VITAMINS. ENZYMES DRUGS. ANGIOPROTECTORS. (Thiamimi bromidum, Riboflavinum, Calcii pangamanas, Acidum folicum, Acidum nicotinicum, Piridoxinum, Cyanocobalaminum, Calcii pantotenas, Acidum ascorbinicum, Rutinum, Cvercitinum, Retinoli acetas, Ergocalcipherolum, Tocopheroli acetas, Vicasolium)

 

Vitamins

History: Approximately 40 vitamin and mineral nutrients are required by man. Vitamins can be defined as organic substances that must be provided in not more than small amounts from the environment to sustain healthy life.

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Vitamins are either not synthesized at all by the body or are synthesized in quantities too small to fulfill daily nutritional needs. For centuries, some diseases have been known to be related to deficient intake of a specific vitamin including night blindness (vitamin A deficiency), beriberi (thiamine deficiency), pellagra (niacin deficiency), scurvy (ascorbic acid deficiency), and rickets (vitamin D deficiency). Folic acid deficiency during gestation has recently been associated with neural tube defects in the fetus.

Vitamins were originally identified through animal experiments. Animal were fed a diet that was thought to cause a particular disease in man and then treated with the nutrient that was deficient in the diet producing the disease. Funk, in 1911, was able to identify an extract that prevented beriberi and coined the term "vitamine" because he believed the substance to be an amine that was vital to life. It was later confirmed by McCollum and Davis that a number of factors were present in fats (fat-soluble A) which were different from water-soluble factors they called a "water-soluble B" fraction. The B vitamins were found in an extract from rice husks and continue to be classified together even though they have different chemical structures and biologic functions.

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Today, the fat-soluble vitamins are known as vitamins A, D, E, and K. Water-soluble vitamins include thiamine, riboflavin, nicotinic acid (niacin), pyridoxine, pantothenic acid, biotin, folic acid, and cyanocobalamin.

The daily requirements for vitamins are estimated in the United States by the Food and Nutrition Board of the National Academy of Sciences. Recommended dietary allowances (RDA) are published for males and females of different ages and have been periodically revised since 1941.

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The RDA document also discusses substances that have not been proven essential by man. These substances are grouped into four categories: (1) those known to be essential for some animals but not shown to be needed by man (e.g., nickel, vanadium, and silicon); (2) substances that act as growth factors for lower forms of life (e.g., para-aminobenzoic acid, carnitine, and pimelic acid); (3) substances that are in foods but whose actions are probably pharmacologic or non-existent and; (4) substances for which scientific proof of a nutrient action has not been established (e.g., pangamic acid, laetrile). This latter category includes substances often promoted by the health-food industry.

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Vitamin products are regulated by the US FDA primarily as foods and not as drugs. Therefore, most vitamin products are not subject to the same requirements to establish safety and efficacy as are OTC and prescription drugs. The distinction as to whether a vitamin is a drug or a food supplement is determined by its intended use. If the vitamin is intended to treat or prevent disease, it is considered a drug.

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If, however, its use is simply as a nutritional supplement, then the vitamin is considered a food supplement and is not subject to the strict guidelines as mandated in the Food, Drug, and Cosmetic Act. Vitamin products must contain ingredients as labeled but there is no requirement to establish that the ingredients in the product are able to be absorbed from the product or are active after oral administration. In part to remedy this situation, the USP has published voluntary standards governing in vitro dosage form disintegration and dissolution. Vitamin and mineral supplement manufacturers may choose to test their products against these standards and indicate that they passed the tests on their product labels.

DMLA Vitamines, zinc et bêta-carotène

Mechanism of Action: Since vitamins represent a diverse collection of biologically active compounds, they exert their effects through a wide range of mechanisms. Their classification as vitamins is not because they have similar biochemical effects but because all are needed for continued good health. In general, most vitamins exert their effect by binding to a specific cofactor. Because it is thought that binding to the cofactor can be saturated at some vitamin concentration, increasing the dose of the vitamin, does not produce proportionately greater physiologic effects.

Rather, pharmacologic or toxic effects of the vitamin may occur. An example of an effect of a pharmacologic effect for a vitamin is the cholesterol lowering action of niacin (vitamin B3) when used in doses at least 40 times the RDA. Nevertheless, many individuals attribute near magical qualities to vitamins despite the fact that they merely represent dietary nutrients in tablet or capsule form. Recently, however, great interest in the antioxidant properties of vitamins C and E and beta-carotene has arisen. These data have been reviewed by Jha et al. It is thought that the body, particularly in smokers, generates highly reactive oxidative molecules which can be damaging to tissues unless neutralized. Adequate concentrations of the "antioxidant" vitamins affords the protection from these molecules the body needs. Oxidation of LDL cholesterol is an important step in the pathogenesis of atherosclerotic lesions. Vitamins with antioxidant properties include vitamin E (alpha-tocopherol), beta-carotene, and vitamin C. Other pharmacologic actions of vitamins are discussed in detail on the respective monographs for each vitamin.

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Distinguishing Features: Although dissimilar in function, fat- and water-soluble vitamins share some general characteristics. The body stores only limited amounts of water-soluble vitamins as these are easily eliminated by the kidneys. Fat-soluble vitamins are readily stored in large quantities and can accumulate to toxic concentrations. Health-food outlets and literature often promote the benefits of natural source products, however, products that are equally bioavailable are equally effective regardless of origin (natural or synthetic).

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Besides satisfying the body's daily needs to prevent the development of a deficiency state, some vitamins have therapeutic uses: pyridoxine can be used in the treatment of sideroblastic anemia and to offset certain drug-induced neuropathies, niacin exerts an antilipemic action, and ascorbic acid can be used to acidify the urine. Some derivatives of vitamin A - though not nutrients in the strict definition - exert powerful effects on the skin and the hematopoetic system, underscoring how important vitamins are to general health. Although more data are needed, preliminary results indicate that routine intake of doses of vitamins with antioxidant properties in excess of the standard RDA may indeed be protective against myocardial infarction. Data is most convincing for vitamin E, however, results from randomized trials has tempered enthusiasm generated from earlier epidemiologic cohort studies. The beneficial effects of beta-carotene on risk of myocardial infarction appear to be limited to smokers. Vitamin C was found to reduce risk in only one cohort study. Clinicians should also consider that subjects using antioxidant vitamins in these studies were less likely to be smokers and have hypertension, more likely to exercise regularly, and consumed more alcohol.

Adverse Reactions: Due to their prompt elimination via the kidneys, sweat glands, and other sites of excretion, water-soluble vitamins are generally considered to be non-toxic even when taken in larger than physiologic doses. Various toxicities, however, have been associated with water-soluble vitamins. In doses greater than the RDA, niacin can be hepatotoxic, ascorbic acid has been associated with nephrolithiasis, and pyridoxine, paradoxically, in very high doses has caused peripheral neuropathy. Fat soluble vitamins, on the other hand, can readily accumulate to toxic levels when taken in doses substantially greater than the RDA. The liver is highly efficient in storing vitamin A and even modest doses of vitamin D taken in combination with calcium supplements can lead to hypercalcemia severe enough produce coma. Since there is no established benefit of taking vitamins in excess quantities, the AMA Council on Scientific Affairs has recommended that the daily intake of vitamins be limited to 150% of the RDA for any single vitamin in patients with no documented need for therapeutic doses.

VItamin B12

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Vitamin B12 serves as a cofactor for several essential biochemical reactions in humans. Deficiency of vitamin B12 leads to anemia, gastrointestinal symptoms, and neurologic abnormalities.

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While deficiency of vitamin B12 due to an inadequate supply in the diet is unusual, deficiency of B12 in adults—especially older adults—due to abnormal absorption of dietary vitamin B12 is a relatively common and easily treated disorder.

Chemistry

Vitamin B12 consists of a porphyrin-like ring with a central cobalt atom attached to a nucleotide.

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Various organic groups may be covalently bound to the cobalt atom, forming different cobalamins. Deoxyadenosylcobalamin and methylcobalamin are the active forms of the vitamin in humans.

 

Vitamin B12 and folate metabolism

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Cyanocobalamin and hydroxocobalamin (both available for therapeutic use) and other cobalamins found in food sources are converted to the above active forms. The ultimate source of vitamin B12 is from microbial synthesis; the vitamin is not synthesized by animals or plants. The chief dietary source of vitamin B12 is microbially derived vitamin B12 in meat (especially liver), eggs, and dairy products. Vitamin B12 is sometimes called extrinsic factor to differentiate it from intrinsic factor, a protein normally secreted by the stomach.

Pharmacokinetics

The average diet in the USA contains 5–30 g of vitamin B12 daily, 1–5 g of which is usually absorbed.

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The vitamin is avidly stored, primarily in the liver, with an average adult having a total vitamin B12 storage pool of 3000–5000 g. Only trace amounts of vitamin B12 are normally lost in urine and stool. Since the normal daily requirements of vitamin B12 are only about 2 g, it would take about 5 years for all of the stored vitamin B12 to be exhausted and for megaloblastic anemia to develop if B12 absorption stopped.

