Metabolic Diseases

Cure Arthritis Naturally

Cure Arthritis Naturally

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Sitagliptin (Januvia)

Amlodipine (Norvasc)

AMP-Activated Protein Kinase with AMP (red) bound in the catalytic subunit

Inflammation, a biological response needed in the protection or repair of the body, must be exquisitely regulated.

Disregulation of the process, either chronic or acute, plays a role in a wide variety of disease states from cardiovascular disease to arthritis to psoriasis to degenerative illnesses.

Inflammation can now be alleviated by various therapeutic agents, but none of these is ideal.

ANTI-INFLAMMATORY AGENTS

MOLECULES AND MEDICINE

ACETYLSALICYLIC ACID (ASPIRIN™)

Structural Formula Ball-and-Stick Model Space-filling Model

Year of discovery: 1897; Year of introduction: 1899 (Bayer); Drug category: Non-steroidal antiinflammatory drug (NSAID); Main uses: Treatment of pain, inflammation and fever; also as an anticlotting agent for the prevention of heart attack. Approximate number of people using the drug regularly: Over 100 million; Related drugs: Ibuprofen (Advil), Naproxen (Aleve), Celecoxib (Celebrex), Clopidogrel (Plavix).

The acetyl (CH3CO) derivative of salicylic acid has been widely used as a general purpose pain reliever for over a hundred years. It is potent, relatively safe and inexpensive. Annual production of aspirin is in excess of 40,000 tons worldwide.

Written records from 500 B.C. indicate that the Greek doctor Hippocrates used the bark of the willow tree as a pain reliever for individuals suffering from rheumatism and various forms of inflammation.1 Research showed later that the active ingredient was salicylic acid (see formula below).

Salicylic acid

Salicylic acid

By the end of the 19th century, doctors regularly prescribed salicylic acid for the treatment of arthritic pain. However, salicylic acid is no longer used as an oral medicine, since it is very irritating to the stomach and can cause serious gastrointestinal bleeding. Its main use is in topical medications to remove warts and callouses.

Acetylsalicylic acid was discovered by the German chemist Felix Hoffmann, who tried to make a less irritating medicine for his arthritic father. In 1897 he prepared aspirin, a more potent and less irritating anti-inflammatory agent, and just two years later Bayer & Co. began marketing it as Aspirin. Aspirin acts by inhibiting the enzyme cyclooxygenase (COX), which directs the synthesis of a family of cell regulators called prostaglandins (PGs). In the stomach, a particular PG (PGE2) is beneficial because it inhibits the excessive production of hydrochloric acid (HCI) and enhances the formation of a protective layer of mucus. [For more detail regarding the function of COX, see page 40.]

Aspirin was widely used during the flu epidemic in Europe in 1917-1918 because it effectively lowers dangerously high fevers. Such fevers are caused by elevated levels of PGE2 in the brain which are decreased by aspirin. By the 1950s aspirin had become by far the most widely used painkiller globally. That massive usage allowed the detection of aspirin's anticlotting properties and the realization that it could be used to lower the risk of heart attack due to the clotting of blood in disease-narrowed arteries. Taken soon after a heart attack, aspirin may also limit the size of the infarcted area/

Subsequent research indicated that aspirin inhibits blood clotting at low dosages (80-90 mg per day). During the late 1980s, studies also showed that aspirin can limit brain damage due to occlusive stroke caused by a blood clot, if taken early. The use of aspirin is contraindicated in hemorrhagic stroke, because it may increase bleeding.3

The anticlotting action of aspirin at low doses is due to the irreversible inhibition of cyclooxygenase in blood platelets by transfer of the acetyl group from aspirin to a critical serine hydroxyl group at the catalytic site of the enzyme (see page 40). Since mature platelets have a lifetime of only about 2 weeks and are not able to synthesize new protein, the clotting ability of aspirin-treated platelets is permanently blocked.

1. Curr. Opin. Invest. Drugs (Thomson Curr. Drugs) 2003, 4, 517-518; 2. Drugs of Today 2006. 42, 467-479; 3. Mini-Rev. Med. Chem. 2006, 6, 1351-1355; Refs. p. 80

PART II. ANTI-INFLAMMATORY AGENTS

Ball-and-Stick Model Space-filling Model

= Carbon = Hydrogen A = Oxygen

= Carbon = Hydrogen A = Oxygen

Year of discovery: Early 1970s; Year of introduction: 1976 (as Naprosyn by Syntex); Drug category: Non-steroidal anti-inflammatory drug (NSAID); Main uses For many different types of pain, mild fever or minor inflammation; Other brand names: Anaprox, Naprelan and Naprogesic; Related drugs: Aspirin, Ibuprofen (Advil) and Celecoxib (Celebrex).

