least to the
            satisfaction of editors of medical magazines) one of aspirin's effects, but it distracted attention from all
            the other effects of aspirin and salicylic acid.
        </p>
        <p>
            Aspirin is an antioxidant that protects against lipid peroxidation, but it also stimulates mitochondrial
            respiration. It can inhibit abnormal cell division, but promote normal cell division. It can facilitate
            learning, while preventing excitotoxic nerve injury. It reduces clotting, but it can decrease excessive
            menstrual bleeding. These, and many other strangely beneficial effects of aspirin, strongly suggest that it
            is acting on very basic biological processes, in a coherent way.
        </p>
        <p>
            In explaining aspirin's effects, as in explaining those of estrogen and progesterone, or polyunsaturated
            fats and vitamin E, I think we need concepts of a very broad sort, such as "stability and instability."
        </p>
        <p>
            The COX (cyclooxygenase) enzymes, that make prostaglandins, are just one system among many that are
            activated by stress. Aromatase, that makes estrogen, enzymes that make histamine, serotonin and nitric
            oxide, the cytokines, and the stress-induced hormones of the pituitary and adrenal glands, are turned on in
            difficult situations, and have to be turned off when the threat has been overcome. The production of energy
            is the basis for overcoming all threats, and it has to be conserved in readiness for future needs.
        </p>

        <p>
            The fetus produces saturated fats such as palmitic acid, and the monounsaturated fat, oleic acid, which can
            be turned into the Mead acid, ETrA (5,8,11-eicosatrienoic acid), and its derivatives, which are
            antiinflammatory, and some of which act on the "bliss receptor," or the cannibinoid receptor. In the adult,
            tissues such as cartilage, which are protected by their structure or composition from the entry of exogenous
            fats, contain the Mead acid despite the presence of linoleic acid in the blood.
        </p>
        <p>
            At birth, the baby's mitochondria contain a phospholipid, cardiolipin, containing palmitic acid, but as the
            baby eats foods containing polyunsaturated fatty acids, the palmitic acid in cardiolipin is replaced by the
            unsaturated fats. As the cardiolipin becomes more unsaturated, it becomes less stable, and less able to
            support the activity of the crucial respiratory enzyme, cytochrome oxidase.
        </p>
        <p>
            The respiratory activity of the mitochondria declines as the polyunsaturated oils replace palmitic acid, and
            this change corresponds to the life-long decline of the person's metabolic rate.
        </p>
        <p>
            In old age, a person's life expectancy strongly depends on the amount of oxygen that can be used. When the
            mitochondria can't use oxygen vigorously, cells must depend on inefficient glycolysis for their energy.
        </p>
        <p>
            Estrogen activates the glycolytic pathway, while interfering with mitochondrial respiration. This resembles
            the aged or stressed metabolism, in which lactic acid is produced instead of carbon dioxide.
        </p>