Vitamin B12 in physiologic amounts is absorbed only after it complexes with intrinsic factor, a glycoprotein secreted by the parietal cells of the gastric mucosa. Intrinsic factor combines with the vitamin B12 that is liberated from dietary sources in the stomach and duodenum, and the intrinsic factor-vitamin B12 complex is subsequently absorbed in the distal ileum by a highly specific receptor-mediated transport system.

Vitamin B12 deficiency in humans most often results from malabsorption of vitamin B12, due either to lack of intrinsic factor or to loss or malfunction of the specific absorptive mechanism in the distal ileum. Nutritional deficiency is rare but may be seen in strict vegetarians after many years without meat, eggs, or dairy products. Once absorbed, vitamin B12 is transported to the various cells of the body bound to a plasma glycoprotein, transcobalamin II. Excess vitamin B12 is transported to the liver for storage. Significant amounts of vitamin B12 are excreted in the urine only when very large amounts are given parenterally, overcoming the binding capacities of the transcobalamins (50–100 g).

Pharmacodynamics

Two essential enzymatic reactions in humans require vitamin B12 (Figure 33–1). In one, methylcobalamin serves as an intermediate in the transfer of a methyl group from N_5- methyltetrahydrofolate to methionine (Figure 33–1 A; Figure 33–2, reaction 1).

In the absence of vitamin B12, conversion of the major dietary and storage folate, N5-methyltetrahydrofolate, to tetrahydrofolate, the precursor of folate cofactors, cannot occur. As a result, a deficiency of folate cofactors necessary for several biochemical reactions involving the transfer of one-carbon groups develops. In particular, the depletion of tetrahydrofolate prevents synthesis of adequate supplies of the deoxythymidylate (dTMP) and purines required for DNA synthesis in rapidly dividing cells as shown in Figure 33–3, reaction 2.

The accumulation of folate as N5-methyltetrahydrofolate and the associated depletion of tetrahydrofolate cofactors in vitamin B12 deficiency have been referred to as the "methylfolate trap." This is the biochemical step whereby vitamin B12 and folic acid metabolism are linked and explains why the megaloblastic anemia of vitamin B12 deficiency can be partially corrected by ingestion of relatively large amounts of folic acid. Folic acid can be reduced to dihydrofolate by the enzyme dihydrofolate reductase (Figure 33–2, reaction 3) and thus serve as a source of the tetrahydrofolate required for synthesis of the purines and dTMP that are needed for DNA synthesis.

The other enzymatic reaction that requires vitamin B12 is isomerization of methylmalonyl-CoA to succinyl-CoA by the enzyme methylmalonyl-CoA mutase (Figure 33–1 B). In vitamin B12 deficiency, this conversion cannot take place, and the substrate, methylmalonyl-CoA, accumulates.

In the past, it was thought that abnormal accumulation of methylmalonyl-CoA causes the neurologic manifestations of vitamin B12 deficiency. However, newer evidence instead implicates the disruption of the methionine synthesis pathway as the cause of neurologic problems. Whatever the biochemical explanation for neurologic damage, the important point is that administration of folic acid in the setting of vitamin B12 deficiency will not prevent neurologic manifestations even though it will largely correct the anemia caused by the vitamin B12 deficiency.

Clinical Pharmacology

Vitamin B12 is used to treat or prevent deficiency. There is no evidence that vitamin B12 injections have any benefit in persons who do not have vitamin B12 deficiency. The most characteristic clinical manifestation of vitamin B12 deficiency is megaloblastic anemia.

The typical clinical findings in megaloblastic anemia are macrocytic anemia (MCV usually > 120 fL), often with associated mild or moderate leukopenia or thrombocytopenia (or both), and a characteristic hypercellular bone marrow with megaloblastic maturation of erythroid and other precursor cells.

Figure 33–1.

Vitamin B12 deficiency also causes a neurologic syndrome that usually begins with paresthesias and weakness in peripheral nerves and progresses to spasticity, ataxia, and other central nervous system dysfunctions. A characteristic pathologic feature of the neurologic syndrome is degeneration of myelin sheaths followed by disruption of axons in the dorsal and lateral horns of the spinal cord and in peripheral nerves. Correction of vitamin B12 deficiency arrests the progression of neurologic disease, but it may not fully reverse neurologic symptoms that have been present for several months.

Although most patients with neurologic abnormalities caused by vitamin B12 deficiency have full-blown megaloblastic anemias when first seen, occasional patients have few if any hematologic abnormalities. Once a diagnosis of megaloblastic anemia is made, it must be determined whether vitamin B12 or folic acid deficiency is the cause. (Other causes of megaloblastic anemia are very rare.)

 

Figure 33–2.

This can usually be accomplished by measuring serum levels of the vitamins. The Schilling test, which measures absorption and urinary excretion of radioactively labeled vitamin B12, can be used to further define the mechanism of vitamin B12 malabsorption when this is found to be the cause of the megaloblastic anemia.

The most common causes of vitamin B12 deficiency are pernicious anemia, partial or total gastrectomy, and diseases that affect the distal ileum, such as malabsorption syndromes, inflammatory bowel disease, or small bowel resection.

Pernicious anemia results from defective secretion of intrinsic factor by the gastric mucosal cells.

Patients with pernicious anemia have gastric atrophy and fail to secrete intrinsic factor (as well as hydrochloric acid). The Schilling test shows diminished absorption of radioactively labeled vitamin B12, which is corrected when hog intrinsic factor is administered with radioactive B12, since the vitamin can then be normally absorbed.

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Vitamin B12 deficiency also occurs when the region of the distal ileum that absorbs the vitamin B12-intrinsic factor complex is damaged, as when the ileum is involved with inflammatory bowel disease, or when the ileum is surgically resected. In these situations, radioactively labeled vitamin B12 is not absorbed in the Schilling test, even when intrinsic factor is added. Other rare causes of vitamin B12 deficiency include bacterial overgrowth of the small bowel, chronic pancreatitis, and thyroid disease. Rare cases of vitamin B12 deficiency in children have been found to be secondary to congenital deficiency of intrinsic factor and congenital selective vitamin B12 malabsorption due to defects of the receptor sites in the distal ileum. Since almost all cases of vitamin B12 deficiency are caused by malabsorption of the vitamin, parenteral injections of vitamin B12 are required for therapy. For patients with potentially reversible diseases, the underlying disease should be treated after initial treatment with parenteral vitamin B12. Most patients, however, do not have curable deficiency syndromes and require lifelong treatment with vitamin B12 injections.

Vitamin B12 for parenteral injection is available as cyanocobalamin or hydroxocobalamin. Hydroxocobalamin is preferred because it is more highly protein-bound and therefore remains longer in the circulation. Initial therapy should consist of 100–1000 g of vitamin B12 intramuscularly daily or every other day for 1–2 weeks to replenish body stores.

Maintenance therapy consists of 100–1000 g intramuscularly once a month for life. If neurologic abnormalities are present, maintenance therapy injections should be given every 1–2 weeks for 6 months before switching to monthly injections.

Oral vitamin B12-intrinsic factor mixtures and liver extracts should not be used to treat vitamin B12 deficiency; however, oral doses of 1000 g of vitamin B12 daily are usually sufficient to treat patients with pernicious anemia who refuse or cannot tolerate the injections.

 

Folic Acid

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Reduced forms of folic acid are required for essential biochemical reactions that provide precursors for the synthesis of amino acids, purines, and DNA. Folate deficiency is not uncommon, even though the deficiency is easily corrected by administration of folic acid. The consequences of folate deficiency go beyond the problem of anemia because folate deficiency is implicated as a cause of congenital malformations in newborns and may play a role in vascular disease (see Folic Acid Supplementation: A Public Health Dilemma).

Chemistry

Folic acid (pteroylglutamic acid) is a compound composed of a heterocycle, p-aminobenzoic acid, and glutamic acid (Figure 33–3). Various numbers of glutamic acid moieties may be attached to the pteroyl portion of the molecule, resulting in monoglutamates, triglutamates, or polyglutamates.

Folic_Acid

 Folic acid can undergo reduction, catalyzed by the enzyme dihydrofolate reductase ("folate reductase"), to give dihydrofolic acid (Figure 33–2, reaction 3). Tetrahydrofolate can subsequently be transformed to folate cofactors possessing one-carbon units attached to the 5-nitrogen, to the 10- nitrogen, or to both positions (Figure 33–2). The folate cofactors are interconvertible by various enzymatic reactions and serve the important biochemical function of donating one-carbon units at various levels of oxidation. In most of these, tetrahydrofolate is regenerated and becomes available for reutilization.

Pharmacokinetics

The average diet in the USA contains 500–700 g of folates daily, 50–200 g of which is usually absorbed, depending on metabolic requirements (pregnant women may absorb as much as 300–400 g of folic acid daily). Various forms of folic acid are present in a wide variety of plant and animal tissues; the richest sources are yeast, liver, kidney, and green vegetables. Normally, 5–20 mg of folates are stored in the liver and other tissues.

Folates are excreted in the urine and stool and are also destroyed by catabolism, so serum levels fall within a few days when intake is diminished. Since body stores of folates are relatively low and daily requirements high, folic acid deficiency and megaloblastic anemia can develop within 1–6 months after the intake of folic acid stops, depending on the patient's nutritional status and the rate of folate utilization. Unaltered folic acid is readily and completely absorbed in the proximal jejunum. Dietary folates, however, consist primarily of polyglutamate forms of N_5-methyltetrahydrofolate.

