663 lines
44 KiB
HTML
663 lines
44 KiB
HTML
<html>
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<head><title>Aspirin, brain, and cancer</title></head>
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<body>
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<h1>
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Aspirin, brain, and cancer
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</h1>
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<p>
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When a drug such as caffeine or aspirin turns out to have a great variety of protective effects, it's
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important to understand what it's doing.
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</p>
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<p>
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Because aspirin has been abused by pharmaceutical companies that have competing products to sell, as well as
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by the original efforts to promote aspirin itself, people can easily find reasons why they shouldn't take
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it.
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</p>
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<p>
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Early in the 20th century, people were told that fevers were very bad, and that aspirin should be used
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whenever there is a fever.
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</p>
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<p>
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In the 1980s, there was a big publicity campaign warning parents that giving aspirin to a child with the flu
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could cause the potentially deadly Reye syndrome. Aspirin sales declined sharply, as sales of acetaminophen
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(Tylenol, etc.) increased tremendously. But in Australia, a study of Reye syndrome cases found that six
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times as many of them had been using acetaminophen as had used aspirin. (Orlowski, et al., 1987)
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</p>
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<p>
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Until the 1950s and 1960s, when new products were being promoted, little was said about the possibility of
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stomach ulceration from aspirin. Lately, there has been more publicity about the damage it can do to the
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stomach and intestine, much of it in connection with the sale of the new "COX-2 inhibitors." (These new
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drugs, rather than protecting the circulatory system as aspirin does, damage it.) Aspirin rapidly breaks
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down into acetic acid and salicylic acid (which is found in many fruits), and salicylic acid is protective
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to the stomach and intestine, and other organs. When aspirin was compared with the other common
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antiinflammatory drugs, it was found that the salicylic acid it releases protects against the damage done by
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another drug. (Takeuchi, et al, 2001; Ligumsky, et al., 1985.) Repeated use of aspirin protects the stomach
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against very strong irritants. The experiments in which aspirin produces stomach ulcers are designed to
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produce ulcers, not to realistically model the way aspirin is used.
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</p>
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<p>
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Recently, the public has been led to believe that drugs are being designed to fit certain cellular
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"receptors." The history of the "COX-2 inhibitors" is instructive, in a perverse way. The structures of DES
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and other synthetic estrogens were said to relate to "the estrogen receptor." Making these estrogenic
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molecules more soluble in water made them somewhat anti-estrogenic, leading to products such as Tamoxifen.
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But some of the molecules in this group were found to be antiinflammatory. The structure of Celecoxib and
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other "COX-2 inhibitors" is remarkably similar to the "designer estrogens." Considering this, it's a little
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odd that so few in the U.S. are openly discussing the possibility that estrogen's function is directly
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related to inflammation, and involves the production of many inflammatory mediators, including COX-2. (See
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Lerner, et al., 1975; Luo, et al., 2001; Cushman, et al, 2001; Wu, et al., 2000; Herrington, et al., 2001.)
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</p>
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<p>
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Soot and smoke contain many chemicals that produce inflammation (Brune, et al., 1978). In the 1930s, soot
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was known to be both carcinogenic and estrogenic, and analysis of its components led to the production of
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the early commercial estrogens. Any intelligent person reading the chemical and biological publications of
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that time will see how closely associated cancer, inflammation, and estrogen are.
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</p>
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<p>
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Soon after vitamin E was discovered, tocopherol was defined as a brain-protective, pregnancy protective,
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male fertility protective, antithrombotic, antiestrogenic agent. But very soon, the estrogen industry made
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it impossible to present ideas that explained vitamin E, progesterone, vitamin A, or thyroid hormone in
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terms of the protection they provide against estrogenic substances. Since the polyunsaturated fats caused
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the same conditions that were caused by unopposed estrogen, vitamin E came to be known as an "antioxidant,"
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because it reduced their toxicity. (Vitamin E is now known to suppress COX-2, synergizing with aspirin and
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opposing estrogen.)
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</p>
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<p>
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In 1970, when I was beginning to see the ways in which unopposed estrogen and accumulated polyunsaturated
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fats interacted with a vitamin E deficiency during aging and in infertility, I got some prostaglandins to
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experiment with, since they are products of the oxidation of linoleic acid. The prostaglandins are an
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interesting link between estrogens and inflammation, in normal physiology as well as in disease.