The remarkable success of aspirin as a medicine for the relief of inflammation, pain and fever stimulated the search for even more effective agents, starting in the mid-twentieth century. The overall objective was the discovery of safer and more potent antiinflammatory compounds, and especially of compounds that are devoid of the erosive gastric side effects of aspirin. Thousands of compounds were synthesized and tested in mice over more than two decades. Many active compounds were discovered, including phenylbutazolidin, indomethacin and piroxi-cam, but all exhibited side effects, especially gastric irritation.

h3co ch2cooh

Indomethacin (Indocin™)

Piroxicam (Feldene™)

Piroxicam (Feldene™)

In one approach, the structure of acetylsalicylic acid (aspirin) was methodically modified in the hope that these changes would result in better properties. The replacement of the hydroxyl group of salicylic acid by nitrogen-containing groups led to a class of compounds known as anthranilic acid derivatives that retained most of the desirable properties of aspirin (see below).

emerged. Ibufenac (isobutylphenylacetic acid) is comprised of three subunits: (1) acetic acid (blue), (2) a benzene ring (red) and (3) a branched chain attached to the benzene ring (green, see structures below). Although this drug was several times more potent than aspirin, it showed occasional hepatotoxicity in humans. When a methyl group (orange) was added to the acetic acid subunit (forming a propionic acid subunit), a much safer drug (ibuprofen) resulted, with diminished gastrointestinal irritation and no hepatotoxicity, even when administered in large doses (over 1 gram/day).1 Although ibuprofen was a great success, continuing research led to more potent molecules. During the early 1970s, the Syntex Co. prepared naproxen, a propionic acid derivative with a naphthalene nucleus (two benzene rings fused together, shown in red).2 It had twice the potency of ibuprofen and, in addition, a longer half-life (ca. -12 hours), allowing a once-daily dosing. Not long after its introduction as Naprosyn in 1976 (and later as Aleve), the sales of naproxen exceeded $1 billion annually. Because of their significantly better potency and safety profile, ibuprofen and naproxen are today the most widely used non-steroidal anti-inflammatory agents.

H0--CH3

Acetic acid

YXXX

Ibufenac

N-R2

oh oh

Salicylic acid

Anthranilic acid derivatives

Acetaminophen (Tylenol, see page 210), ibufenac and ibuprofen (Motrin or Advil) also

Propionic acid

Extra carbon atom

Ibufenac

Extra carbon atom

Ibuprofen (Advil1

Ibuprofen (Advil1

1. Int. J. Clin. Pracl., Suppl. 2003, 135, 3-8; 2. J. Am. Pharm. Assoc. (Wash). 1996, NS36, 663-667; Refs. p. 80

HOW DO ANTI-INFLAMMATORY DRUGS WORK?

Non-steroidal anti-inflammatory drugs (NSAIDs) function by inhibiting the enzyme cyclooxygenase (COX) which directs the formation of several key mediators of inflammation called prostaglandins, for example PGE2.1 Prostaglandins are synthesized locally in cell membranes by a remarkable sequence that starts with arachidonic acid (AA), a twenty-carbon fatty acid, and leads to the oxygenated products prostaglandin G2 (PGG2) and prostaglandin H2 (PGH2). This transformation proceeds via hydrogen atom abstraction from AA by an activated tyrosine oxygen (radical) and subsequent rapid combination with two molecules of oxygen to give PGG2. Subsequently, PGH2 and the other prostaglandins are formed (see scheme below). Using X-ray crystallography, researchers were able to capture AA (shown in red, Panel A) bound in the active site of COX with tyrosine

385 (green) in close proximity to the #13 carbon atom.2 This process is completely blocked by ibuprofen (shown in red, Panel B), which binds tightly to the active site of COX and^ denies access to the normal substrate AA.3 Naproxen inhibits COX in the same way, but aspirin blocks the enzyme by an entirely different mechanism. After aspirin binds to the enzyme, it transfers its acetyl (CH3CO) group to a critical hydroxyl (OH) group, leading to a catalytically inactive form of COX that is no longer able to convert AA to prostaglandins. John Vane, who discovered that aspirin works by blocking prostaglandin synthesis, shared the Nobel Prize in Medicine in 1982 with Sune Bergstrom and his student Bengt Samuelsson who clarified the structures of the prostaglandins.