Before absorption, all but one of the glutamyl residues of the polyglutamates must be hydrolyzed by the enzyme -1-glutamyl transferase ("conjugase") within the brush border of the intestinal mucosa  The monoglutamate N_5-methyltetrahydrofolate is subsequently transported into the bloodstream by both active and passive transport and is then widely distributed throughout the body. Inside cells, N_5-methyltetrahydrofolate is converted to tetrahydrofolate by the demethylation reaction that requires vitamin B12 (Figure 33–2, reaction 1).

Pharmacodynamics

Tetrahydrofolate cofactors participate in one-carbon transfer reactions. As described above in the section on vitamin B12, one of these essential reactions produces the dTMP needed for DNA synthesis. In this reaction, the enzyme thymidylate synthase catalyzes the transfer of the one-carbon unit of N_5,N_10-methylenetetrahydrofolate to deoxyuridine monophosphate (dUMP) to form dTMP (Figure 33–2, reaction 2). Unlike all of the other enzymatic reactions that utilize folate cofactors, in this reaction the cofactor is oxidized to dihydrofolate, and for each mole of dTMP produced, one mole of tetrahydrofolate is consumed. In rapidly proliferating tissues, considerable amounts of tetrahydrofolate can be consumed in this reaction, and continued DNA synthesis requires continued regeneration of tetrahydrofolate by reduction of dihydrofolate, catalyzed by the enzyme dihydrofolate reductase. The tetrahydrofolate thus produced can then reform the cofactor N_5,N_10-methylenetetrahydrofolate by the action of serine transhydroxy- methylase and thus allow for the continued synthesis of dTMP. The combined catalytic activities of dTMP synthase, dihydrofolate reductase, and serine transhydroxymethylase are often referred to as the dTMP synthesis cycle. Enzymes in the dTMP cycle are the targets of two anticancer drugs; methotrexate inhibits dihydrofolate reductase, and a metabolite of 5-fluorouracil inhibits thymidylate synthase. Cofactors of tetrahydrofolate participate in several other essential reactions. As described above, N_5-methy- lenetetrahydrofolate is required for the vitamin B12-dependent reaction that generates methionine from homocysteine (Figure 33–1 A; Figure 33–2, reaction 1). In addition,

tetrahydrofolate cofactors donate one-carbon units during the de novo synthesis of essential purines.

In these reactions, tetrahydrofolate is regenerated and can reenter the tetrahydrofolate cofactor pool.

Clinical Pharmacology

Folate deficiency results in a megaloblastic anemia that is microscopically indistinguishable from the anemia caused by vitamin B12 deficiency (see above). However, folate deficiency does not cause the characteristic neurologic syndrome seen in vitamin B12 deficiency. In patients with megaloblastic anemia, folate status is assessed with assays for serum folate or for red blood cell folate.

Red blood cell folate levels are often of greater diagnostic value than serum levels, since serum folate levels tend to be quite labile and do not necessarily reflect tissue levels. Folic acid deficiency, unlike vitamin B12 deficiency, is often caused by inadequate dietary intake of folates. Alcoholics and patients with liver disease develop folic acid deficiency because of poor diet and diminished hepatic storage of folates. There is also evidence that alcohol and liver disease interfere with absorption and metabolism of folates. Pregnant women and patients with hemolytic anemia have increased folate requirements and may become folic acid-deficient, especially if their diets are marginal. Evidence implicates maternal folic acid deficiency in the occurrence of fetal neural tube defects, eg, spina bifida.

Patients with malabsorption syndromes also frequently develop folic acid deficiency. Folic acid deficiency is occasionally associated with cancer, leukemia, myeloproliferative disorders, certain chronic skin disorders, and other chronic debilitating diseases. Patients who require renal dialysis also develop folic acid deficiency, because folates are removed from the plasma each time the patient is dialyzed. Folic acid deficiency can be caused by drugs that interfere with folate absorption or metabolism. Phenytoin, some other anticonvulsants, oral contraceptives, and isoniazid can cause folic acid deficiency by interfering with folic acid absorption. Other drugs such as methotrexate and, to a lesser extent, trimethoprim and pyrimethamine, inhibit dihydrofolate reductase and may result in a deficiency of folate cofactors and ultimately in megaloblastic anemia.

Parenteral administration of folic acid is rarely necessary, since oral folic acid is well absorbed even in patients with malabsorption syndromes.

A dose of 1 mg of folic acid orally daily is sufficient to reverse megaloblastic anemia, restore normal serum folate levels, and replenish body stores of folates in almost all patients.

Therapy should be continued until the underlying cause of the deficiency is removed or corrected. Therapy may be required indefinitely for patients with malabsorption or dietary inadequacy.

Folic acid supplementation to prevent folic acid deficiency should be considered in high-risk patients, including pregnant women, alcoholics, and patients with hemolytic anemia, liver disease, certain skin diseases, and patients on renal dialysis.

By January 1998, all products made from enriched grains in the USA were required to be supplemented with folic acid. This FDA ruling was issued to reduce the incidence of congenital neural tube defects. Scientific studies show a strong correlation between maternal folic acid deficiency and the incidence of neural tube defects such as spinal bifida and anencephaly. The FDA requirement for folic acid supplementation is a public health measure aimed at the significant number of women in the USA who do not receive prenatal care and are not aware of the importance of adequate folic acid ingestion for preventing birth defects in their babies. Pregnant women have increased requirements for folic acid; at least 400 g/d is recommended. It is estimated that the level of folic acid fortification now required in enriched grain products provides an additional 80–100 g of folic acid per day to the diet of women of childbearing age and 70–120 g/d to the diet of middle-aged and older adults. There may be an added benefit for adults. N_5-methyltetrahydrofolate is required for the conversion of homocysteine to methionine (Figure 33–1; Figure 33–2, reaction 1). Impaired synthesis of N_5-methyltetrahydrofolate results in elevated serum concentrations of homocysteine. Data from several sources suggest a positive correlation between elevated serum homocysteine and occlusive vascular diseases such as ischemic heart disease and stroke.

Clinical data suggest that the folate supplementation program has improved the folate status and reduced the prevalence of hyperhomocysteinemia in a population of middle-aged and older adults who did not use vitamin supplements. It is possible, though as yet unproved, that the increased ingestion of folic acid will also reduce the risk of vascular disease in this population. While these two potential benefits of supplemental folic acid are compelling, the decision to require folic acid in grains was—and still is—controversial. As described in the text, ingestion of folic acid can partially or totally correct the anemia caused by vitamin B12 deficiency. However, folic acid supplementation will not prevent the potentially irreversible neurologic damage caused by vitamin B12 deficiency. People with pernicious anemia and other forms of vitamin B12 deficiency are usually identified because of signs and symptoms of anemia, which tend to occur before neurologic symptoms. The opponents of folic acid supplementation are concerned that increased folic acid intake in the general population will mask vitamin B12 deficiency and increase the prevalence of neurologic disease in our elderly population. To put this in perspective, approximately 4000 pregnancies, including 2500 live births, in the USA each year are affected by neural tube defects. In contrast, it is estimated that over 10% of the elderly population in the USA, or several million people, are at risk of the neuropsychiatric complications of vitamin B12 deficiency (Rothenberg, 1999). In acknowledgment of this controversy, the FDA kept its requirements for folic acid supplementation at a somewhat low level. They also recommend that all adults should keep their ingestion of folic acid below 1 mg/d.

VItamin D

http://www.nutriform.fr/img/interrogation.JPG  http://www.universalis.fr/images/corpus/medias/mini/v11/atelier.swf/v23/v230724b.jpg

Vitamin D is a secosteroid produced in the skin from 7-dehydrocholesterol under the influence of ultraviolet irradiation. Vitamin D is also found in certain foods and is used to supplement dairy products. Both the natural form (vitamin D3, cholecalciferol) and the plant-derived form (vitamin D2, ergocalciferol) are present in the diet. These forms differ in that ergocalciferol contains a double bond (C22–23) and an additional methyl group in the side chain

(Figure 42–2).

Vitamin D is a prohormone that serves as precursor to a number of biologically active metabolites (Figure 42–2).

 

http://www.minkhollow.ca/HatchingProgram/Candling/Resources/BS/sm-bs-d-6.JPGhttp://www.7sur7.be/static/FOTO/art/11/12/2/large_276993.jpghttp://www.vitamines-mineraux.com/pic/noix.jpg

Vitamin D is first hydroxylated in the liver to form 25-hydroxyvitamin D (25[OH]D). This metabolite is further converted in the kidney to a number of other forms, the beststudied of which are 1,25-dihydroxyvitamin D (1,25[OH]2D) and 24,25-dihydroxyvitamin D (24,25[OH]2D). Of the natural metabolites, only vitamin D, 25(OH)D (as calcifediol), and 1,25(OH)2D (as calcitriol) are available for clinical use (see Table 42–1)

http://www.bioneptune.com/images/produits/onguents/vitamine-d.jpg 

 Moreover, a number of analogs of 1,25(OH)2 are being synthesized in an effort to extend the usefulness of this metabolite to a variety of nonclassic conditions. Calcipotriene (calcipotriol), for example, is currently being used to treat psoriasis, a hyperproliferative skin disorder. Doxercalciferol and paricalcitol have recently been approved for the treatment of secondary hyperparathyroidism in patients with renal failure.

http://www.psycholoog.net/images/vitamineD.jpeg  http://www.pau.fr/xox_01/images/article/20060725_163349_1.jpg

source de vitamines D-3) ...