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</p>
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<p>
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I wanted to test their effects on the uterus, especially the sites where the embryos implant. There was a
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theory that the electrical charge of the surface of the uterus was decreased at the implantation sites, to
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reduce the repulsion between two negatively charged things. Although there were regions of lower surface
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charge along the lining of the uterus, the charge changed as waves of muscle contraction moved along the
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uterus, and the prostaglandins affected the contractions.
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</p>
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<p>
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To understand the differences between the different types of prostaglandin, I tested them on my arm, and
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those with the most hydroxyl groups produced regions with an increased negative charge. For comparison, I
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exposed another spot to sunlight for an hour, and found that there was a similar increase in the negative
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charge in that spot. Apparently the prostaglandins were causing an injury or excitation, a mild
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inflammation, in the skin cells.
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</p>
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<p>
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A few years later, aspirin was found to inactivate the enzyme that forms prostaglandins, by the transfer of
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the acetyl radical to the enzyme. This became the orthodox "explanation" for what aspirin does, though it
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neglected to explain that salicylic acid (lacking the acetyl radical) had been widely known in the previous
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century for its very useful antiinflammatory actions. The new theory did explain (at least to the
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satisfaction of editors of medical magazines) one of aspirin's effects, but it distracted attention from all
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the other effects of aspirin and salicylic acid.
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</p>
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<p>
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Aspirin is an antioxidant that protects against lipid peroxidation, but it also stimulates mitochondrial
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respiration. It can inhibit abnormal cell division, but promote normal cell division. It can facilitate
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learning, while preventing excitotoxic nerve injury. It reduces clotting, but it can decrease excessive
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menstrual bleeding. These, and many other strangely beneficial effects of aspirin, strongly suggest that it
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is acting on very basic biological processes, in a coherent way.
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</p>
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<p>
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In explaining aspirin's effects, as in explaining those of estrogen and progesterone, or polyunsaturated
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fats and vitamin E, I think we need concepts of a very broad sort, such as "stability and instability."
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</p>
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<p>
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The COX (cyclooxygenase) enzymes, that make prostaglandins, are just one system among many that are
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activated by stress. Aromatase, that makes estrogen, enzymes that make histamine, serotonin and nitric
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oxide, the cytokines, and the stress-induced hormones of the pituitary and adrenal glands, are turned on in
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difficult situations, and have to be turned off when the threat has been overcome. The production of energy
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is the basis for overcoming all threats, and it has to be conserved in readiness for future needs.
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</p>
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<p>
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The fetus produces saturated fats such as palmitic acid, and the monounsaturated fat, oleic acid, which can
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be turned into the Mead acid, ETrA (5,8,11-eicosatrienoic acid), and its derivatives, which are
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antiinflammatory, and some of which act on the "bliss receptor," or the cannibinoid receptor. In the adult,
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tissues such as cartilage, which are protected by their structure or composition from the entry of exogenous
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fats, contain the Mead acid despite the presence of linoleic acid in the blood.
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</p>
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<p>
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At birth, the baby's mitochondria contain a phospholipid, cardiolipin, containing palmitic acid, but as the
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baby eats foods containing polyunsaturated fatty acids, the palmitic acid in cardiolipin is replaced by the
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unsaturated fats. As the cardiolipin becomes more unsaturated, it becomes less stable, and less able to
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support the activity of the crucial respiratory enzyme, cytochrome oxidase.
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</p>
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<p>
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The respiratory activity of the mitochondria declines as the polyunsaturated oils replace palmitic acid, and
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this change corresponds to the life-long decline of the person's metabolic rate.
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</p>
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<p>
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In old age, a person's life expectancy strongly depends on the amount of oxygen that can be used. When the
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mitochondria can't use oxygen vigorously, cells must depend on inefficient glycolysis for their energy.
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</p>
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<p>
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Estrogen activates the glycolytic pathway, while interfering with mitochondrial respiration. This resembles
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the aged or stressed metabolism, in which lactic acid is produced instead of carbon dioxide.
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</p>
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<p>
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Aspirin activates both glycolysis and mitochondrial respiration, and this means that it shifts the
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mitochondria away from the oxidation of fats, toward the oxidation of glucose, resulting in the increased
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production of carbon dioxide. Its action on the glycolytic enzyme, GAPDH, is the opposite of estrogen's.