1. Prostaglandins & Other Lipid Mediators 2007, 82, 85-94;

2. Science 2000, 289, 1933-1938 (1DIY); 3. Biochemistry 2001, 40, 5172-5180 (1EQG); Refs. p. 80

Arachidonic acid cooh

Arachidonic acid cooh

n Tyr 385 in COX-1

PGE2

and other prostaglandins

Cyclooxygenase-1 Enzyme (COX-1)

n Tyr 385 in COX-1

PGE2

and other prostaglandins cooh ch3

Carbon radical

B. Ibuprofen in the Active Site of Cyclooxygenase-1 Enzyme3

A. Arachidonic Acid in the Active Site of Cyclooxygenase-1 Enzyme2

B. Ibuprofen in the Active Site of Cyclooxygenase-1 Enzyme3

Arachidonic Acid (AA)

Ibuprofen

Figure 1. Mediators of Inflammation

OTHER EICOSANOIDS IN INFLAMMATION

During inflammation many local chemical mediators are produced. These substances are often referred to as local hormones since they are potent and have a specific effect on target cells close to their site of formation. They are also short-lived since they are degraded rapidly and not transported to other sites in the body. In the early stages of inflammation, various highly potent eicosanoids (compounds derived from 20-carbon fatty acids) are generated, including the proinflammatory prostaglandins (such as PGE2) and various leukotrienes (such as LTB4). Leukotrienes are involved in the regulation of blood flow by control of vessel tone and in the immune response. For example, LBT4 attracts white blood cells to the infected cells or tissue and also increases the permeability of blood vessels. (Leukotrienes are also involved in the development of asthmatic conditions.) The formation of prostaglandins from an o>6 fatty acid, arachidonic acid (AA), via cyclooxygenase (COX) enzyme was discussed earlier (see page 40). The biosynthesis of leukotrienes also occurs from AA but is initiated by a different enzyme, 5-lipoxygenase (5-LOX, Figure 2).1

In addition to these proinflammatory mediators, anti-inflammatory protective lipid mediators (e.g., lipoxins, resolvins and protectins) are released in later stages of the inflammation process (see Figure 1) to restore normality.

Figure 1. Mediators of Inflammation

Lipoxins are made from AA via COX and play a role in slowing down the inflammation process. Resolvins and protectins, however, are made from o>3 fatty acids such as alpha linoleic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). o>3 Fatty acids are essential to human health, however, cannot be biosynthesized in the body and must be supplied in the diet. The concentration of ©-3 fatty acids is particularly high in the brain where they play a role in cognitive and behavioral function. When the body has ample supply of oo-3 fatty acids, the concentration of the protectins and resolvins is increased, resulting in a faster resolution of inflammation. The formation of neuroprotectin D1 is shown on Figure 3.

Seafood is a rich source of dietary o>3 fatty acids. It is probably no coincidence that Eskimos, who consume large quantities of fatty fish and live in a harsh environment, appear to be less prone to arthritis and heart disease.2

1. Curr. Top. Med. Chem. 2007, 7, 297-309; 2. Curr. Vase. Pharmacol. 2007, 5, 163-172; Refs. p. 80

5-LOX

5-LOX

Arachidonic Acid (AA) [An o>6 fatty acid]

COOH

5-LOX

cooh nh2

Leukotriene e4 (LTE4)

cooh nh2

Leukotriene e4 (LTE4)

1. Curr. Top. Med. Chem. 2007, 7, 297-309; 2. Curr. Vase. Pharmacol. 2007, 5, 163-172; Refs. p. 80

Arachidonic Acid (AA) [An o>6 fatty acid]

COOH

5-LOX

Leukotriene D4 (ltd4)

Leukotriene C4 (LTC4)

Leukotriene D4 (ltd4)

Leukotriene C4 (LTC4)

Figure 2. Formation of Various Leukotrienes from Arachidonic Acid via 5-Lipoxygenase

Figure 2. Formation of Various Leukotrienes from Arachidonic Acid via 5-Lipoxygenase

Docosahexaenoic acid (DHA) [An co-3 fatty acid]

Neuroprotectin d1 (npd1 )

Docosahexaenoic acid (DHA) [An co-3 fatty acid]

Neuroprotectin d1 (npd1 )

Figure 3. Formation of Neuroprotectin D1 from Docosahexaenoic Acid via 5-Lipoxygenase

AN OVERVIEW OF INFLAMMATION

Inflammation results from the process by which the immune system responds to foreign materials, irritation, tissue, bone or nerve damage, or infection by microorganisms. The symptoms of localized inflammation include redness, warming, swelling, pain or loss of mobility in the affected area. More widespread inflammation may bring fever, chills, fatigue, headache or loss of appetite. Inflammation may also result when the immune system malfunctions by producing antibodies against itself with pathological consequences.1

Inflammation is a significant factor in a number of diseases (e.g., cardiovascular, respiratory and degenerative). The sequence of biochemical events accompanying inflammation is complex and depends on the stimulus. For instance, pathogenic bacteria produce substances that activate cell surface receptors and initiate a cascade of biochemical events (i.e., a molecular signaling sequence) within the cell that produces certain potent proinflammatory proteins called cytokines such as tumor necrosis factor-a (TNF-a) and interleukin-1. These then trigger the synthesis and release of other small molecular mediators including prostaglandins (PGs), histamine, bradykinin (a nine amino acid peptide) and leukotrienes. Eventually even gene expression is affected.2

The prostaglandins, normally present in very low concentrations, act as short-lived but powerful regulators which are produced from arachidonic acid (AA) by the cyclooxygenase enzyme (COX) via cyclic endoperoxides (see below). The biosynthesis of PGs depends on the enzymatic cleavage of membrane lipids to generate free AA and is tightly regulated. The anti-inflammatory steroid Cortisol blocks the release of AA from membranes (see section on steroids, page 45).