Other analogs are being investigated for the treatment of various malignancies. The regulation of vitamin D metabolism is complex, involving calcium, phosphate, and a variety of hormones, the most important of which is PTH, which stimulates the production of 1,25(OH)2D by the kidney. mechanism of action of the vitamin D metabolites remains under active investigation. However, calcitriol is well established as the most potent agent with respect to stimulation of intestinal calcium and phosphate transport and bone resorption.

Calcitriol appears to act on the intestine both by induction of new protein synthesis (eg, calcium-binding protein) and by modulation of calcium flux across the brush border and basolateral membranes by a means does not require new protein synthesis. The molecular action of calcitriol on bone has received less attention. However, like PTH, calcitriol can induce RANK ligand in osteoblasts and proteins such as osteocalcin, which may regulate the mineralization process. The metabolites 25(OH)D and 24,25(OH)2D are far less potent stimulators of intestinal calcium and phosphate transport or bone resorption. However, 25(OH)D appears to be more potent than 1,25(OH)2D in stimulating renal reabsorption of calcium and phosphate and may be the major metabolite regulating calcium flux and contractility in muscle. Specific receptors for 1,25(OH)2D exist in target The issues. However, the role and even the existence of receptors for 25(OH)D and 24,25(OH)2D remain controversial.

http://www.lanutrition.fr/upload/fckeditor/Image/sante/comprimes/gelule%20vitamine%20E.jpg

A summary of the principal actions of PTH and vitamin D on the three main target tissues— intestine, kidney, and bone—is presented in Table 42–2. The net effect of PTH is to raise serum calcium and reduce serum phosphate; the net effect of vitamin D is to raise both. Regulation of calcium and phosphate homeostasis is achieved through a variety of feedback loops. Calcium is the principal regulator of PTH secretion. It binds to a novel ion recognition site that is part of a Gq protein–coupled receptor and links changes in intracellular free calcium concentration to changes in

extracellular calcium. As serum calcium levels rise and bind to this receptor, intracellular calcium levels increase and inhibit PTH secretion. Phosphate regulates PTH secretion indirectly by forming complexes with calcium in the serum. Since it is the ionized concentration of calcium that is detected by the parathyroid gland, increases in serum phosphate levels reduce the ionized calcium and lead to enhanced PTH secretion. Such feedback regulation is appropriate to the net effect of PTH to raise serum calcium and reduce serum phosphate levels. Likewise, both calcium and phosphate at high levels reduce the amount of 1,25(OH)2D produced by the kidney and increase the amount of 24,25(OH)2D produced. Since 1,25(OH)2D raises serum calcium and phosphate, whereas 24,25(OH)2D has less effect, such feedback regulation is again appropriate. 1,25(OH)2D itself directly inhibits PTH secretion (independently of its effect on serum calcium) by a direct action on PTH gene transcription. This provides yet another negative feedback loop, because PTH is a major stimulus for 1,25(OH)2D production. This ability of 1,25(OH)2D to inhibit PTH secretion directly is being exploited using calcitriol analogs that have less effect on serum calcium.

Such drugs are proving useful in the management of secondary hyperparathyroidism accompanying renal failure and may be useful in selected cases of primary hyperparathyroidism.

 

A number of hormones modulate the actions of PTH and vitamin D in regulating bone mineral homeostasis. Compared with that of PTH and vitamin D, the physiologic impact of such secondary regulation on bone mineral homeostasis is minor. However, in pharmacologic amounts, a number of these hormones have actions on the bone mineral homeostatic mechanisms that can be exploited therapeutically.

The principal effects of calcitonin are to lower serum calcium and phosphate by actions on bone and kidney. Calcitonin inhibits osteoclastic bone resorption. Although bone formation is not impaired at first after calcitonin administration, with time both formation and resorption of bone are reduced.

Thus, the early hope that calcitonin would prove useful in restoring bone mass has not been realized. In the kidney, calcitonin reduces both calcium and phosphate reabsorption as well as reabsorption of other ions, including sodium, potassium, and magnesium. Tissues other than bone and kidney are also affected by calcitonin. Calcitonin in pharmacologic amounts decreases gastrin secretion and reduces gastric acid output while increasing secretion of sodium, potassium, chloride, and water in the gut. Pentagastrin is a potent stimulator of calcitonin secretion (as is hypercalcemia), suggesting a possible physiologic relationship between gastrin and calcitonin. In the adult human, no readily demonstrable problem develops in cases of calcitonin deficiency (thyroidectomy) or excess (medullary carcinoma of the thyroid). However, the ability of calcitonin to block bone resorption and lower serum calcium makes it a useful drug for the treatment of Paget's disease, hypercalcemia, and osteoporosis.

Clinical Pharmacology

Disorders of bone mineral homeostasis generally present with abnormalities in serum or urine calcium levels (or both), often accompanied by abnormal serum phosphate levels. These abnormal mineral concentrations may themselves cause symptoms requiring immediate treatment (eg, coma in malignant hypercalcemia, tetany in hypocalcemia). More commonly, they serve as clues to an underlying disorder in hormonal regulators (eg, primary hyperparathyroidism), target tissue response (eg, chronic renal failure), or drug misuse (eg, vitamin D intoxication). In such cases, treatment of the underlying disorder is of prime importance.

Since bone and kidney play central roles in bone mineral homeostasis, conditions that alter bone mineral homeostasis usually affect either or both of these tissues secondarily. Effects on bone can result in osteoporosis (abnormal loss of bone; remaining bone histologically normal), osteomalacia (abnormal bone formation due to inadequate mineralization), or osteitis fibrosa (excessive bone resorption with fibrotic replacement of resorption cavities). Biochemical markers of skeletal involvement include changes in serum levels of the skeletal isoenzyme of alkaline phosphatase and

osteocalcin (reflecting osteoblastic activity) and urine levels of hydroxyproline and pyridinoline cross-links (reflecting osteoclastic activity). The kidney becomes involved when the calcium-timesphosphate product in serum exceeds the point at which ectopic calcification occurs (nephrocalcinosis) or when the calcium-times-oxalate (or phosphate) product in urine exceeds saturation, leading to nephrolithiasis. Subtle early indicators of such renal involvement include polyuria, nocturia, and hyposthenuria. Radiologic evidence of nephrocalcinosis and stones is not generally observed until later. The degree of the ensuing renal failure is best followed by monitoring the decline in creatinine clearance.

Abnormal Serum Calcium & Phosphate Levels

Hypercalcemia

Hypercalcemia causes central nervous system depression, including coma, and is potentially lethal. Its major causes (other than thiazide therapy) are hyperparathyroidism and cancer with or without bone metastases. Less common causes are hypervitaminosis D, sarcoidosis, thyrotoxicosis, milkalkali syndrome, adrenal insufficiency, and immobilization. With the possible exception of hypervitaminosis D, these latter disorders seldom require emergency lowering of serum calcium. A number of approaches are used to manage the hypercalcemic crisis.

When rapidity of action is required, 1,25(OH)2D3 (calcitriol), 0.25–1 g daily, is the vitamin D metabolite of choice, since it is capable of raising serum calcium within 24–48 hours. Calcitriol also raises serum phosphate, though this action is usually not observed early in treatment. The combined effects of calcitriol and all other vitamin D metabolites and analogs on both calcium and phosphate make careful monitoring of these mineral levels especially important to avoid ectopic calcification secondary to an abnormally high serum calcium x phosphate product. Since the choice of the levels of high-energy organic

http://www.lactopole.com/images/lait/vitamines.jpg  http://www.carlsbourg.be/img/db/co/mc_motte_facettes.jpg  http://www.bcv-viandedeveau.be/beelden/voedingswaarde/lenteschenkel_fr.jpg

Vitamin D deficiency, once thought to be rare in this country, is being recognized more often, especially in the pediatric and geriatric populations on vegetarian diets and with reduced sunlight exposure. This problem can be avoided by daily intake of 400–800 units of vitamin D and treated by higher dosages (4000 units per day). No other metabolite is indicated. The diet should also

contain adequate amounts of calcium and phosphate.

Use of Vitamin D Preparations

The choice of vitamin D preparation to be used in the setting of chronic renal failure in the dialysis patient depends on the type and extent of bone disease and hyperparathyroidism. No consensus has been reached regarding the advisability of using any vitamin D metabolite in the predialysis patient. 1,25(OH)2D3 (calcitriol) will rapidly correct hypocalcemia and at least partially reverse the secondary hyperparathyroidism and osteitis fibrosa. Many patients with muscle weakness and bone pain gain an improved sense of well-being.