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</p>
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<p>
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The shift away from fat oxidation under the influence of aspirin doesn't lead to an accumulation of free
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fatty acids in the circulation, since aspirin inhibits the release of fatty acids from both phospholipids
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and triglycerides. Estrogen has the opposite effects, increasing fat oxidation while increasing the level of
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circulating free fatty acids, since it activates lipolysis, as do several other stress-related hormones.
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</p>
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<p>
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The polyunsaturated fatty acids, such as linolenic, linoleic, arachidonic, EPA, and DHA, have many directly
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toxic, antirespiratory actions, apart from the production of the prostaglandins or eicosanoids. Just by
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preventing the release of these fatty acids, aspirin would have broadly antiinflammatory effects.
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</p>
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<p>
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Since the polyunsaturated fats and prostaglandins stimulate the expression of aromatase, the enzyme that
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synthesizes estrogen, aspirin decreases the production of estrogen. So many of aspirin's effects oppose
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those of estrogen, it would be tempting to suggest that its "basic action" is the suppression of estrogen.
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But I think it's more likely that both estrogen and aspirin are acting on some basic processes, in
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approximately opposite ways.
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</p>
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<p>
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Bioelectrical functions, and the opposition between carbon dioxide and lactic acid, and the way water is
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handled in cells, are basic conditions that have a general or global effect on all of the other more
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specific biochemical and physiological processes. Originally, estrogen and progesterone were each thought to
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affect only one or a few biochemical events, but it has turned out that each has a multitude of different
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biochemical actions, which are integrated in globally meaningful ways. The salicylic acid molecule is much
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smaller and simpler than progesterone, but the range of its beneficial effects is similar. Because of
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aspirin's medical antiquity, there has been no inclination to explain its actions in terms of an "aspirin
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receptor," as for valium and the opiates, leaving its biochemistry, except for the inadequate idea of
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COX-inhibition, simply unexplained.
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</p>
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<p>
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If we didn't eat linoleic acid and the other so-called "essential fatty acids," we would produce large
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amounts of the "Mead acid," n-9 eicosatrienoic acid, and its derivatives. This acid in itself is
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antiinflammatory, and its derivatives have a variety of antistress actions. The universal toxicity of the
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polyunsaturated fats that suppress the Mead fats as they accumulate, and the remarkable vitality of the
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animals that live on a diet deficient in the essential fatty acids, indicate that the Mead fats are
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important factors in the stability of our mammalian tissues. This protective lipid system probably interacts
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with cellular proteins, modifying the way they bind water and carbon dioxide and ions, affecting their
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electrons and their chemical reactivity.
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</p>
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<p>
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If salicylic acid and the structurally similar antiinflammatories, local anesthetics, muscle relaxants,
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expectorants, and antihistamines, act as surrogates for the absent Mead acid family, and thereby act as
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defenses against all the toxic effects of the unstable fats, it would explain the breadth and apparent
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coherence of their usefulness. And at the same time it explains some of the ways that estrogen goes out of
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control, when it exacerbates the toxicity of the accumulated unstable fats.
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</p>
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<p>
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The competition between aspirin and salicylic acid, and other antiinflammatories, for the active site on the
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COX enzyme (Rao, et al., 1982), shows that the structural features of these molecules are in some ways
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analogous to those of the polyunsaturated fatty acids. Wherever there are phospholipids, free fatty acids,
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fatty acid esters, ethers, etc. (i.e., in mitochondria, chromosomes, cytoskeleton, collagen
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networks--essentially everywhere in and around the cell), the regulatory influence of specific fatty
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acids--or their surrogates--will be felt.
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</p>
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<p>
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Although it would undoubtedly be best to grow up eating foods with relatively saturated fats, the use of
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aspirin preventively and therapeutically seems very reasonable under the present circumstances, in which,
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for example, clean and well ripened fruits are not generally available in abundance. Preventing blindness,
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degenerative brain diseases, heart and lung diseases, and cancer with aspirin should get as much support as
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the crazy public health recommendations are now getting from government and foundations and the medical
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businesses.
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</p>
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<p>
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When people with cancer ask for my recommendations, they usually think I'm joking when I tell them to use
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aspirin, and very often they don't take it, on the basis of what seems to be a very strong cultural
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prejudice. Several years ago, a woman whose doctors said it would be impossible to operate on her extremely
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painful "inflammatory breast cancer," had overnight complete relief of the pain and swelling from taking a
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few aspirins. The recognized anti-metastatic effect of aspirin, and its ability to inhibit the development
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of new blood vessels that would support the tumor's growth, make it an appropriate drug to use for pain
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control, even if it doesn't shrink the tumor. In studies of many kinds of tumor, though, it does cause
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regression, or at least slows tumor growth. And it protects against many of the systemic consequences of
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cancer, including wasting (cachexia), immunosuppression, and strokes.
