Gout treatment compounds

Colchicine (6) is used in the treatment of a broad range of diseases including acute gout and Mediterranean fever [28] and induces depolymerization of tubulin. This compound (6) distorts the tubulin/microtubule equilibrium by binding to the tubulin dimer and halting mitosis in the metaphase. The reason this approach is such a successful target in cancer therapy is that... 

Phenylbutazone (Butazolidin) is metabolized to oxy-phenbutazone (Phlogistol), and both compounds have all of the activities associated with the NSAIDs. Their use is accompanied by serious adverse reactions, such as anemia, nephritis, renal failure or necrosis, and liver damage. Because of their toxicity, they are prescribed only for the treatment of pain associated with gout or phlebitis or as a last resort for other painful inflammatory diseases resistant to newer and less toxic treatments. Interactions with a large number of other drugs... 

Initial treatment of gout and its associated hyperuricemia must involve therapy directed toward terminating the painful inflammatory process that is a prominent feature of acute gouty arthritis. A variety of nonsteroidal antiinflammatory compounds (e.g., in-... 

The literature on these ring systems in the last 10 years is vast. An Internet search alone provides 3500 citations for sildenafil (60a, Viagra). Not only Viagra is of medical interest allopurinol (ALP) 61, the classical treatment of gout arthritis, is still of interest, and pyrazolopyridazines and thiazolopyridazines have also been shown to be of biological importance. These activities extend beyond an interest in the synthesis and chemistry of these compounds indicated by the large number of patented potential applications. 

Gout is caused by the deposition of crystals of monosodium urate hydrate which are ingested by leucocyctes and trigger the inflammatory response. The biosynthesis of uric acid involves the oxidation of the more soluble compound xanthine (2,6-dihydroxypurine) by xanthine oxidase, and this enzyme is inhibited by allopurinol (187). The treatment of gout also relies on uricosuric drugs to accelerate urinary excretion of uric acid and antiinflammatory drugs to ease the pain and inflammation. 

A number of 8-aryl substituted pyrido[3,4-t/]-l,2,3-triazin-4(3//)-ones have been found to be most efficacious as inhibitors of xanthine oxidase, potential compounds for the treatment of ischemia and gout <88EUP274654>. A number of 3//,4//-pyrido[3,2-e]-l,2,4-triazine and 3/f,4//-pyrido[3,4-e]-1,2,4-triazine 3-acetamides have shown antiinflammatory, diuretic, antihypertensive, and psychotropic effects <89FES279>. During a search for potential antidepressant compounds, the pyrido-1,2,3-triazinone (399) was found to be more active than its isomer (400) <87EJM337>. 

Perhaps the most widely used at present is allopurinol (85 R = H) in the treatment of gout. This and its congeners oxyaUopurinol (87 R = H) and thiopurinol (112) inhibit xanthine oxidase and so inhibit the oxidation of xanthine and hypoxanthine to uric acid, the causative agent of gout. This group of compounds also shows some antineoplastic activity <71JCS(C)1610). 

Psidia punculata Vatke Analysis of the essential oil ( 0.5%) of P. punculata semi-dried leaves gave germacrene-D (27%), p-phellandrene (20%) and p-caiyophyllene (10%) as the major compounds 45). The leaf decoction of this plant is used for treatment of abdominal pains and colds (35). The Maasai use the leaves as an insecticide for fleas in sheep, goat kids and calves. The roots are used to treat gout (37). 

Lithium has various medicinal uses, though at certain levels it can be toxic. In the nineteenth century, lithium was used as a treatment for gout, a painful condition where uric acid builds up around certain joints, particularly around the feet. As uric acid builds up, its molecules form crystals. These crystallized molecules are fairly insoluble, which can hamper treatment. However, doctors discovered that if lithium was incorporated into the uric acid compounds, the compound was more soluble, and thus easier to dissolve. Bathing in lithium-rich springs and spas soon became popular for treating gout. Unfortunately, it was discovered that the lithium was too diluted in these spa waters to have any beneficial effect. 