Dihydrotachysterol, an analog of 1,25(OH)2D, is also available for clinical use, though it is used much less frequently than calcitriol. Dihydrotachysterol appears to be as effective as calcitriol, differing principally in its time course of action; calcitriol increases serum calcium in 1–2 days, whereas dihydrotachysterol requires 1–2 weeks. For an equipotent dose (0.2 mg dihydrotachy-sterol versus 0.5 g calcitriol), dihydrotachysterol costs about one fourth as much as calcitriol. Adisadvantage of dihydrotachysterol is the inability to measure it in serum. Neither dihydrotachysterol nor calcitriol corrects the osteomalacic component of renal osteodystrophy in the majority of patients, and neither should be used in patients with hypercalcemia, especially if the bone disease is primarily osteomalacic.

Calcifediol (25[OH]D3) may also be used to advantage. Calcifediol is less effective than calcitriol in stimulating intestinal calcium transport, so that hypercalcemia is less of a problem with calcifediol.

Like dihydrotachysterol, calcifediol requires several weeks to restore normocalcemia in hypocalcemic individuals with chronic renal failure. Presumably because of the reduced ability of the diseased kidney to metabolize calcifediol to more active metabolites, high doses (50–100 g daily) must be given to achieve the supraphysiologic serum levels required for therapeutic effectiveness.

Vitamin D has been used in treating renal osteodystrophy. However, patients with a substantial degree of renal failure who are thus unable to convert vitamin D to its active metabolites usually are refractory to vitamin D. Its use is decreasing as more effective alternatives become available.

Two analogs of calcitriol, doxercalciferol and paricalcitol, are approved for the treatment of secondary hyperparathyroidism of chronic renal failure. Their principal advantage is that they are less likely than calcitriol to induce hypercalcemia. Their biggest impact will be in patients in whom the use of calcitriol may lead to unacceptably high serum calcium levels.

Regardless of the drug employed, careful attention to serum calcium and phosphate levels is required. Calcium supplements (dietary and in the dialysate) and phosphate restriction (dietary and with oral ingestion of phosphate binders) should be employed along with the use of vitamin D metabolites. Monitoring serum PTH and alkaline phosphatase levels is useful in determining whether therapy is correcting or preventing secondary hyperparathyroidism.

Although not generally available, percutaneous bone biopsies for quantitative histomorphometry may help in choosing appropriate therapy and following the effectiveness of such therapy. Unlike the rapid changes in serum values, changes in bone morphology require months to years. Monitoring serum levels of the vitamin D metabolites is useful to determine compliance, absorption, and metabolism.

The common features that appear to be important in this group of diseases are malabsorption of calcium and vitamin D. Liver disease may, in addition, reduce the production of 25(OH)D from vitamin D, though the importance of this in all but patients with terminal liver failure remains in dispute. The malabsorption of vitamin D is probably not limited to exogenous vitamin D. The liver secretes into bile a substantial number of vitamin D metabolites and conjugates that are reabsorbed in (presumably) the distal jejunum and ileum. Interference with this process could deplete the body of endogenous vitamin D metabolites as well as limit absorption of dietary vitamin D.

In mild forms of malabsorption, vitamin D (25,000–50,000 units three times per week) should suffice to raise serum levels of 25(OH)D into the normal range. Many patients with severe disease do not respond to vitamin D. Clinical experience with

Vitamin D is a secosteroid produced in the skin from 7-dehydrocholesterol under the influence of ultraviolet irradiation. Vitamin D is also found in certain foods and is used to supplement dairy products. Both the natural form (vitamin D3, cholecalciferol) and the plant-derived form (vitamin D2, ergocalciferol) are present in the diet. These forms differ in that ergocalciferol contains a double bond (C22–23) and an additional methyl group in the side chain (Figure 42–2).

Vitamin D is a prohormone that serves as precursor to a number of biologically active metabolites (Figure 42–2). Vitamin D is first hydroxylated in the liver to form 25-hydroxyvitamin D (25[OH]D). This metabolite is further converted in the kidney to a number of other forms, the beststudied of which are 1,25-dihydroxyvitamin D (1,25[OH]2D) and 24,25-dihydroxyvitamin D (24,25[OH]2D). Of the natural metabolites, only vitamin D, 25(OH)D (as calcifediol), and 1,25(OH)2D (as calcitriol) are available for clinical use (see Table 42–1). Moreover, a number of analogs of 1,25(OH)2 are being synthesized in an effort to extend the usefulness of this metabolite to a variety of nonclassic conditions. Calcipotriene (calcipotriol), for example, is currently being used to treat psoriasis, a hyperproliferative skin disorder. Doxercalciferol and paricalcitol have recently been approved for the treatment of secondary hyperparathyroidism in patients with renal failure. Other analogs are being investigated for the treatment of various malignancies. The regulation of vitamin D metabolism is complex, involving calcium, phosphate, and a variety of hormones, the most important of which is PTH, which stimulates the production of 1,25(OH)2D by

the kidney. mechanism of action of the vitamin D metabolites remains under active investigation. However, calcitriol is well established as the most potent agent with respect to stimulation of intestinal calcium and phosphate transport and bone resorption. Calcitriol appears to act on the intestine both by induction of new protein synthesis (eg, calcium-binding protein) and by modulation of calcium flux across the brush border and basolateral membranes by a means does not require new protein synthesis. The molecular action of calcitriol on bone has received less attention. However, like PTH, calcitriol can induce RANK ligand in osteoblasts and proteins such as osteocalcin, which may regulate the mineralization process. The metabolites 25(OH)D and 24,25(OH)2D are far less potent stimulators of intestinal calcium and phosphate transport or bone resorption. However, 25(OH)D appears to be more potent than 1,25(OH)2D in stimulating renal reabsorption of calcium and phosphate and may be the major metabolite regulating calcium flux and contractility in muscle. Specific receptors for 1,25(OH)2D exist in target The issues. However, the role and even the existence of receptors for 25(OH)D and 24,25(OH)2D remain controversial.

A summary of the principal actions of PTH and vitamin D on the three main target tissues— intestine, kidney, and bone—is presented in Table 42–2. The net effect of PTH is to raise serum calcium and reduce serum phosphate; the net effect of vitamin D is to raise both. Regulation of calcium and phosphate homeostasis is achieved through a variety of feedback loops. Calcium is the principal regulator of PTH secretion. It binds to a novel ion recognition site that is part of a Gq protein–coupled receptor and links changes in intracellular free calcium concentration to changes in

extracellular calcium. As serum calcium levels rise and bind to this receptor, intracellular calcium levels increase and inhibit PTH secretion. Phosphate regulates PTH secretion indirectly by forming complexes with calcium in the serum. Since it is the ionized concentration of calcium that is detected by the parathyroid gland, increases in serum phosphate levels reduce the ionized calcium and lead to enhanced PTH secretion. Such feedback regulation is appropriate to the net effect of PTH to raise serum calcium and reduce serum phosphate levels. Likewise, both calcium and phosphate at high levels reduce the amount of 1,25(OH)2D produced by the kidney and increase the amount of 24,25(OH)2D produced. Since 1,25(OH)2D raises serum calcium and phosphate, whereas 24,25(OH)2D has less effect, such feedback regulation is again appropriate. 1,25(OH)2D itself directly inhibits PTH secretion (independently of its effect on serum calcium) by a direct action on PTH gene transcription. This provides yet another negative feedback loop, because PTH is a major stimulus for 1,25(OH)2D production. This ability of 1,25(OH)2D to inhibit PTH secretion directly is being exploited using calcitriol analogs that have less effect on serum calcium.

http://pediatriesherbrooke.free.fr/ABCD/iconographie/rachitisme.jpg

Such drugs are proving useful in the management of secondary hyperparathyroidism accompanying renal failure and may be useful in selected cases of primary hyperparathyroidism.

 

A number of hormones modulate the actions of PTH and vitamin D in regulating bone mineral homeostasis. Compared with that of PTH and vitamin D, the physiologic impact of such secondary regulation on bone mineral homeostasis is minor. However, in pharmacologic amounts, a number of these hormones have actions on the bone mineral homeostatic mechanisms that can be exploited therapeutically.

Calcitonin

The calcitonin secreted by the parafollicular cells of the mammalian thyroid is a single-chain peptide hormone with 32 amino acids and a molecular weight of 3600. A disulfide bond between positions 1 and 7 is essential for biologic activity. Calcitonin is produced from a precursor with MW 15,000. The circulating forms of calcitonin are multiple, ranging in size from the monomer (MW 3600) to forms with an apparent molecular weight of 60,000. Whether such heterogeneity includes precursor forms or covalently linked oligomers is not known. Because of its heterogeneity, calcitonin is standardized by bioassay in rats. Activity is compared to a standard maintained by the

British Medical Research Council (MRC) and expressed as MRC units. Human calcitonin monomer has a half-life of about 10 minutes with a metabolic clearance of 8–9 mL/kg/min. Salmon calcitonin has a longer half-life and a reduced metabolic clearance (3 mL/kg/min), making it more attractive as a therapeutic agent. Much of the clearance occurs in the kidney, although little intact calcitonin appears in the urine.