        <p>
            Aspirin activates both glycolysis and mitochondrial respiration, and this means that it shifts the
            mitochondria away from the oxidation of fats, toward the oxidation of glucose, resulting in the increased
            production of carbon dioxide. Its action on the glycolytic enzyme, GAPDH, is the opposite of estrogen's.
        </p>
        <p>
            The shift away from fat oxidation under the influence of aspirin doesn't lead to an accumulation of free
            fatty acids in the circulation, since aspirin inhibits the release of fatty acids from both phospholipids
            and triglycerides. Estrogen has the opposite effects, increasing fat oxidation while increasing the level of
            circulating free fatty acids, since it activates lipolysis, as do several other stress-related hormones.
        </p>
        <p>
            The polyunsaturated fatty acids, such as linolenic, linoleic, arachidonic, EPA, and DHA, have many directly
            toxic, antirespiratory actions, apart from the production of the prostaglandins or eicosanoids. Just by
            preventing the release of these fatty acids, aspirin would have broadly antiinflammatory effects.
        </p>
        <p>
            Since the polyunsaturated fats and prostaglandins stimulate the expression of aromatase, the enzyme that
            synthesizes estrogen, aspirin decreases the production of estrogen. So many of aspirin's effects oppose
            those of estrogen, it would be tempting to suggest that its "basic action" is the suppression of estrogen.
            But I think it's more likely that both estrogen and aspirin are acting on some basic processes, in
            approximately opposite ways.
        </p>
        <p>
            Bioelectrical functions, and the opposition between carbon dioxide and lactic acid, and the way water is
            handled in cells, are basic conditions that have a general or global effect on all of the other more
            specific biochemical and physiological processes. Originally, estrogen and progesterone were each thought to
            affect only one or a few biochemical events, but it has turned out that each has a multitude of different
            biochemical actions, which are integrated in globally meaningful ways. The salicylic acid molecule is much
            smaller and simpler than progesterone, but the range of its beneficial effects is similar. Because of
            aspirin's medical antiquity, there has been no inclination to explain its actions in terms of an "aspirin
            receptor," as for valium and the opiates, leaving its biochemistry, except for the inadequate idea of
            COX-inhibition, simply unexplained.
        </p>
        <p>
            If we didn't eat linoleic acid and the other so-called "essential fatty acids," we would produce large
            amounts of the "Mead acid," n-9 eicosatrienoic acid, and its derivatives. This acid in itself is
            antiinflammatory, and its derivatives have a variety of antistress actions. The universal toxicity of the
            polyunsaturated fats that suppress the Mead fats as they accumulate, and the remarkable vitality of the
            animals that live on a diet deficient in the essential fatty acids, indicate that the Mead fats are
            important factors in the stability of our mammalian tissues. This protective lipid system probably interacts
            with cellular proteins, modifying the way they bind water and carbon dioxide and ions, affecting their
            electrons and their chemical reactivity.
        </p>
        <p>
            If salicylic acid and the structurally similar antiinflammatories, local anesthetics, muscle relaxants,
            expectorants, and antihistamines, act as surrogates for the absent Mead acid family, and thereby act as
            defenses against all the toxic effects of the unstable fats, it would explain the breadth and apparent
            coherence of their usefulness. And at the same time it explains some of the ways that estrogen goes out of
            control, when it exacerbates the toxicity of the accumulated unstable fats.
        </p>
        <p>
            The competition between aspirin and salicylic acid, and other antiinflammatories, for the active site on the
            COX enzyme (Rao, et al., 1982), shows that the structural features of these molecules are in some ways
            analogous to those of the polyunsaturated fatty acids. Wherever there are phospholipids, free fatty acids,
            fatty acid esters, ethers, etc. (i.e., in mitochondria, chromosomes, cytoskeleton, collagen
            networks--essentially everywhere in and around the cell), the regulatory influence of specific fatty
            acids--or their surrogates--will be felt.
        </p>

        <p>
            Although it would undoubtedly be best to grow up eating foods with relatively saturated fats, the use of
            aspirin preventively and therapeutically seems very reasonable under the present circumstances, in which,
            for example, clean and well ripened fruits are not generally available in abundance. Preventing blindness,
            degenerative brain diseases, heart and lung diseases, and cancer with aspirin should get as much support as
            the crazy public health recommendations are now getting from government and foundations and the medical
            businesses.
        </p>
        <p>
            When people with cancer ask for my recommendations, they usually think I'm joking when I tell them to use
            aspirin, and very often they don't take it, on the basis of what seems to be a very strong cultural
            prejudice. Several years ago, a woman whose doctors said it would be impossible to operate on her extremely
            painful "inflammatory breast cancer," had overnight complete relief of the pain and swelling from taking a
            few aspirins. The recognized anti-metastatic effect of aspirin, and its ability to inhibit the development
            of new blood vessels that would support the tumor's growth, make it an appropriate drug to use for pain
            control, even if it doesn't shrink the tumor. In studies of many kinds of tumor, though, it does cause
            regression, or at least slows tumor growth. And it protects against many of the systemic consequences of
            cancer, including wasting (cachexia), immunosuppression, and strokes.
        </p>
        <p>
            Opiates are the standard medical prescription for pain control in cancer, but they are usually prescribed in
            inadequate quantities, "to prevent addiction." Biologically, they are the most inappropriate means of pain
            control, since they increase the release of histamine, which synergizes with the tumor-derived factors to
            suppress immunity and stimulate tumor growth.
        </p>
        <p>
            It has recently become standard practice in most places to advise a person who is having a heart attack to
            immediately chew and swallow an aspirin tablet.
        </p>