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</p>
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<p>
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Opiates are the standard medical prescription for pain control in cancer, but they are usually prescribed in
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inadequate quantities, "to prevent addiction." Biologically, they are the most inappropriate means of pain
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control, since they increase the release of histamine, which synergizes with the tumor-derived factors to
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suppress immunity and stimulate tumor growth.
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</p>
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<p>
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It has recently become standard practice in most places to advise a person who is having a heart attack to
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immediately chew and swallow an aspirin tablet.
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</p>
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<p>
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The same better-late-than-never philosophy can be applied to Alzheimer's disease, Parkinson's disease, and
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other degenerative nerve diseases. Aspirin protects against several kinds of toxicity, including
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excitotoxicity (glutamate), dopamine toxicity, and oxidative free radical toxicity. Since its effects on the
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mitochondria are similar to those of thyroid (T3), using both of them might improve brain energy production
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more than just thyroid. (By activating T3, aspirin can sometimes increase the temperature and pulse rate.)
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Magnesium, niacinamide, and other nerve protective substances work together.
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</p>
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<p>
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In multiple organ failure, which can be caused by profound shock caused by trauma, infection, or other
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stress, aspirin is often helpful, but carbon dioxide and hypertonic glucose and sodium are more important.
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</p>
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<p>
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Aspirin, like progesterone or vitamin E, can improve fertility, by suppressing a prostaglandin, and
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improving uterine circulation.
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</p>
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<p>
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Although the animal studies that showed stomach damage from aspirin often used single doses equivalent to 10
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or 100 aspirin tablets, the slight irritation produced by a normal dose of aspirin can be minimized by
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dissolving the aspirin in water. The stomach develops a tolerance for aspirin over a period of a few days,
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allowing the dose to be increased if necessary. And both aspirin and salicylic acid can be absorbed through
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the skin, so rheumatic problems have been treated by adding the drug to bath water.
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</p>
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<p>
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The unsaturated (n-6 and n-3) fats that accumulate in our tissues, instead of being part of the system for
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reestablishing order and stability, tend to amplify the instability that is triggered by excitation, by
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estrogen, or by external stresses.
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</p>
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<p>
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I think it's important that we don't allow the drug publicists to obscure the broad importance of substances
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such as aspirin, vitamin E, progesterone, and thyroid. For 60 years, a myth that was created to sell
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estrogen has harmed both science and the health of many people.
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</p>
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<p><strong><h3>REFERENCES</h3></strong></p>
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<p>
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Free Radic Biol Med 2000 Dec 1;29(11):1135-42. <strong>Synergistic inhibition of cyclooxygenase-2</strong>
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<strong>
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expression by vitamin E and aspirin.</strong> Abate A, Yang G, Dennery PA, Oberle S, Schroder H
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</p>
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<p>
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Proc Natl Acad Sci U S A 1995 Aug 15;92(17):7926-30. <strong>The mode of action of aspirin-like drugs:
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effect on inducible nitric oxide synthase.</strong> Amin AR, Vyas P, Attur M, Leszczynska-Piziak J,
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Patel IR, Weissmann G, Abramson SB. "These studies indicate that the inhibition of iNOS expression and
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function represents another mechanism of action for aspirin, if not for all aspirin-like drugs."
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</p>
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<p>
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Obstet Gynecol 2001 Mar;97(3):423-7. <strong>Aspirin effects on endometrial cancer cell growth.</strong>
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Arango HA, Icely S, Roberts WS, Cavanagh D, Becker JL
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</p>
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<p>
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J Neurochem 2001 Mar;76(6):1895-904. <strong>Neuroprotective effects of non-steroidal anti-inflammatory
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drugs by direct scavenging of nitric oxide radicals.</strong> Asanuma M, Nishibayashi-Asanuma S,
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Miyazaki I, Kohno M, Ogawa N.
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</p>
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<p>
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J Neurochem 1998 Oct;71(4):1635-42. <strong>Aspirin and salicylate protect against MPTP-induced dopamine
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depletion in mice.</strong>
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Aubin N, Curet O, Deffois A, Carter C.