The principal effects of calcitonin are to lower serum calcium and phosphate by actions on bone and kidney. Calcitonin inhibits osteoclastic bone resorption. Although bone formation is not impaired at first after calcitonin administration, with time both formation and resorption of bone are reduced.

Thus, the early hope that calcitonin would prove useful in restoring bone mass has not been realized. In the kidney, calcitonin reduces both calcium and phosphate reabsorption as well as reabsorption of other ions, including sodium, potassium, and magnesium. Tissues other than bone and kidney are also affected by calcitonin. Calcitonin in pharmacologic amounts decreases gastrin secretion and reduces gastric acid output while increasing secretion of sodium, potassium, chloride, and water in the gut. Pentagastrin is a potent stimulator of calcitonin secretion (as is hypercalcemia), suggesting a possible physiologic relationship between gastrin and calcitonin. In the adult human, no readily demonstrable problem develops in cases of calcitonin deficiency (thyroidectomy) or excess (medullary carcinoma of the thyroid). However, the ability of calcitonin to block bone resorption and lower serum calcium makes it a useful drug for the treatment of Paget's disease, hypercalcemia, and osteoporosis.

Clinical Pharmacology

Disorders of bone mineral homeostasis generally present with abnormalities in serum or urine calcium levels (or both), often accompanied by abnormal serum phosphate levels. These abnormal mineral concentrations may themselves cause symptoms requiring immediate treatment (eg, coma in malignant hypercalcemia, tetany in hypocalcemia). More commonly, they serve as clues to an underlying disorder in hormonal regulators (eg, primary hyperparathyroidism), target tissue response (eg, chronic renal failure), or drug misuse (eg, vitamin D intoxication). In such cases, treatment of the underlying disorder is of prime importance.

Since bone and kidney play central roles in bone mineral homeostasis, conditions that alter bone mineral homeostasis usually affect either or both of these tissues secondarily. Effects on bone can result in osteoporosis (abnormal loss of bone; remaining bone histologically normal), osteomalacia (abnormal bone formation due to inadequate mineralization), or osteitis fibrosa (excessive bone resorption with fibrotic replacement of resorption cavities). Biochemical markers of skeletal involvement include changes in serum levels of the skeletal isoenzyme of alkaline phosphatase and

osteocalcin (reflecting osteoblastic activity) and urine levels of hydroxyproline and pyridinoline cross-links (reflecting osteoclastic activity). The kidney becomes involved when the calcium-timesphosphate product in serum exceeds the point at which ectopic calcification occurs (nephrocalcinosis) or when the calcium-times-oxalate (or phosphate) product in urine exceeds saturation, leading to nephrolithiasis. Subtle early indicators of such renal involvement include polyuria, nocturia, and hyposthenuria. Radiologic evidence of nephrocalcinosis and stones is not generally observed until later. The degree of the ensuing renal failure is best followed by monitoring the decline in creatinine clearance.

Abnormal Serum Calcium & Phosphate Levels

Hypercalcemia

Hypercalcemia causes central nervous system depression, including coma, and is potentially lethal. Its major causes (other than thiazide therapy) are hyperparathyroidism and cancer with or without bone metastases. Less common causes are hypervitaminosis D, sarcoidosis, thyrotoxicosis, milkalkali syndrome, adrenal insufficiency, and immobilization. With the possible exception of hypervitaminosis D, these latter disorders seldom require emergency lowering of serum calcium. A number of approaches are used to manage the hypercalcemic crisis.

Calcitonin

Calcitonin has proved useful as ancillary treatment in a large number of patients. Calcitonin by itself seldom restores serum calcium to normal, and refractoriness frequently develops. However, its lack of toxicity permits frequent administration at high doses (200 MRC units or more). An effect on serum calcium is observed within 4–6 hours and lasts for 6–10 hours. Calcimar (salmon calcitonin) is available for parenteral and nasal administration.

Calcium

A number of calcium preparations are available for intravenous, intramuscular, and oral use.

Calcium gluceptate (0.9 meq calcium/mL), calcium gluconate (0.45 meq calcium/mL), and calcium chloride (0.68–1.36 meq calcium/mL) are available for intravenous therapy. Calcium gluconate is the preferred form because it is less irritating to veins. Oral preparations include calcium carbonate (40% calcium), calcium lactate (13% calcium), calcium phosphate (25% calcium), and calcium citrate (21% calcium). Calcium carbonate is often the preparation of choice because of its high percentage of calcium, ready availability (eg, Tums), low cost, and antacid properties. In achlorhydric patients, calcium carbonate should be given with meals to increase absorption or the patient switched to calcium citrate, which is somewhat better absorbed. Combinations of vitamin D and calcium are available, but treatment must be tailored to the individual patient and individual disease, a flexibility lost by fixed-dosage combinations. Treatment of severe symptomatic hypocalcemia can be accomplished with slow infusion of 5–20 mL of 10% calcium gluconate.

Rapid infusion can lead to cardiac arrhythmias. Less severe hypocalcemia is best treated with oral forms sufficient to provide approximately 400–800 mg of elemental calcium (1–2 g calcium carbonate) per day. Dosage must be adjusted to avoid hypercalcemia and hypercalciuria.

When rapidity of action is required, 1,25(OH)2D3 (calcitriol), 0.25–1 g daily, is the vitamin D metabolite of choice, since it is capable of raising serum calcium within 24–48 hours. Calcitriol also raises serum phosphate, though this action is usually not observed early in treatment. The combined effects of calcitriol and all other vitamin D metabolites and analogs on both calcium and phosphate make careful monitoring of these mineral levels especially important to avoid ectopic calcification secondary to an abnormally high serum calcium x phosphate product. Since the choice of the

levels of high-energy organic

Vitamin D deficiency, once thought to be rare in this country, is being recognized more often, especially in the pediatric and geriatric populations on vegetarian diets and with reduced sunlight exposure. This problem can be avoided by daily intake of 400–800 units of vitamin D and treated by higher dosages (4000 units per day). No other metabolite is indicated. The diet should also

contain adequate amounts of calcium and phosphate.

Use of Vitamin D Preparations

The choice of vitamin D preparation to be used in the setting of chronic renal failure in the dialysis patient depends on the type and extent of bone disease and hyperparathyroidism. No consensus has been reached regarding the advisability of using any vitamin D metabolite in the predialysis patient. 1,25(OH)2D3 (calcitriol) will rapidly correct hypocalcemia and at least partially reverse the secondary hyperparathyroidism and osteitis fibrosa. Many patients with muscle weakness and bone pain gain an improved sense of well-being.

Dihydrotachysterol, an analog of 1,25(OH)2D, is also available for clinical use, though it is used much less frequently than calcitriol. Dihydrotachysterol appears to be as effective as calcitriol, differing principally in its time course of action; calcitriol increases serum calcium in 1–2 days, whereas dihydrotachysterol requires 1–2 weeks. For an equipotent dose (0.2 mg dihydrotachy-sterol versus 0.5 g calcitriol), dihydrotachysterol costs about one fourth as much as calcitriol. Adisadvantage of dihydrotachysterol is the inability to measure it in serum. Neither dihydrotachysterol nor calcitriol corrects the osteomalacic component of renal osteodystrophy in the majority of patients, and neither should be used in patients with hypercalcemia, especially if the bone disease is primarily osteomalacic.

Calcifediol (25[OH]D3) may also be used to advantage. Calcifediol is less effective than calcitriol in stimulating intestinal calcium transport, so that hypercalcemia is less of a problem with calcifediol.

Like dihydrotachysterol, calcifediol requires several weeks to restore normocalcemia in hypocalcemic individuals with chronic renal failure. Presumably because of the reduced ability of the diseased kidney to metabolize calcifediol to more active metabolites, high doses (50–100 g daily) must be given to achieve the supraphysiologic serum levels required for therapeutic effectiveness.

http://www.creapharma.ch/PICT1481.jpghttp://www.demeyere.be/sfeerbeelden/931/big.jpg

Vitamin D has been used in treating renal osteodystrophy. However, patients with a substantial degree of renal failure who are thus unable to convert vitamin D to its active metabolites usually are refractory to vitamin D. Its use is decreasing as more effective alternatives become available.

Two analogs of calcitriol, doxercalciferol and paricalcitol, are approved for the treatment of secondary hyperparathyroidism of chronic renal failure. Their principal advantage is that they are less likely than calcitriol to induce hypercalcemia. Their biggest impact will be in patients in whom the use of calcitriol may lead to unacceptably high serum calcium levels.

Regardless of the drug employed, careful attention to serum calcium and phosphate levels is required. Calcium supplements (dietary and in the dialysate) and phosphate restriction (dietary and with oral ingestion of phosphate binders) should be employed along with the use of vitamin D metabolites. Monitoring serum PTH and alkaline phosphatase levels is useful in determining whether therapy is correcting or preventing secondary hyperparathyroidism.

Although not generally available, percutaneous bone biopsies for quantitative histomorphometry may help in choosing appropriate therapy and following the effectiveness of such therapy. Unlike the rapid changes in serum values, changes in bone morphology require months to years. Monitoring serum levels of the vitamin D metabolites is useful to determine compliance, absorption, and metabolism.