        <p>
            The same better-late-than-never philosophy can be applied to Alzheimer's disease, Parkinson's disease, and
            other degenerative nerve diseases. Aspirin protects against several kinds of toxicity, including
            excitotoxicity (glutamate), dopamine toxicity, and oxidative free radical toxicity. Since its effects on the
            mitochondria are similar to those of thyroid (T3), using both of them might improve brain energy production
            more than just thyroid. (By activating T3, aspirin can sometimes increase the temperature and pulse rate.)
            Magnesium, niacinamide, and other nerve protective substances work together.
        </p>
        <p>
            In multiple organ failure, which can be caused by profound shock caused by trauma, infection, or other
            stress, aspirin is often helpful, but carbon dioxide and hypertonic glucose and sodium are more important.
        </p>
        <p>
            Aspirin, like progesterone or vitamin E, can improve fertility, by suppressing a prostaglandin, and
            improving uterine circulation.
        </p>
        <p>
            Although the animal studies that showed stomach damage from aspirin often used single doses equivalent to 10
            or 100 aspirin tablets, the slight irritation produced by a normal dose of aspirin can be minimized by
            dissolving the aspirin in water. The stomach develops a tolerance for aspirin over a period of a few days,
            allowing the dose to be increased if necessary. And both aspirin and salicylic acid can be absorbed through
            the skin, so rheumatic problems have been treated by adding the drug to bath water.
        </p>
        <p>
            The unsaturated (n-6 and n-3) fats that accumulate in our tissues, instead of being part of the system for
            reestablishing order and stability, tend to amplify the instability that is triggered by excitation, by
            estrogen, or by external stresses.
        </p>
        <p>
            I think it's important that we don't allow the drug publicists to obscure the broad importance of substances
            such as aspirin, vitamin E, progesterone, and thyroid. For 60 years, a myth that was created to sell
            estrogen has harmed both science and the health of many people.
        </p>

        <p><strong><h3>REFERENCES</h3></strong></p>
        <p>
            Free Radic Biol Med 2000 Dec 1;29(11):1135-42. <strong>Synergistic inhibition of cyclooxygenase-2</strong>
            <strong>
                expression by vitamin E and aspirin.</strong> Abate A, Yang G, Dennery PA, Oberle S, Schroder H
        </p>
        <p>
            Proc Natl Acad Sci U S A 1995 Aug 15;92(17):7926-30. <strong>The mode of action of aspirin-like drugs:
                effect on inducible nitric oxide synthase.</strong> Amin AR, Vyas P, Attur M, Leszczynska-Piziak J,
            Patel IR, Weissmann G, Abramson SB. "These studies indicate that the inhibition of iNOS expression and
            function represents another mechanism of action for aspirin, if not for all aspirin-like drugs."
        </p>

        <p>
            Obstet Gynecol 2001 Mar;97(3):423-7. <strong>Aspirin effects on endometrial cancer cell growth.</strong>
            Arango HA, Icely S, Roberts WS, Cavanagh D, Becker JL
        </p>
        <p>
            J Neurochem 2001 Mar;76(6):1895-904. <strong>Neuroprotective effects of non-steroidal anti-inflammatory
                drugs by direct scavenging of nitric oxide radicals.</strong> Asanuma M, Nishibayashi-Asanuma S,
            Miyazaki I, Kohno M, Ogawa N.
        </p>
        <p>
            J Neurochem 1998 Oct;71(4):1635-42. <strong>Aspirin and salicylate protect against MPTP-induced dopamine
                depletion in mice.</strong>

            Aubin N, Curet O, Deffois A, Carter C.
        </p>
        <p>
            Psychopharmacology (Berl) 1998 Aug;138(3-4):369-74. <strong>The influence of acetylsalicylic acid on
                cognitive processing: an event-related potentials study.</strong>
            Austermann M, Grotemeyer KH, Evers S, Rodding D, Husstedt IW
        </p>
        <p>
            Brain Res 1999 Oct 2; 843(1-2): 118-29. <strong>Cyclooxygenase-2 selective inhibitors aggravate
                kainic</strong>
            <strong>acid induced seizure and neuronal cell death in the hippocampus.</strong> Baik EJ, Kim EJ, Lee SH,
            Moon C
        </p>
        <p>
            Cancer Lett 1978 Jun;4(6):333-42. <strong>Inflammatory, tumor initiating and promoting activities of
                polycyclic aromatic hydrocarbons and diterpene esters in mouse skin as compared with their prostaglandin
                releasing potency in vitro.</strong> Brune K, Kalin H, Schmidt R, Hecker E.
        </p>