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</p>
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<p>
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Psychopharmacology (Berl) 1998 Aug;138(3-4):369-74. <strong>The influence of acetylsalicylic acid on
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cognitive processing: an event-related potentials study.</strong>
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Austermann M, Grotemeyer KH, Evers S, Rodding D, Husstedt IW
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</p>
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<p>
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Brain Res 1999 Oct 2; 843(1-2): 118-29. <strong>Cyclooxygenase-2 selective inhibitors aggravate
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kainic</strong>
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<strong>acid induced seizure and neuronal cell death in the hippocampus.</strong> Baik EJ, Kim EJ, Lee SH,
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Moon C
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</p>
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<p>
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Cancer Lett 1978 Jun;4(6):333-42. <strong>Inflammatory, tumor initiating and promoting activities of
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polycyclic aromatic hydrocarbons and diterpene esters in mouse skin as compared with their prostaglandin
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releasing potency in vitro.</strong> Brune K, Kalin H, Schmidt R, Hecker E.
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</p>
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<p>
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J Neurooncol 2000;46(3):215-29. <strong>Acetaminophen selectively reduces glioma cell growth and increases
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radiosensitivity in culture.</strong> Casper D, Lekhraj R, Yaparpalvi US, Pidel A, Jaggernauth WA,
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Werner P, Tribius S, Rowe JD, LaSala PA "Glioblastoma multiforme (GBM) is a highly lethal brain cancer.
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Using cultures of rodent and human malignant glioma cell lines, we demonstrated that millimolar
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concentrations of acetylsalicylate, acetaminophen, and ibuprofen all significantly reduce cell numbers after
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several days of culture."
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</p>
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<p>
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Neurosci Lett 2000 Aug 11;289(3):201-4. <strong>Ibuprofen protects dopaminergic neurons against glutamate
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toxicity in vitro.</strong> Casper D, Yaparpalvi U, Rempel N, Werner P. "We examined the effects of
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aspirin, acetaminophen, and ibuprofen on cultured primary rat embryonic neurons from mesencephalon, the area
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primarily affected in Parkinson's disease. We evaluated whether these drugs protect dopaminergic neurons
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against excitotoxicity. All three NSAIDs significantly attenuated the decrease in dopamine uptake caused by
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glutamate, indicating preservation of neuronal integrity."
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</p>
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<p>
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Lipids 1996 Aug;31(8):829-37.<strong>
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Effect of dietary n-9 eicosatrienoic acid on the fatty acid composition of plasma lipid fractions and
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tissue phospholipids.</strong> Cleland LG, Neumann MA, Gibson RA, Hamazaki T, Akimoto K, James MJ
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"Dietary enrichment with ETrA warrants further investigation for possible beneficial effects in models of
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inflammation and autoimmunity, as well as in other conditions in which mediators derived from n-6 fatty
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acids can affect homeostasis adversely."
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</p>
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<p>
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Can J Ophthalmol 1981 Jul;16(3):113-8.<strong>
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Senile cataracts: evidence for acceleration by diabetes and deceleration by salicylate.</strong> Cotlier
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E.
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</p>
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<p>
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Int Ophthalmol 1981 May;3(3):173-7. <strong>Aspirin effect on cataract formation in patients with rheumatoid
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arthritis alone or combined with diabetes.</strong>
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Cotlier E. "The effects of aspirin on cataract formation may result from 1) lowering of plasma tryptophan
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levels and increased excretion of tryptophan metabolites, 2) inhibition of aldose reductase and sorbitol
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formation in the diabetic lens, 3) inhibition of tryptophan or kynurenine binding to lens protein."
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</p>
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<p>
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Arterioscler Thromb Vasc Biol 2001 Feb;21(2):255-61. <strong>Tamoxifen and cardiac risk factors</strong>
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<strong>in healthy women: Suggestion of an anti-inflammatory effect.</strong> Cushman M, Costantino JP,
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Tracy RP, Song K, Buckley L, Roberts JD, Krag DN.
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</p>
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<p>
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Med Sci Sports Exerc 2001 Dec;33(12):2029-35. <strong>Acetylsalicylic acid inhibits the pituitary response
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to exercise-related stress in humans.</strong>
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Di Luigi L, Guidetti L, Romanelli F, Baldari C, Conte D.