The common features that appear to be important in this group of diseases are malabsorption of calcium and vitamin D. Liver disease may, in addition, reduce the production of 25(OH)D from vitamin D, though the importance of this in all but patients with terminal liver failure remains in dispute. The malabsorption of vitamin D is probably not limited to exogenous vitamin D. The liver secretes into bile a substantial number of vitamin D metabolites and conjugates that are reabsorbed in (presumably) the distal jejunum and ileum. Interference with this process could deplete the body of endogenous vitamin D metabolites as well as limit absorption of dietary vitamin D.

In mild forms of malabsorption, vitamin D (25,000–50,000 units three times per week) should suffice to raise serum levels of 25(OH)D into the normal range. Many patients with severe disease do not respond to vitamin D. Clinical experience with the other metabolites is limited, but both calcitriol and calcifediol have been used successfully in doses similar to those recommended for treatment of renal osteodystrophy. Theoretically, calcifediol should be the drug of choice under these conditions, since no impairment of the renal metabolism of 25(OH)D to 1,25(OH)2D and 24,25(OH)2D exists in these patients. Both calcitriol and 24,25(OH)2D may be of importance in reversing the bone disease. As in the other diseases discussed, treatment of intestinal osteodystrophy with vitamin D and its metabolites should be accompanied by appropriate dietary calcium supplementation and monitoring of serum calcium and phosphate levels.

This protein carboxylation is physiologically coupled with the oxidative deactivation of vitamin K. The anticoagulant prevents reductive metabolism of the inactive vitamin K epoxide back to its active hydroquinone form (Figure 34–6). Mutational change of the responsible enzyme, vitamin K epoxide reductase, can give rise to genetic resistance to warfarin in humans and especially in rats.

There is an 8- to 12-hour delay in the action of warfarin. Its anticoagulant effect results from a balance between partially inhibited synthesis and unaltered degradation of the four vitamin Kdependent clotting factors. The resulting inhibition of coagulation is dependent on their degradation rate in the circulation. These half-lives are 6, 24, 40, and 60 hours for factors VII, IX, X, and II, respectively. Larger initial doses of warfarin—up to about 0.75 mg/kg—hasten the onset of the anticoagulant effect. Beyond this dosage, the speed of onset is independent of the dose size. The only effect of a larger loading dose is to prolong the time that the plasma concentration of drug remains above that required for suppression of clotting factor synthesis. The only difference among oral anticoagulants in producing and maintaining hypoprothrombinemia is the half-life of each drug.

 

Figure 34–6.

Toxicity

Warfarin crosses the placenta readily and can cause a hemorrhagic disorder in the fetus. Furthermore, fetal proteins with -carboxyglutamate residues found in bone and blood may be affected by warfarin; the drug can cause a serious birth defect characterized by abnormal bone formation. Thus, warfarin should never be administered during pregnancy. Cutaneous necrosis with reduced activity of protein C sometimes occurs during the first weeks of therapy. Rarely, the same process causes frank infarction of breast, fatty tissues, intestine, and extremities. The pathologic lesion associated with the hemorrhagic infarction is venous thrombosis, suggesting that it is caused by warfarin-induced depression of protein C synthesis.

The most serious interactions with warfarin are those that increase the anticoagulant effect and the risk of bleeding. The most dangerous of these interactions are the pharmacokinetic interactions with the pyrazolones phenylbutazone and sulfinpyrazone.

The mechanisms for their hypoprothrombinemic interaction are a stereoselective inhibition of oxidative metabolic transformation of S-warfarin (the more potent isomer) and displacement of albumin-bound warfarin, increasing the free fraction. For this and other reasons, neither phenylbutazone nor sulfinpyrazone is in common use in the USA. Metronidazole, fluconazole, and trimethoprim-sulfamethoxazole also stereoselectively inhibit the metabolic transformation of S-warfarin, whereas amiodarone, disulfiram, and cimetidine inhibit metabolism of both enantiomorphs of warfarin. Aspirin, hepatic disease, and hyperthyroidism augment warfarin pharmacodynamically—aspirin by its effect on platelet function and the latter two by increasing the turnover rate of clotting factors. The third-generation cephalosporins eliminate the bacteria in the intestinal tract that produce vitamin K and, like warfarin, also directly inhibit vitamin K epoxide reductase. Heparin directly prolongs the prothrombin time by inhibiting the activity of several clotting factors.

Barbiturates and rifampin cause a marked decrease of the anticoagulant effect by induction of the hepatic enzymes that transform racemic warfarin. Cholestyramine binds warfarin in the intestine and reduces its absorption and bioavailability.

Pharmacodynamic reductions of anticoagulant effect occur with vitamin K (increased synthesis of clotting factors), the diuretics chlorthalidone and spironolactone (clotting factor concentration), hereditary resistance (mutation of vitamin K reactivation cycle molecules), and hypothyroidism (decreased turnover rate of clotting factors).

 

Enzymes drugs

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The immune response occurs when immunologically competent cells are activated in response to foreign organisms or antigenic substances liberated during the acute or chronic inflammatory response. The outcome of the immune response for the host may be beneficial, as when it causes invading organisms to be phagocytosed or neutralized. On the other hand, the outcome may be deleterious if it leads to chronic inflammation without resolution of the underlying injurious process. Chronic inflammation involves the release of a number of mediators that are not prominent in the acute response. One of the most important conditions involving these mediators is rheumatoid arthritis, in which chronic inflammation results in pain and destruction of bone and cartilage that can lead to severe disability and in which systemic changes occur that can result in shortening of life.

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http://www.brooklyn.cuny.edu/bc/ahp/MBG/MBG4/Enzymes.02.GIFPurine Nucleoside Kinase

 

 

Exogenous adenosine is the precursor of the entire purine nucleotide pool in T vaginalis through its partial conversion to inosine and the action of purine nucleoside kinase, a unique enzyme in the organism, which converts adenosine and inosine to the corresponding nucleotides. It performs a critical role in T vaginalis purine salvage and has a unique substrate specificity suitable as a target of chemotherapy.

 

Background On Enzymes
Trypanothione Synthase, Reductase, & Peroxidase

Protozoa with kinetoplasts are unusual in that a considerable proportion of their intracellular spermidine and glutathione is found in the unique conjugate N1-N8-(glutathionyl)spermidine, which has been assigned the name trypanothione.

Trypanothione synthase, reductase, and peroxidase

activities have been detected in these parasites. A knockout of the gene encoding trypanothione reductase from the African trypanosome Trypanosoma brucei resulted in apparent cessation of growth of the organism. Nifurtimox, a nitrofuran derivative effective in treating Chagas' disease (caused by Trypanosoma cruzi), has been found to be a potent inhibitor of trypanothione reductase, and other inhibitors are under study. No extensive studies of trypanothione synthetase or peroxidase have been performed. The antitrypanosomal trivalent arsenicals are taken up by the African trypanosome Trypanosoma brucei and complex with trypanothione, forming a product that is also an effective inhibitor of trypanothione reductase.

 

Glycolipid Synthetic Enzymes

The variant surface glycoprotein on the plasma membranes of bloodstream African trypanosomes provides the organisms with the means of evading host immune responses. The glycoprotein is anchored to the cell surface by a glycosyl phosphatidylinositol that contains myristate as its only fatty acid component. Thus, the introduction of a subversive substrate to replace myristate from the glycolipid anchor could result in loss of the variant surface glycoprotein, which might suppress development of trypanosomes in mammalian blood. A myristate analog, 10-(propoxy) decanoic acid, was found incorporated into the glycolipid and also active against T brucei in vitro tests.

However, further validation of this approach to antitrypanosomal chemotherapy must await results of in vivo tests.

Shikimate Pathway Enzymes

The availability of P falciparum genome database led to the identification of shikimate pathway enzymes in this organism. The pathway is known to exist in bacteria, fungi, algae, and plants but not in mammals. A herbicide, glyphosate, known to inhibit the enzyme 5'-enolpyruvylshikimate 3- phosphate synthase, was found to inhibit growth of P falciparum. However, it is not known if the in vitro antimalarial action of glyphosate is by inhibiting this enzyme. Furthermore, the shikimate pathway leads to biosynthesis of aromatic amino acids. Since P falciparum grows on digested

hemoglobin, it is not clear if biosynthesis of aromatic amino acids plays an essential role in this organism.

Isoretinoid Biosynthetic Enzymes

A mevalonate-independent isoprenoid biosynthetic pathway occurring only among bacteria, algae, and plants was also identified in P falciparum and T gondii. Fosmidomycin, known to inhibit 1-deoxy-D-xylulose-5-phosphate isomerase in this pathway, was found to also inhibit in vitro growth of P falciparum and to cure P vinckei infection in mice. However, the same questions about whether the pathway plays an indispensable role in this parasitic organism and whether fosmidomycin inhibits the parasites by inhibiting the particular enzyme remain to be answered.

Enzymes Indispensable Only in Parasites

Because of the many metabolic deficiencies among parasites resulting from the unique environments in which parasites live in their hosts, there are enzymes whose functions may be essential for the survival of the parasites, but the same enzymes are not indispensable to the host— ie, the host may be able to survive the complete loss of these enzyme functions by achieving the same result through alternative pathways. This discrepancy opens up opportunities for antiparasitic chemotherapy, though insufficiently selective inhibition of parasite enzymes remains an important safety concern.