        <p>
            J Neurooncol 2000;46(3):215-29. <strong>Acetaminophen selectively reduces glioma cell growth and increases
                radiosensitivity in culture.</strong> Casper D, Lekhraj R, Yaparpalvi US, Pidel A, Jaggernauth WA,
            Werner P, Tribius S, Rowe JD, LaSala PA "Glioblastoma multiforme (GBM) is a highly lethal brain cancer.
            Using cultures of rodent and human malignant glioma cell lines, we demonstrated that millimolar
            concentrations of acetylsalicylate, acetaminophen, and ibuprofen all significantly reduce cell numbers after
            several days of culture."
        </p>
        <p>
            Neurosci Lett 2000 Aug 11;289(3):201-4. <strong>Ibuprofen protects dopaminergic neurons against glutamate
                toxicity in vitro.</strong> Casper D, Yaparpalvi U, Rempel N, Werner P. "We examined the effects of
            aspirin, acetaminophen, and ibuprofen on cultured primary rat embryonic neurons from mesencephalon, the area
            primarily affected in Parkinson's disease. We evaluated whether these drugs protect dopaminergic neurons
            against excitotoxicity. All three NSAIDs significantly attenuated the decrease in dopamine uptake caused by
            glutamate, indicating preservation of neuronal integrity."
        </p>

        <p>
            Lipids 1996 Aug;31(8):829-37.<strong>
                Effect of dietary n-9 eicosatrienoic acid on the fatty acid composition of plasma lipid fractions and
                tissue phospholipids.</strong> Cleland LG, Neumann MA, Gibson RA, Hamazaki T, Akimoto K, James MJ
            "Dietary enrichment with ETrA warrants further investigation for possible beneficial effects in models of
            inflammation and autoimmunity, as well as in other conditions in which mediators derived from n-6 fatty
            acids can affect homeostasis adversely."
        </p>
        <p>
            Can J Ophthalmol 1981 Jul;16(3):113-8.<strong>
                Senile cataracts: evidence for acceleration by diabetes and deceleration by salicylate.</strong> Cotlier
            E.
        </p>

        <p>
            Int Ophthalmol 1981 May;3(3):173-7. <strong>Aspirin effect on cataract formation in patients with rheumatoid
                arthritis alone or combined with diabetes.</strong>
            Cotlier E. "The effects of aspirin on cataract formation may result from 1) lowering of plasma tryptophan
            levels and increased excretion of tryptophan metabolites, 2) inhibition of aldose reductase and sorbitol
            formation in the diabetic lens, 3) inhibition of tryptophan or kynurenine binding to lens protein."
        </p>
        <p>
            Arterioscler Thromb Vasc Biol 2001 Feb;21(2):255-61. <strong>Tamoxifen and cardiac risk factors</strong>
            <strong>in healthy women: Suggestion of an anti-inflammatory effect.</strong> Cushman M, Costantino JP,
            Tracy RP, Song K, Buckley L, Roberts JD, Krag DN.
        </p>
        <p>
            Med Sci Sports Exerc 2001 Dec;33(12):2029-35. <strong>Acetylsalicylic acid inhibits the pituitary response
                to exercise-related stress in humans.</strong>

            Di Luigi L, Guidetti L, Romanelli F, Baldari C, Conte D.
        </p>
        <p>
            Ann Med 2000 Dec;32 Suppl 1:21-6<strong>. Cyclo-oxygenase products and atherothrombosis.</strong> FitzGerald
            GA, Austin S, Egan K, Cheng Y, Pratico D
        </p>
        <p>
            Acta Diabetol Lat 1981;18(1):27-36. <strong>Effects of acetylsalicylic acid on plasma glucose, free fatty
                acid, betahydroxybutyrate, glucagon and C-peptide responses to salbutamol in insulin-dependent diabetic
                subjects.</strong>
            Giugliano D, Passariello N, Torella R, Cerciello T, Varricchio M, Sgambato S.
        </p>
        <p>
            J Reprod Fertil 1994 Aug;101(3):523-9. <strong>Relationships among GnRH, substance P, prostaglandins, sex
                steroids and aromatase activity in the brain of the male lizard Podarcis sicula sicula during
                reproduction.</strong> Gobbetti A, Zerani M, Di Fiore MM, Botte V "Acetylsalicylic acid decreased PGF2
            alpha, oestradiol and aromatase activity, but increased the amount of androgens released."
        </p>