CELL

ARACHI-

COX

CYCLIC

MEMBRANE

ACID

PROSTA- 1 OLANDINS

THROMBOX-

The release of histamine causes local vasodilation and increased permeability of blood vessels. It also stimulates the production of prostaglandins and bradykinin and amplifies their effects. The net result is increased blood flow to the area of the damaged tissue, warming, redness and pain, the signature of inflammation.

Prostaglandins and bradykinin combine to produce pain. Prostaglandins lower the sensing threshold of the nerve endings, making them more sensitive to the presence of bradykinin, thus amplifying the pain signal. This signaling process also involves changes in initial ion concentrations at ion-sensitive neuronal cells which transmit information to the brain.

NERVE CELL SENSITIVITY I

Certain immune mediators attract white blood cells to a site of inflammation where they move from the blood vessels, destroy pathogens and produce collateral damage and more inflammation (page 112). In a healthy individual the immune and inflammatory response are self correcting by a sequence of molecular events which effectively downregulate the proinflammatory process. In certain disease states such as rheumatoid arthritis and osteoarthritis, or as a result of aging, this downregulation is dysfunctional. An important current treatment of rheumatoid arthritis involves the administration of a monoclonal antibody (Enbrel™, Amgen and Wyeth) against the TNF-a receptor protein which blocks TNF-a binding and the subsequent inflammation cascade.

Another macromolecule that plays an important role in inflammation is NF-kB which, when produced and released intracellular^, migrates into the cell nucleus where it activates various proinflammatory genes, including COX. The signaling pathway that leads to free NF-kB in the cell is complex and its suppression by synthetic molecules, which has not yet been achieved, may actually be harmful, because the accompanying immunosuppressant effect may allow infection. The immune response, in common with inflammation, is dependent on NF-kB.

1. Inflammation: Basic Principles and Clinical Correlates (Lippincott Williams & Wilkins. 1999); 2. Cytokines and Joint Injury (Birkhauser Basel, 2004); Refs. p. 80

CELECOXIB (CELEBREX™)

Ball-and-Stick Model

Space-filling Model

Space-filling Model

= Carbon = Hydrogen = Oxygen ^ = Fluorine ^ = Nitrogen = Sulfur

Year of discovery: 1993; Year of introduction: 1999 (Pfizer); Drug category: Non-steroidal antiinflammatory drug (NSAID); Main uses: Treatment of osteoarthritis, rheumatoid arthritis and acute pain (e.g., painful menstruation); Approximate number of people taking the drug annually: Over 23 million; Older drugs: Aspirin, Ibuprofen (Advil) and Naproxen (Aleve).

Non-steroidal anti-inflammatory agents such as aspirin, ibuprofen and naproxen (see page 39) act by inhibiting the biosynthesis of prostaglandins (PGs) from arachidonic acid (AA). There are two human enzymes that catalyze the first step in the biosynthesis of PGs, cyclooxygenase 1- and 2 (COX-1 and COX-2; see page 40). Although COX-1 and COX-2 catalyze the same biochemical reaction, they are distinctly different in terms of amino acid content (about 60% identity), tissue distribution, and physiological function. COX-1 has been described as a "constitutive" enzyme because it appears to have a steady presence in tissues and organs, for example in the stomach, where it affects gastric acidity and mucous secretion. In contrast, COX-2 levels are normally low, but become elevated at sites of inflammation, in certain tumor cells or in response to stimuli such as growth or wound-response factors. Glucocorticoid steroids and anti-inflammatory cytokines (see page 45) downregulate the expression of COX-2.

COX-1 and COX-2 are both membrane-associated proteins to which the membrane-bound substrate AA is transferred directly. The two enzymes have roughly similar substrate binding sites, but that of COX-2 is slightly larger and differently shaped. Since COX-2 is not expressed in stomach and since gastric ulcers and serious gastric bleeding develop in about 1% of chronic users of COX-1 inhibitors, research to find inhibitors that are selective for COX-2 over COX-1 was initiated. The selective COX-2 inhibitor celecoxib (Celebrex) emerged from this effort in 1999, and became an important medicine for treatment of osteoarthritis in people who cannot tolerate aspirin or non-selective alternative COX-1/COX-2 inhibitors.