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</p>
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<p>
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Ann Med 2000 Dec;32 Suppl 1:21-6<strong>. Cyclo-oxygenase products and atherothrombosis.</strong> FitzGerald
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GA, Austin S, Egan K, Cheng Y, Pratico D
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</p>
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<p>
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Acta Diabetol Lat 1981;18(1):27-36. <strong>Effects of acetylsalicylic acid on plasma glucose, free fatty
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acid, betahydroxybutyrate, glucagon and C-peptide responses to salbutamol in insulin-dependent diabetic
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subjects.</strong>
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Giugliano D, Passariello N, Torella R, Cerciello T, Varricchio M, Sgambato S.
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</p>
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<p>
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J Reprod Fertil 1994 Aug;101(3):523-9. <strong>Relationships among GnRH, substance P, prostaglandins, sex
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steroids and aromatase activity in the brain of the male lizard Podarcis sicula sicula during
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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."
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</p>
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<p>
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Natl Med J India 1998 Jan-Feb;11(1):14-7. <strong>Aspirin: a neuroprotective agent at high doses?</strong>
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Gomes I.
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<p>
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Radiat Res 1991 Sep;127(3):317-24<strong>. Effects of some nonsteroidal anti-inflammatory agents on
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</p>
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<p>
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Micron 2001 Apr;32(3):307-15. <strong>Collagen as a model system to investigate the use of aspirin as an
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|
inhibitor of protein glycation and crosslinking.</strong> Hadley J, Malik N, Meek K.
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</p>
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<p>
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J Pharmacol Exp Ther 1981 Aug;218(2):464-9. <strong>Protective effects of aspirin in endotoxic
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shock.</strong> Halushka PV, Wise WC, Cook JA.
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</p>
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<p>
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J Pharmacol Exp Ther 2000 May; 293(2):417-25. <strong>Cyclooxygenase-2 contributes to
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N-methyl-D-aspartate-mediated neuronal cell death in primary cortical cell culture.</strong> Hewett SJ,
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Uliasz TF, Vidwans AS, Hewett JA
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</p>
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<p>
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Med Hypotheses 1999 Apr;52(4):291-2. <strong>Genetic induction and upregulation of cyclooxygenase (COX) and
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aromatase (CYP19): an extension of the dietary fat hypothesis of breast cancer.</strong> Harris RE,
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Robertson FM, Abou-Issa HM, Farrar WB, Brueggemeier R A novel model of mammary carcinogenesis is proposed
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involving sequential induction and upregulation of cyclooxygenase and aromatase genes by essential fatty
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acids prominent in the US diet.
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</p>
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<p>
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J Clin Endocrinol Metab 2001 Sep; 86(9):4216-22. <strong>Differential effects of E and droloxifene on
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C-reactive protein and other markers of inflammation in healthy postmenopausal women.</strong>
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Herrington DM, <hr />
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</p>
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<p>
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J Natl Cancer Inst 1998 Mar 18;90(6):455-60. <strong>Expression of cyclooxygenase-1 and cyclooxygenase-2 in
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|
human breast cancer.</strong> Hwang D, Scollard D, Byrne J, Levine E "Our results suggest that
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|
overexpression of COX may not be unique to colon cancer and may be a feature common to other epithelial
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|
tumors."
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</p>
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<p>
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Ginekol Pol 1999 Mar;70(3):126-34. <strong>[Evaluation of the effectiveness of a low-dose aspirin in the
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|
treatment of intrauterine growth retardation (IUGR)].</strong> Kalinka J, Sieroszewski P, Hanke W,
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Laudanski T, Suzin J
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</p>
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<p>
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J Cardiovasc Pharmacol 1995 Feb;25(2):273-81. <strong>Inhibitory effects of aspirin on coronary
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hyperreactivity to autacoids after arterial balloon injury in miniature pigs.</strong> Kuga T, Ohara Y,
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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 < 0.01). Hyperconstriction induced by autacoids 1
|
|
week after injury were significantly less in group B than in group A (p < 0.01) and were significantly
|
|
less in group C than in group A (p < 0.01) or group B (p < 0.05)."
|
|
</p>
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|
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|
<p>
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|
Proc Soc Exp Biol Med 1975 Feb;148(2):329-32. <strong>Correlation of anti-inflammatory activity with
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|
inhibition of prostaglandin synthesis activity of nonsteroidal anti-estrogens and estrogens</strong>
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(38532). Lerner EJ, Carminati P, Schiatti P.