        <p>
            Natl Med J India 1998 Jan-Feb;11(1):14-7. <strong>Aspirin: a neuroprotective agent at high doses?</strong>
            Gomes I.
        </p>
        <p>
            Radiat Res 1991 Sep;127(3):317-24<strong>. Effects of some nonsteroidal anti-inflammatory agents on
                experimental radiation pneumonitis.</strong> Gross NJ, Holloway NO, Narine KR.
        </p>
        <p>
            Micron 2001 Apr;32(3):307-15. <strong>Collagen as a model system to investigate the use of aspirin as an
                inhibitor of protein glycation and crosslinking.</strong> Hadley J, Malik N, Meek K.
        </p>

        <p>
            J Pharmacol Exp Ther 1981 Aug;218(2):464-9. <strong>Protective effects of aspirin in endotoxic
                shock.</strong> Halushka PV, Wise WC, Cook JA.
        </p>
        <p>
            J Pharmacol Exp Ther 2000 May; 293(2):417-25. <strong>Cyclooxygenase-2 contributes to
                N-methyl-D-aspartate-mediated neuronal cell death in primary cortical cell culture.</strong> Hewett SJ,
            Uliasz TF, Vidwans AS, Hewett JA
        </p>
        <p>
            Med Hypotheses 1999 Apr;52(4):291-2. <strong>Genetic induction and upregulation of cyclooxygenase (COX) and
                aromatase (CYP19): an extension of the dietary fat hypothesis of breast cancer.</strong> Harris RE,
            Robertson FM, Abou-Issa HM, Farrar WB, Brueggemeier R A novel model of mammary carcinogenesis is proposed
            involving sequential induction and upregulation of cyclooxygenase and aromatase genes by essential fatty
            acids prominent in the US diet.
        </p>

        <p>
            J Clin Endocrinol Metab 2001 Sep; 86(9):4216-22. <strong>Differential effects of E and droloxifene on
                C-reactive protein and other markers of inflammation in healthy postmenopausal women.</strong>
            Herrington DM, <hr />
        </p>
        <p>
            J Natl Cancer Inst 1998 Mar 18;90(6):455-60. <strong>Expression of cyclooxygenase-1 and cyclooxygenase-2 in
                human breast cancer.</strong> Hwang D, Scollard D, Byrne J, Levine E "Our results suggest that
            overexpression of COX may not be unique to colon cancer and may be a feature common to other epithelial
            tumors."
        </p>

        <p>
            Ginekol Pol 1999 Mar;70(3):126-34. <strong>[Evaluation of the effectiveness of a low-dose aspirin in the
                treatment of intrauterine growth retardation (IUGR)].</strong> Kalinka J, Sieroszewski P, Hanke W,
            Laudanski T, Suzin J
        </p>
        <p>
            J Cardiovasc Pharmacol 1995 Feb;25(2):273-81. <strong>Inhibitory effects of aspirin on coronary
                hyperreactivity to autacoids after arterial balloon injury in miniature pigs.</strong> Kuga T, Ohara Y,
            Shimokawa H, Ibayashi S, Tomoike H, Takeshita A. "Coronary vasoconstriction induced by histamine and
            serotonin were examined angiographically before, 1 h, 1 week, and 1 month after balloon injury in 29
            hypercholesterolemic miniature pigs." "Hyperconstriction induced by the autacoids 1 h after injury were
            significantly less in groups B and C than in group A (p &lt; 0.01). Hyperconstriction induced by autacoids 1
            week after injury were significantly less in group B than in group A (p &lt; 0.01) and were significantly
            less in group C than in group A (p &lt; 0.01) or group B (p &lt; 0.05)."
        </p>

        <p>
            Proc Soc Exp Biol Med 1975 Feb;148(2):329-32. <strong>Correlation of anti-inflammatory activity with
                inhibition of prostaglandin synthesis activity of nonsteroidal anti-estrogens and estrogens</strong>
            (38532). Lerner EJ, Carminati P, Schiatti P.
        </p>
        <p>
            Proc Soc Exp Biol Med 1985 Feb;178(2):250-3. <strong>Salicylic acid blocks indomethacin-induced
                cyclooxygenase inhibition and lesion formation in rat gastric mucosa.</strong> Ligumsky M, Guth PH,
            Elashoff J, Kauffman GL Jr, Hansen D, Paulsen G. "Salicylic acid has been shown to decrease gastric mucosal
            lesions induced by indomethacin in the rat."
        </p>
        <p>
            Z Naturforsch [C] 2001 May-Jun; 56(5-6):455-63. <strong>Constant expression of cyclooxygenase-2 gene in
                prostate and the lower urinary tract of estrogen-treated</strong>
            <strong>male rats.</strong> Luo C, Strauss L, Ristimaki A, Streng T, Santti R.
        </p>