A competing drug, rofecoxib (Vioxx), was developed at Merck and Co. and was marketed about the same time as celecoxib. However, it subsequently had to be withdrawn when it was linked to a 1% increase in risk of heart attack. Celecoxib appears to be considerably safer than rofecoxib.1

Rofecoxib (Vioxx)

SC-558

Rofecoxib (Vioxx)

SC-558

Although COX-1 and COX-2 bind AA in the same three-dimensional geometry, the ligand-binding pockets are different for inhibitors of COX-1 and COX-2. The picture below shows a close structural relative of celecoxib, SC-558, bound in the active site of COX-2.2 The selectivity results because the phenylsulfonyl group (shown in green above) binds in a pocket (formed from His90, Arg513 and Val523) that is not available in COX-1 since it is occupied by a bulky isoleucine side chain rather than the smaller isopropyl group of valine (Val523). The carboxyl group of rofecoxib interacts not with Arg513 but with a different residue, Arg120.

1. Future Cardiology 2005, 1, 709-722; 2. Nature (London) 1996, 384, 644-648. (1CX2); Refs. p. 80

PREDNISONE (DELTASONE™)

Structural Formula

Structural Formula

Ball-and-Stick Model

: Carbon = Hydrogen A = Oxygen

: Carbon = Hydrogen A = Oxygen

Year of discovery: Early 1950s; Year of introduction: 1955 (as Meticorten by Schering and as Deltasone by Pharmacia and Upjohn); Drug category: Anti-inflammatory agent/immuno-suppressant/adrenocortical steroid; Main uses: For treatment of inflammatory diseases (e.g., asthma, Crohn's disease) and prevention of organ transplant rejection; Related drugs: Cortisol (Hydrocortisone), Fluticasone (Flonase), (and others shown on next page).

Human adrenal glands, though weighing only a few grams, are essential for life; adrenalectomized animals survive only for a matter of days. Research in the 1930s by Oskar Wintersteiner at Columbia, Edward C. Kendall at the Mayo Foundation, and Thaddeus Reichstein at the Federal Technical Institute (ETH) in Zurich resulted in the identification of more than 25 members of the adrenocortical family of steroids including Cortisol and the corresponding 11-ketone, cortisone.

Cortisol

Cortisone

Cortisol

Cortisone

Kendall and Philip S. Hench's demonstration in the 1940s that Cortisol and cortisone exerted profound anti-inflammatory effects in humans, had a major impact on the medical sciences.1 Reichstein, Kendall and Hench shared the Nobel Prize in Medicine in 1950 for their discoveries.

Cortisol has a wide range of activities in the body and its levels are tightly controlled. Its biosynthesis (from the early precursor cholesterol) in the adrenals is stimulated by corticotrophin, a 39 amino acid peptide produced in the brain and carried to the adrenals by blood. Cortisol levels are partly regulated by two enzymes, one that oxidizes the 11-CHOH unit to C=0 and the other that catalyzes the reverse reaction. The intrinsic bioactivity of Cortisol is much greater than that of cortisone, which essentially serves mainly as a storage depot. Cortisone is inactive at corticosteroid receptors.

The receptors that mediate the many biological activities of corticosteroid hormones are of two general types: (1) glucocorticoid (GR) and (2) mineralocorticoid receptors (MR).

Cortisol has both GR and MR activity, but the former dominates. Another adrenal steroid, aldosterone, shows much more potent MR activity than GR activity. MR activation causes sodium retention in the body, and was of great importance during evolution because NaCI was frequently in short supply. Since an excess of NaCI in the body causes hypertension, an antagonist of aldosterone (Eplerenone, Inspra™) is used medically when the cause of elevated blood pressure is excessive body production of aldosterone.

Aldosterone Eplerenone (Inspra

Cortisol is associated with a remarkable variety of biological activities and plays many functional roles throughout the body, for example in the brain, peripheral muscle and the various organs. It is a principal effector in the hypothalamic-pituitary-adrenal (HPA) axis of physiological control (see next page). In the brain Cortisol plays a crucial role in cognition, maintenance of neurons and the regulation of stress and mood.

CORTICOTROPHIN RELEASING FACTOR{CRF

NEGATIVE FEEDBACK: INHIBITION OF FURTHER RELEASE OF CRF

CORTICOTROPHIN RELEASING FACTOR{CRF

NEGATIVE FEEDBACK: INHIBITION OF FURTHER RELEASE OF CRF

The Hypothalamic-Pituitary-Adrenal Axis.

The Hypothalamic-Pituitary-Adrenal Axis.