Lanosterol C-14 Demethylase

T cruzi and leishmania contain ergosterol as the principal sterol in plasma membranes. The azole antifungal agents (eg, ketoconazole, miconazole, itraconazole), which are known to act by inhibiting the cytochrome P450-dependent C-14 demethylation of lanosterol in the ergosterol biosynthetic pathway, also inhibit growth of T cruzi and leishmania by blocking C-14 demethylation of lanosterol in these parasites. Recently, an antifungal bistriazole, D0870, demonstrated encouraging in vivo anti-T cruzi activity in mouse infection models. It is thus likely that lanosterol C-14 demethylase plays an essential role in ergosterol synthesis and therefore qualifies as a target for chemotherapy against T cruzi and leishmania.

The same C-14 demethylation of lanosterol is also required for cholesterol synthesis in mammals. As rather nonselective inhibitors of lanosterol C-14 demethylases, the azoles may exert a variety of endocrine side effects by inhibiting this enzyme in the adrenal glands and gonads while remaining acceptable as systemic antifungal agents. Because of its excessive toxicity, D0870 was not developed as an antifungal or antiparasitic agent. However, since human and yeast lanosterol C- 14 demethylases share only 38–42% sequence identities, there may be a good chance of designing inhibitors that are more selective against the fungal or parasitic enzymes.

DNA helps create enzymes, ...

Purine Phosphoribosyl Transferases

The absence of de novo purine nucleotide synthesis in protozoal parasites as well as in the trematode Schistosoma mansoni is reflected in the relative importance of purine phosphoribosyl transferases in many parasite species. G lamblia has an exceedingly simple scheme of purine salvage. It possesses only two pivotal enzymes: the adenine and guanine phosphoribosyl transferases, which convert exogenous adenine and guanine to the corresponding nucleotides. There is no salvage of hypoxanthine, xanthine, or any purine nucleosides and no interconversion between adenine and guanine nucleotides in the parasite.

Functions of the two phosphoribosyl transferases are thus both essential for the survival and development of G lamblia (Figure 52–1). The guanine phosphoribosyl transferase is an interesting enzyme because it does not recognize hypoxanthine, xanthine, or adenine as substrate. This substrate specificity distinguishes the giardia enzyme from the mammalian enzyme, which uses hypoxanthine, and the bacterial one, which uses xanthine as substrate. Design of a highly specific inhibitor of this enzyme is thus possible. The crystal structures of both guanine and adenine phosphoribosyltransferases from G lamblia have been solved recently, which should provide good opportunities for specific inhibitor design.

Dihydrofolate Reductase-Thymidylate Synthase Bifunctional Enzyme

Dihydrofolate reductase (DHFR), a classic target in antimicrobial and anticancer chemotherapy, has been shown to be a useful therapeutic target in plasmodium, toxoplasma, and eimeria species.

Pyrimethamine is the prototypical DHFR inhibitor, exerting inhibitory effects in all three groups.

However, pyrimethamine resistance in P falciparum has become widespread in recent years. This is largely attributable to specific point mutations in P falciparum DHFR that have rendered the enzyme less susceptible to the inhibitor.

A highly unusual feature of DHFR in Apicomplexa and Kinetoplastida is its association with thymidylate synthase in the same protein. DHFR activity is always located at the amino terminal portion, while the thymidylate synthase activity resides in the carboxyl terminal. The two enzyme functions do not appear to be interdependent; eg, the DHFR portion of the P falciparum enzyme molecule was found to function normally in the absence of the thymidylate synthase portion. It is likely that since the protozoan parasites do not perform de novo synthesis of purine nucleotides, the primary function of the tetrahydrofolate produced by DHFR is to provide 5,10- methylenetetrahydrofolate only for the thymidylate synthase-catalyzed reaction. Physical association of the two enzymes may improve efficiency of TMP synthesis. If an effective means of disrupting the coordination between the two activities can be developed, this bifunctional protein may qualify as a target for antiparasitic therapy.

Thiamin Transporter

Carbohydrate metabolism provides the main energy source in coccidia. Diets deficient in thiamin, riboflavin, or nicotinic acid—all cofactors in carbohydrate metabolism—result in suppression of parasitic infestation of chickens by E tenella and E acervulina. A thiamin analog, amprolium—1- [(4-amino-2-propyl-5-pyrimidinyl)-methyl]-2-picolinium chloride—has long been used as an effective anticoccidial agent in chickens and cattle with relatively low host toxicity. The antiparasitic activity of amprolium is reversible by thiamin and is recognized to involve inhibition of thiamin transport in the parasite. Unfortunately, amprolium has a rather narrow spectrum of antiparasitic activity; it has poor activity against toxoplasmosis, a closely related parasitic infection.

Mitochondrial Electron Transporter

Mitochondria of E tenella appear to lack cytochrome c and to contain cytochrome o—a cytochrome oxidase commonly found in the bacterial respiratory chain—as the terminal oxidase. Certain 4- hydroxyquinoline derivatives such as buquinolate, decoquinate, and methyl benzoquate that have long been known to be relatively nontoxic and effective anticoccidial agents have been found to act on the parasites by inhibiting mitochondrial respiration. Direct investigation on isolated intact E tenella mitochondria indicated that the 4-hydroxyquinolines have no effect on NADH oxidase or succinoxidase activity but that they are extremely potent inhibitors of NADH- or succinate-induced mitochondrial respiration. On the other hand, the ascorbate-induced E tenella mitochondrial respiration was totally insusceptible to these 4-hydroxyquinolines. The block by the anticoccidial agents thus may be located between the oxidases and cytochrome b in the electron transport chain.

Team of Enzymes Working ...

 

A certain component at this location must be essential for mediating the electron transport and would appear to be highly sensitive to the 4-hydroxyquinolines. This component must be a very specific chemotherapeutic target in eimeria species, since the 4-hydroxyquinolines have no effect on chicken liver and mammalian mitochondrial respiration and no activity against any parasites other than eimeria.

Many 2-hydroxynaphthoquinones have demonstrated therapeutic activities against Apicomplexa.

Parvaquinone and buparvaquinone have been developed for the treatment of theileriosis in cattle and other domestic animals. Atovaquone is an antimalarial drug and is also used in the treatment of Pneumocystis jiroveci and P carinii infections. The 2-hydroxynaphthoquinones are analogs of ubiquinone. The primary site of action of atovaquone in Plasmodium is the cytochrome bc1 complex, where an apparent drug-binding site is present in cytochrome b. In plasmodium, ubiquinone also plays an important role as an electron acceptor for dihydroorotate oxidase.

Consequently, pyrimidine biosynthesis in plasmodium is also inhibited by atovaquone. This chemical compound has also been found to be active against T gondii cysts in the brains of infected mice.

 

The cell damage associated with inflammation acts on cell membranes to cause leukocytes to release lysosomal enzymes; arachidonic acid is then liberated from precursor compounds, and various eicosanoids are synthesized. Compounds, the cyclooxygenase pathway of arachidonate metabolism produces prostaglandins, which have a variety of effects on blood vessels, on nerve endings, and on cells involved in inflammation. The discovery of cyclooxygenase (COX) isoforms (COX-1 and COX-2) led to the concepts that the constitutive COX-1 isoform tends to be homeostatic in function, while COX-2 is induced during inflammation and tends to facilitate the inflammatory response. On this basis, highly selective COX-2 inhibitors have been developed and marketed on the assumption that such selective inhibitors would be safer than nonselective COX-1 inhibitors but without loss of efficacy. The lipoxygenase pathway of arachidonate metabolism yields leukotrienes, which have a powerful chemotactic effect on eosinophils, neutrophils, and macrophages and promote bronchoconstriction and alterations in vascular permeability. Kinins, neuropeptides, and histamine are also released at the site of tissue injury, as are complement components, cytokines, and other products of leukocytes and platelets. Stimulation of the neutrophil membranes produces oxygen-derived free radicals.

Superoxide anion is formed by the reduction of molecular oxygen, which may stimulate the production of other reactive molecules such as hydrogen peroxide and hydroxyl radicals. The interaction of these substances with arachidonic acid results in the generation of chemotactic substances, thus perpetuating the inflammatory process.

Reduction of inflammation with nonsteroidal anti-inflammatory drugs (NSAIDs) often results in relief of pain for significant periods. Furthermore, most of the nonopioid analgesics (aspirin, etc) also have anti-inflammatory effects, so they are appropriate for the treatment of both acute and chronic inflammatory conditions.

Another important group of agents are characterized as slow-acting antirheumatic drugs (SAARDs) or disease-modifying antirheumatic drugs (DMARDs). They may slow the bone damage associated with rheumatoid arthritis and are thought to affect more basic inflammatory mechanisms than do the NSAIDs. Unfortunately, they may also be more toxic than the nonsteroidal anti-inflammatory agents.

 

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2.    http://www.youtube.com/watch?v=D6EPGDb6kEo

3.    http://www.youtube.com/watch?v=FMt_BOrswQc&feature=related

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10.http://www.youtube.com/watch?v=E90D4BmaVJM&feature=related