        <p>
            Neuropharmacology 2000 Apr 27;39(7):1309-18. <strong>Mechanisms of the neuroprotective effect of aspirin
                after oxygen and glucose deprivation in rat forebrain slices.</strong> Moro MA, De Alba J, Cardenas A,
            De Cristobal J, Leza JC, Lizasoain I, Diaz-Guerra MJ, Bosca L, Lorenzo P "Apart from its preventive actions
            against stroke due to its antithrombotic properties, recent data in the literature suggest that high
            concentrations of ASA also exert direct neuroprotective effects." "We have found that ASA inhibits neuronal
            damage at concentrations lower than those previously reported (0.1-0.5 mM), and that these effects correlate
            with the inhibition of excitatory amino acid release, of NF-kappaB translocation to the nucleus and iNOS
            expression caused by ASA." "Our results also show that the effects of ASA are independent of COX inhibition.
            Taken together, our present findings show that ASA is neuroprotective in an in vitro model of brain
            ischaemia at doses close to those recommended for its antithrombotic effects."
        </p>
        <p>
            Pediatrics 1987 Nov;80(5):638-42. <strong>A catch in the Reye.</strong> Orlowski JP, Gillis J, Kilham HA.
        </p>

        <p>
            Prostaglandins Leukot Med 1982 Jul;9(1):109-15. <strong>
                Effect of acetaminophen and salicylate on aspirin-induced inhibition of human platelet
                cyclo-oxygenase.</strong> Rao GH, Reddy KR, White JG. "Recent studies have shown that salicylic acid, a
            metabolite of aspirin, effectively competes for the same site on the platelet cyclo-oxygenase enzyme."
        </p>
        <p>
            Stroke 1997 Oct;28(10):2006-11. <strong>Acetylsalicylic acid increases tolerance against hypoxic and
                chemical hypoxia.</strong> Riepe MW, Kasischke K, Raupach A.
        </p>
        <p>
            Cancer Res 1998 Dec 1;58(23):5354-60. <strong>Prevention of NNK-induced lung tumorigenesis in A/J mice by
                acetylsalicylic acid and NS-398.</strong> Rioux N, Castonguay A
        </p>

        <p>
            J Endocrinol 1989 Jun;121(3):513-9. <strong>Indomethacin inhibits the effects of oestrogen</strong>
            <strong>
                in the anterior pituitary gland of the rat.</strong> Rosental DG, Machiavelli GA, Chernavsky AC,
            Speziale NS, Burdman JA.
        </p>
        <p>
            Int J Cancer 2001 Aug 15;93(4):497-506.<strong>
                Cyclooxygenase inhibitors retard murine mammary tumor progression by reducing tumor cell migration,
                invasiveness and angiogenesis.</strong> Rozic JG, Chakraborty C, Lala PK.
        </p>
        <p>
            Res Commun Mol Pathol Pharmacol 1998 Sep;101(3):259-68. <strong>Protective ability of acetylsalicylic acid
                (aspirin) to scavenge radiation induced free radicals in J774A.1 macrophage cells.</strong> Saini T,
            Bagchi M, Bagchi D, Jaeger S, Hosoyama S, Stohs SJ.
        </p>

        <p>
            Mol Cell Biochem 1999 Sep;199(1-2):93-102. <strong>
                Antioxidant properties of aspirin: characterization of the ability of aspirin to inhibit silica-induced
                lipid peroxidation, DNA damage, NF-kappaB activation, and TNF-alpha production.</strong> Shi X, Ding M,
            Dong Z, Chen F, Ye J, Wang S, Leonard SS, Castranova V, Vallyathan V
        </p>
        <p>
            J Physiol Paris 2001 Jan-Dec;95(1-6):51-7. <strong>Protection by aspirin of indomethacin-induced small
                intestinal damage in rats: mediation by salicylic acid.</strong> Takeuchi K, Hase S, Mizoguchi H,
            Komoike Y, Tanaka A. "Most of non-steroidal anti-inflammatory drugs (NSAIDs) except aspirin (ASA) produce
            intestinal damage in rats." "ASA did not provoke any damage, despite inhibiting (prostaglandin) PG
            production, and prevented the occurrence of intestinal lesions induced by indomethacin, in a dose-related
            manner."
        </p>