The discovery of the anti-inflammatory properties of cortisol/cortisone in the 1940s spurred the development of several synthetic analogs of cortisone during the 1950s. Many of these compounds are several times more potent than Cortisol, longer lasting and cause less sodium retention. One of the most widely used synthetic analogs, prednisone, was introduced by Schering in 1955 as Meticorten. Prednisone and other steroids of this class have many therapeutic applications. They are useful in rheumatic/inflammatory disorders, allergies, malignancies such as leukemia and multiple myeloma, and skin diseases. Prednisone can be used orally or intramuscularly to treat cases of acute inflammation. It is a powerful immunosuppressant because it reduces B- and T-cell-mediated immunity. For this reason it is administered to patients after organ transplant to prevent rejection. Fortunately, prednisone and other members of this class do not cross the blood brain barrier, and thus have minimal effects on mental function. Unfortunately, long term use of these corticosteroid hormones in systemic therapy is contraindicated because of inevitable and serious side effects (e.g., osteoporosis).

upOHl

OH H3C

OH H3C

Dexamethasone

Other members of the prednisone class with longer half-lives and greater potency than prednisone are in common use; the most widely used of which is dexamethasone (see stereostructure at bottom left).

The anti-inflammatory activities of glucocorticoids are not fully understood because they affect the expression of numerous genes.2 However, one way in which they exert anti-inflammatory effects is by promoting the synthesis of lipocortin-1, a calcium-binding protein that binds to cell membranes.3 In the membrane, lipocortin-1 inhibits the enzyme phospholipase A2 (PLA2) which is responsible for the selective removal of acyl groups from the C-2 position of phospholipids to release free arachidonic acid (AA). The net result is a diminished production of AA and its biooxidation products including proinflammatory eicosanoids, prostaglandins and leukotrienes. In addition, the expression of the cyclooxygenase enzyme (COX) is downregulated.

OCO-nC17H35 O

OCO-nC17H35 O

Phospholipid

(Arachidonic Acid bound at C-2)

Phospholipid

(Arachidonic Acid bound at C-2)

(Proinflammatory agents)

Dexamethasone

(Proinflammatory agents)

Another way in which prednisone and other corticosteroids reduce inflammation is through their effect on the body's production of TNF-a and other cytokines. For certain inflammatory diseases, e.g., Crohn's disease (inflammatory bowel disease), combination therapy with prednisone and an anti-TNF monoclonal antibody allows the use of lower doses of each.

1 N Engl. J. Med 2005. 353. 1711-1723; 2. Br. J. Pharmacol. 2006. 148. 245-254; 3. Ann. N. Y. Acad. Sci. 2006, 1088, 396-409; Refs. p. 81

METHOTREXATE (TREXALL™)

Structural Formula

Ball-and-Stick Model

Structural Formula

= Carbon

= Hydrogen

Year of discovery: 1948 (Lederle); Year of introduction: 1953; Drug category: Antimeta-bolite/disease-modifying anti-inflammatory agent/immunosuppressant; Main uses: For treatment of inflammation associated with autoimmunity (rheumatoid arthritis, Crohn's disease and psoriasis); Other brand names: Rheumatrex; Related drugs: Trimetrexate (Neutrexin), Pemetrexed (Alimta).

Methotrexate is an inhibitor of folic acid biosynthesis which slows the proliferation of cells. It has been known since the 1930s that folic acid is essential for the development of new cells. Adequate dietary intake of folic acid is absolutely necessary for human health. A deficiency of folic acid is especially serious in pregnant women, since it leads to maldevelopment of the fetus and results in defects of the spine, brain and skull.

Folic acid undergoes reduction in the body by the enzyme dihydrofolate reductase (DHFR) in two stages, giving first dihydrofolate and then the essential metabolite tetrahydrofolate. Parts of the tetrahydrofolate molecule are required as building blocks for the synthesis of the nucleoside thymidine, an ingredient for DNA formation. The figure below shows in red the segment of the six-membered ring of thymidine that originates from tetrahydrofolate. Methotrexate blocks DHFR and interferes with DNA synthesis.

Folic Acid (Folate)

Tetrahydrofolate

Folic Acid (Folate)

Tetrahydrofolate yS

Thymidine

Because tetrahydrofolate is essential for normal cell division, it is especially critical in tissues that divide rapidly (e.g., bone marrow, blood cells, skin, gastrointestinal tissues and the immune system). Since cancer cells divide even more rapidly, blockade of the synthesis of tetrahydrofolate by inhibition of the enzyme DHFR appeared to be promising for effective cancer therapy. Methotrexate (MTX) was successfully developed in 1948 by the Lederle Company and marketed under the trade name Trexall. Although MTX was originally used in cancer chemotherapy, its main use is now in the treatment of autoimmune and inflammatory diseases, especially psoriasis and rheumatoid arthritis.1 The combination of the anti-TNF-a monoclonal antibody Enbrel and MTX is currently a standard treatment of rheumatoid arthritis.