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</p>
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<p>
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|
Proc Soc Exp Biol Med 1985 Feb;178(2):250-3. <strong>Salicylic acid blocks indomethacin-induced
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|
cyclooxygenase inhibition and lesion formation in rat gastric mucosa.</strong> Ligumsky M, Guth PH,
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|
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
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|
prostate and the lower urinary tract of estrogen-treated</strong>
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|
<strong>male rats.</strong> Luo C, Strauss L, Ristimaki A, Streng T, Santti R.
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</p>
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|
<p>
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|
Neuropharmacology 2000 Apr 27;39(7):1309-18. <strong>Mechanisms of the neuroprotective effect of aspirin
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|
after oxygen and glucose deprivation in rat forebrain slices.</strong> Moro MA, De Alba J, Cardenas A,
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|
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>
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|
Pediatrics 1987 Nov;80(5):638-42. <strong>A catch in the Reye.</strong> Orlowski JP, Gillis J, Kilham HA.
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</p>
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<p>
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|
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
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|
chemical hypoxia.</strong> Riepe MW, Kasischke K, Raupach A.
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|
</p>
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|
<p>
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|
Cancer Res 1998 Dec 1;58(23):5354-60. <strong>Prevention of NNK-induced lung tumorigenesis in A/J mice by
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|
acetylsalicylic acid and NS-398.</strong> Rioux N, Castonguay A
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</p>
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|
<p>
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|
J Endocrinol 1989 Jun;121(3):513-9. <strong>Indomethacin inhibits the effects of oestrogen</strong>
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|
<strong>
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|
in the anterior pituitary gland of the rat.</strong> Rosental DG, Machiavelli GA, Chernavsky AC,
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|
Speziale NS, Burdman JA.
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|
</p>
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|
<p>
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|
Int J Cancer 2001 Aug 15;93(4):497-506.<strong>
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|
Cyclooxygenase inhibitors retard murine mammary tumor progression by reducing tumor cell migration,
|
|
invasiveness and angiogenesis.</strong> Rozic JG, Chakraborty C, Lala PK.
|
|
</p>
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|
<p>
|
|
Res Commun Mol Pathol Pharmacol 1998 Sep;101(3):259-68. <strong>Protective ability of acetylsalicylic acid
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|
(aspirin) to scavenge radiation induced free radicals in J774A.1 macrophage cells.</strong> Saini T,
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Bagchi M, Bagchi D, Jaeger S, Hosoyama S, Stohs SJ.
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</p>
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<p>
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|
Mol Cell Biochem 1999 Sep;199(1-2):93-102. <strong>
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|
Antioxidant properties of aspirin: characterization of the ability of aspirin to inhibit silica-induced
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|
lipid peroxidation, DNA damage, NF-kappaB activation, and TNF-alpha production.</strong> Shi X, Ding M,
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Dong Z, Chen F, Ye J, Wang S, Leonard SS, Castranova V, Vallyathan V
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</p>
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<p>
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J Physiol Paris 2001 Jan-Dec;95(1-6):51-7. <strong>Protection by aspirin of indomethacin-induced small
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|
intestinal damage in rats: mediation by salicylic acid.</strong> Takeuchi K, Hase S, Mizoguchi H,
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|
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>
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|
FASEB J 2001 Oct;15(12):2057-72. <strong>Cyclooxygenase-independent actions of cyclooxygenase</strong>
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|
<strong>
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|
inhibitors.</strong> Tegeder I, Pfeilschifter J, Geisslinger G.
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</p>
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<p>
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|
J Indian Med Assoc 1997 Feb;95(2):43-4, 47. <strong>Role of low dose aspirin in prevention of pregnancy
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|
induced hypertension.</strong> Tewari S, Kaushish R, Sharma S, Gulati N
|
|
</p>
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|
<p>
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|
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.
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|
</p>
|
|
|
|
<p>
|
|
Clin Exp Immunol 1991 Nov;86(2):315-21. <strong>Piroxicam, indomethacin</strong>
|
|
<strong>
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|
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>
|
|
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|
<p>
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|
Semin Perinatol 1986 Oct;10(4):334-55. <strong>The role of arachidonic acid metabolites in
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|
preeclampsia.</strong> Walsh SW, Parisi VM.
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|
</p>
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|
<p>
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|
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
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|
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>
|
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