        <p>
            FASEB J 2001 Oct;15(12):2057-72. <strong>Cyclooxygenase-independent actions of cyclooxygenase</strong>
            <strong>
                inhibitors.</strong> Tegeder I, Pfeilschifter J, Geisslinger G.
        </p>
        <p>
            J Indian Med Assoc 1997 Feb;95(2):43-4, 47. <strong>Role of low dose aspirin in prevention of pregnancy
                induced hypertension.</strong> Tewari S, Kaushish R, Sharma S, Gulati N
        </p>
        <p>
            J Chromatogr B Biomed Appl 1995 Jul 21;669(2):404-7. <strong>Aspirin inhibits collagen-induced platelet
                serotonin release, as measured by microbore high-performance liquid chromatography with electrochemical
                detection.</strong> Tsai TH, Tsai WJ, Chen CF.
        </p>

        <p>
            Clin Exp Immunol 1991 Nov;86(2):315-21. <strong>Piroxicam, indomethacin</strong>
            <strong>
                and aspirin action on a murine fibrosarcoma.</strong> Effects on tumour-associated and peritoneal
            macrophages. Valdez JC, Perdigon G. "We also studied the effect on tumour development of three inhibitors of
            prostaglandin synthesis: indomethacin, piroxicam and aspirin. Intraperitoneal administration of these drugs
            during 8 d was followed by the regression of palpable tumours. Indomethacin (90 mg/d) induced 45%
            regression, while with piroxicam (two 400 mg/d doses and six 200 mg/d doses) and aspirin (1 mg/d) 32% and
            30% regressions, respectively, were observed. The growth rate of nonregressing tumours, which had reached
            different volumes by the end of the treatment, was delayed to a similar extent by the three
            anti-inflammatory non-steroidal drugs (NSAID)."
        </p>
        <p>
            Int J Radiat Biol 1995 May;67(5):587-96. <strong>Amelioration of radiation nephropathy by acetylsalicylic
                acid.</strong> Verheij M, Stewart FA, Oussoren Y, Weening JJ, Dewit L.
        </p>

        <p>
            Semin Perinatol 1986 Oct;10(4):334-55. <strong>The role of arachidonic acid metabolites in
                preeclampsia.</strong> Walsh SW, Parisi VM.
        </p>
        <p>
            Proc Natl Acad Sci U S A 1999 Apr 27;96(9):5292-7. <strong>Suppression of inducible cyclooxygenase 2 gene
                transcription by aspirin and sodium salicylate.</strong> Xu XM, Sansores-Garcia L, Chen XM,
            Matijevic-Aleksic N, Du M, Wu KK. "Aspirin and sodium salicylate at therapeutic concentrations equipotently
            blocked COX-2 mRNA and protein levels induced by interleukin-1beta and phorbol 12-myristate 13-acetate."
        </p>
        <p>
            Hum Reprod 1994 Oct;9(10):1954-7. <strong>The benefits of low-dose aspirin therapy in women with impaired
                uterine perfusion during assisted conception.</strong>

            Wada I, Hsu CC, Williams G, Macnamee MC, Brinsden PR. "Higher pregnancy rates (47 versus 17%) were achieved
            in those taking aspirin from day 1 of HRT." "The addition of low-dose aspirin to a standard HRT protocol in
            women with impaired uterine perfusion is associated with improved blood flow and satisfactory pregnancy
            rates."
        </p>
        <p>
            J Ethnopharmacol 1991 Sep;34(2-3):215-9. <strong>Radiation-protective and platelet aggregation inhibitory
                effects of five traditional Chinese drugs and acetylsalicylic acid following high-dose
                gamma-irradiation.</strong>
            Wang HF, Li XD, Chen YM, Yuan LB, Foye WO.
        </p>
        <p>
            Fertil Steril 1997 Nov;68(5):927-30. <strong>Low-dose aspirin for oocyte donation recipients with a thin
                endometrium: prospective, randomized study.</strong> Weckstein LN, Jacobson A, Galen D, Hampton K,
            Hammel J. "Low-dose aspirin therapy improves implantation rates in oocyte donation recipients with a thin
            endometrium."
        </p>