Methotrexate is a disease-modifying antirheumatic agent that not only reduces the symptoms, such as pain and swelling, but also slows the progression of the disease by preventing further damage to joints. The effective dose of MTX is several orders of magnitude lower for inflammation than for cancer.2 Even at low doses, MTX appears to decrease T-cell proliferation and the levels of proinflammatory factors such as TNF-a and interleukin-10. The figure below shows an X-ray picture of MTX bound to the enzyme DHFR from E. Coli3

1. Pharm. Rep. 2006, 58, 473-492; 2. Biomed. & Pharmacother. 2006, 60, 678-687; 3. Biochemistry 1997. 36, 586-603. (1RG7); Refs. p. 81

ALLOPURINOL (ZYLOPRIM™)

Ball-and-Stick Model

Space-filling Model

Year of discovery: Early 1950s; Year of introduction: 1964 (Burroughs Wellcome, now GlaxoSmithKllne); Drug category. Xanthine oxidase inhibitor for treatment of inflammatory gout; Main uses: For the prevention and treatment of gout attacks and certain types of kidney stones; Related drugs: Colchicine, Probenecid (Benemid).

Allopurinol is used for the treatment of arthritic gout. Arthritis encompasses of over one hundred different rheumatic diseases and conditions affecting joints, muscle and bone. These diseases include osteoarthritis, rheumatoid arthritis and gout. There are many symptoms associated with arthritis, but the most common are pain, aching, stiffness, and swelling of the joints. Currently over 50 million people in the US have arthritis and about 3 million of them suffer from gout, a very painful form. Unlike other forms of arthritis, the cause of gout has been pinpointed as being the deposition of needle-like crystals of uric acid in the connective tissue, joint spaces or both (see below). Such uric acid deposits cause inflammation of the affected joint and result in swelling, stiffness and intense pain. The first sign of gout is usually pain in the joints of the big toes.1 2

Uric acid

Deposit of uric acid crystals

BONE

BONE

Joint with gout

Joint with gout

In healthy humans uric acid is produced by the breakdown of purines. Normally it is excreted in the urine. In individuals with gout, uric acid is overproduced and accumulates because the kidneys do not efficiently eliminate it. As a result, blood levels of uric acid increase and uric acid crystallizes in the joints and even in the kidneys, causing kidney stones. Uric acid is formed in the last step of the metabolic pathway of purines.

The conversion of hypoxanthine to xanthine and of xanthine to uric acid is catalyzed by the enzyme xanthine oxidase (see scheme below).

Xanthine Oxidase

Hypoxanthine

HO N

Xanthine

Xanthine Oxidase

Uric acid

Treatment of gout can be achieved with a combination of therapies. The pain can be reduced with NSAIDs (e.g., naproxen), colchicine and, in acute cases, injection of corticosteroids into the affected joints. These medicines are not safe for long-term use and do not prevent future gout attacks.

Allopurinol, a purine derivative, was first prepared in the 1950s and shown to inhibit the enzyme xanthase oxidase (XO) and thus to block the biosynthesis of uric acid. Allopurinol is an effective inhibitor of XO because it binds to the enzyme effectively competing with xanthine. Since allopurinol has a nitrogen atom at the 2-position (shown in blue) instead of the C-H group of xanthine, it cannot be converted to uric acid.J

1. J. Clin. Invest. 2006, 116, 2073-2075; 2. Crystal-Induced Arthropathies 2006, 189-212; 3. Pharmacol. Rev 2006, 58, 87-114; Refs. p. 81

Chronic obstructive pulmonary disease (COPD) and its congener emphysema are the fourth leading cause of death in the US.

These smoker's diseases are tragic, not only because they are largely preventable, but because there is no cure.

The time between appearance of the first symptoms (in smokers, generally around age 50) and death is about 15-20 years.

Asthma is another life-threatening disease, but it is manageable. It may also be preventable, but the measures for prevention remain obscure.

ANTIASTHMATIC

AND ANTIALLERGIC AGENTS

SALMETEROL (SEREVENT™)

Structural Formula

Ball-and-Stick Model

Structural Formula

= Carbon = Hydrogen = Oxygen M = Nitrogen

= Carbon = Hydrogen = Oxygen M = Nitrogen

Year of discovery: 1980; Year of introduction: 1990 (as Serevent by GSK). It is marketed by GSK as Advair in combination with the corticoid fluticasone; Drug category: (^-Adrenergic receptor agonist; Main uses To treat the worsening of asthma and chronic obstructive pulmonary disease (COPD);

Approximate number of people treated annually: Over 15 million; Related drugs: Formoterol (Foradil, Oxis), Bambuterol (Bambec), Salbutamol (Ventolin). These drugs are also used in combination with inhaled anti-inflammatory steroids of the cortisone family.

Asthma is a chronic inflammatory illness of the respiratory system that causes coughing, wheezing or shortness of breath. These symptoms result from narrowing of airways, inflammation, and accumulation of mucus. In the US alone this disease affects about 5% of the population and usually worsens with age. Asthma attacks may be triggered by allergens, dust, cigarette smoke, cold air, exercise or emotional stress. Children living in urban areas are especially at risk to develop asthma as a consequence of viral infection and urban pollution.

Treatment of asthmatic patients with bronchodilators (substances that dilate the airways and improve bronchial airflow) started in the early 1900s but it was not until the 1960s that anti-inflammatory drugs were also included in the course of therapy. 12

Bronchodilators are p2-adrenergic receptor agonists and can be either short-acting (4-6h) or long-acting (>12h). They work by competitively binding to and activating the p2-adrenergic receptor. As a result the smooth muscles in the lung relax, leading to the dilation of bronchial airways.3

Salmeterol is a long-acting bronchodilator that is usually prescribed to treat severe persistent asthma. Regular daily use of salmeterol in combination with corticosteroids reduces the frequency and severity of asthma attacks.4 Since this therapy requires high doses, side effects such as increased heart rate and insomnia may occur. The long hydrophobic (oily) side chain (red) attached to the nitrogen of salmeterol serves to increase the solubility of the drug in the plasma membrane of the lung, leading to a slow and prolonged release. For this reason salmeterol is an effective long-acting drug.

The use of a short-acting fS2-adrenergic receptor agonist (e.g., salbutamol, see structure below) provides rapid relief of asthma symptoms. When inhaled, such faster-acting substances lessen sudden asthma symptoms, and when taken 15-20 minutes ahead of time, can prevent the onset of symptoms.

Salbutamol ch3

Salbutamol

The combination of salmeterol with the corticosteroid fluticasone (Flovent™, see page 51), known as Advair (GlaxoSmithKline), is now widely used, with annual sales of several billion dollars. Another application of Advair is in the treatment of chronic obstructive pulmonary disease (COPD, see page 53).

1. Principles of Immunopharmacology (2nd Edition) 2005. 281-344; 2. Prim. Care Resp. J. : J. Gen. Pract. Airways Group 2006, 15, 326-331; 3. Therapeutic Strategies in COPD 2005. 61-78; 4. Drugs 2005, 65. 1715-1734; Refs. p.

Carbon = Hydrogen S = Oxygen M = Fluorine y = Sulfur

FLUTICASONE PROPIONATE (FLOVENT™)

Structural Formula Ball-and-Stick Model Space-filling Model

Carbon = Hydrogen S = Oxygen M = Fluorine y = Sulfur

Year of discovery: 1981 (Glaxo Wellcome); Year of introduction: 1994 (Flonase), 1996 (Flovent); Drug category: Anti-inflammatory glucocorticoid; Main uses: Treatment of asthma and allergic and non-allergic rhinitis; Other brand names: Flonase (for the treatment of rhinitis), Advair (in combination with salmeterol for the treatment of asthma and COPD); Related drugs: Beclomethasone (Vanceril), Triamcinolone acetonide (Azmacort), Flunisolide (Aerobid), Budesonide (Pulmicort).

Fluticasone propionate is a synthetic analog of Cortisol that has been developed as an inhaled anti-inflammatory agent for the treatment of asthma, especially in combination with a vasodilator such as salmeterol (see page 50). Although Cortisol and related glucocorticoids (see prednisone, page 44) are effective as inhaled antiasthmatics, they are not suitable for long term use because of cumulative side effects, such as osteoporosis and immunosuppression. Research over two decades led to the improved antiasthmatic corticoid beclomethasone dipropionate, a prodrug of 16-methylprednisone.1

Beclomethasone dipropionate (Vanceril™)

Beclomethasone dipropionate (Vanceril™)

This prodrug is advantageous for two reasons: (1) the residence time in the lung is prolonged relative to prednisone and (2) it is gradually released as local enzymes convert it into 16-methylprednisone, and these differences translate into greater efficacy and convenient dosing. However, because a considerable amount of 16-methylprednisone still enters the circulation, the adverse side effects preclude the long-term use of beclomethasone in chronic asthma.

An intensive effort to solve the problem of side effects associated with prolonged use of inhaled corticosteroids led to the discovery of fluticasone propionate by researchers at Glaxo Wellcome (now GlaxoSmithKline). A key aspect of this research was the finding that the C2H5OCOCH2CO subunit attached to position 17 of beclomethasone could be replaced by the FCH2SCO group without loss of potency and with the great added benefit that the resulting steroid was very quickly deactivated by the action of enzymes in blood and liver. That deactivation occurred because of cleavage of the side chain at position 17 to a 17-carboxylic acid that had no glucocorticoid activity.2

ococ2h5 "'ch3

17-Carboxylic acid

The systematic research leading to the structural changes from Cortisol to fluticasone represents an excellent example of molecular engineering to optimize the properties of a therapeutic agent for a particular application. Although this process may look simple and straightforward in retrospect, in practice much time and effort are required to reach an optimized molecule. The combination of fluticasone propionate with salmeterol (preceding page) is sold as Advair.

1. Adv. Ther. 1997, 14, 153-159; 2 J Allergy Clin. Immunol. 1998, 101, S434-S439; Refs. p. 81

f liver, blood

17-Carboxylic acid

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