        <p>
            Dermatologica 1978;156(2):89-96. <strong>Effect of topical salicylic acid on animal epidermopoiesis.</strong
            > Weirich EG, Longauer JK, Kirkwood AH. In contrast to its antihyperplastic effect on pathological
            proliferation of the epidermis, salicylic acid promotes epidermopoiesis in the normal guinea pig skin. After
            the application of 1% w/w salicylic acid in acetone-ethanol for 4 weeks, the thickness of the surface
            epithelium was increased by 40% and that of the deep epithelium by 19%. The mitotic index rose by 17%.
        </p>
        <p>
            Arch Exp Veterinarmed 1981;35(3):465-70. <strong>[Control of implantation in rats and sows by peroral
                administration of prostaglandin synthetase inhibitors. 2. Effects of prostaglandin F2 alpha,
                progesterone/estrone, and acetylsalicylic acid on implantation and various biochemical parameters of
                amniotic fluid in the rat]</strong> Wollenhaupt K, Steger H. "The highest number of normally developed
            (97 per cent) and the lowest number of degenerated foetuses (three per cent) were recorded following
            acetylsalicylic acid treatment, as compared to the control group (91 and nine per cent)."
        </p>
        <p>
            Biomed Pharmacother 1999 Aug;53(7):315-8. <strong>Aspirin induced apoptosis in gastric cancer cells.</strong
            > Wong BC, Zhu GH, Lam SK
        </p>

        <p>
            Scand J Immunol 2000 Oct;52(4):393-400. <strong>Tamoxifen decreases renal inflammation and alleviates
                disease severity in autoimmune NZB/W F1 mice.</strong> Wu WM, Lin BF, Su YC, Suen JL, Chiang BL. "It has
            been documented that sex hormone may play a role in the pathogenesis of murine lupus."
        </p>
        <p>
            Science 2001 Aug 31;293(5535):1673-7. <strong>Reversal of obesity- and diet-induced insulin resistance with
                salicylates or targeted disruption of Ikkbeta.</strong> Yuan M, Konstantopoulos N, Lee J, Hansen L, Li
            ZW, Karin M, Shoelson SE.
        </p>
        <p></p>
        <hr />
        <p>
            <strong><em>Since the 1970s, aspirin has been thought of as an inhibitor of prostaglandin synthesis, but
                    that is only part of its effect. Sometimes its effect is the opposite of the effects of other
                    prostaglandin inhibitors.</em></strong>
        </p>
        <p>
            <strong><em>It protects against the harmful effects of estrogen, prolactin, serotonin, cortisol, histamine,
                    and radiation (u.v., x-rays, gamma rays).</em></strong>
        </p>

        <p>
            <strong><em>It prevents cancer, and can cause its regression. It inhibits vascular proliferation. It
                    inhibits interleukin 6 (and other inflammatory cytokines), which is a factor in heart disease and
                    breast and liver cancer.</em></strong>
        </p>
        <p>
            <strong><em>It protects the brain, and can improve learning. It's an antioxidant, prevents cataracts, and
                    protects against glycation in diabetes.
                </em></strong>
        </p>
        <p>
            <strong><em>It prevents premature birth and prevents birth defects caused by diabetes, preeclampsia, and
                    exposure to alcohol. It prevents recurrence of neural tube defects and protects against many of the
                    gestational problems associated with lupus.</em></strong>
        </p>
        <p>
            <strong><em>Although aspirin protects against uncontrolled cell proliferation, as in cancer and psoriasis,
                    salicylic acid increases normal cell division in the skin.</em></strong>
        </p>
        <p>
            <strong><em>Aspirin protects against many forms of shock and stess, and corrects imbalances in the nervous
                    system.</em></strong>
        </p>
        <p><strong><em>It protects against several kinds of toxins involved in brain degeneration.</em></strong></p>

        <p>
            <strong><em>"Aspirin elevated ATP levels not only in intact cortical neurons but also in isolated brain
                    mitochondria, an effect concomitant with an increase in NADH-dependent respiration by brain
                    submitochondrial particles."</em></strong>
        </p>
        <p>
            <strong><em>
                    De Cristobal, et al., 2002</em></strong>
        </p>
        <p>
            <strong><em>"The pharmacological action of salicylate cannot be explained by its inhibition of
                    cyclooxygenase (COX) activity." ". . . salicylate exerts its antiinflammatory action in part by
                    suppressing COX-2 induction. . . ." XM Xu, et al., 1999</em></strong>
        </p>

        <p>© Ray Peat 2006. All Rights Reserved. www.RayPeat.com</p>
    </body>
</html>