Probenecid and Gout. The story of the discovery of probenecid and its usefulness in the treatment of gout is well known to medicinal chemists. Certain sulfanilamide compounds were observed to decrease the renal clearance of penicillin in a study aimed primarily at increasing the usefulness of penicillin during those days when this antibiotic was difficult and expensive to make. 

Notwithstanding its obsolescence in the treatment of infectious diseases, probenecid found a very important place in the physician s armamentarium because of its uricosuric activity. Its interference with the reabsorption of uric acid through the renal tubular membrane was an unexpected observation. Probenecid is the first useful synthetic compound for the control of uric acid excretion and the age-old disease, gout. 

Certain side reactions are associated with long-term treatment with chlorothiazide. The most common side effect is a reduction in serum potassium concentration. There is also an elevation in serum uric acid concentration, occasionally with precipitation of acute attacks of gout. In rare instances, hyperglycemia and diabetes mellitus have occurred. Numerous molecular modifications have since been made, with the hope of producing a compound... 

Even some or most of the common garden vegetables and fruits contain trace amounts of alkaloids as well as other potentially beneficial types of compounds. Our daily cups of coffee contain the alkaloid caffeine. Tobacco and some other plants contain the alkaloid nicotine, and there is ongoing research to determine beneficial medicinal properties for nicotine and related compounds, possibly even against cancer. The alkaloid colchicine is sometimes used as a treatment for gout, although it is a drug also used in horticulture to induce mutations in plant species. 

Cinchophen (2-phenylquinoline-4-carboxylic acid, Atophan, XLIII) has been used in the treatment of gout and arthritic conditions, but fell into disrepute as it caused toxic hepatic cirrhosis with a high mortality in sensitive individuals. It must nevertheless be mentioned as it represents another class of chemical compound which possesses anti-inflammatory activity. 

Probenecid inhibits renal tubular reabsorption of water and by this meehanism enhanees the urinary excretion of uric acid. This lowers the level of urate in the serum. It thus serves as a potent uricosuric agent in the treatment of gout. Probenecid also blocks the renal tubular seeretion of penicillins and cephalosporins. It is, therefore, used as an adjuvant therapy with penicillin V or G, ampicillin, cloxacillin, oxacillin, methicillin and naficillin to increase and prolong their plasma levels. Besides it also enhances the plasma levels of anti-inflammatory agents like naproxen and indomethacin, and a host of medicinal compounds such as sulphonamides, sulphonylureas, dapsone, etc. 

Sulfinpyrazone is a structural derivative of the anti-inflammatory drug phenylbutazone. Unlike phenylbutazone, however, sulfinpyrazone does not have significant anti-inflammatory activity. It does have potent uricosuric effects and frequently is used in the treatment of gout. At least four metabolites of sulfinpyrazone have been identified, including the sulfide, sulfone, p-hydroxysulfide, and p-hydroxysulfinpyrazone derivatives (Fig. 31.16) (24). Only the parent sulfinpyrazone and its reduced sulfide metabolite, however, are active as COX inhibitors (98). Because these compounds are reversible inhibitors, the antithrombotic activity lasts only as long as blood levels of the drug and metabolite persist (half-life, 4-6 hours for parent sulfinpyrazone, 11-14 hours for the sulfide metabolite). Sulfinpyrazone is not yet approved in the United States for use in acute myocardial infarction or for transient ischemic attack prophylaxis. 

Toxicological Implications for Man. Because psoralens are potent photoactive compounds, they have been used medically for treatment of skin de pigment at ion or vitiligo (16,17), and psoriasis (18). However, there has recently been concern associated with the medical use of these compounds (19). This concern is due to the observed phototoxicity during therapeutic use (17), the suspected photocarcinogenicity of xanthotoxin (20,21), and the latent onset of tumors in treated laboratory animals (22). Acute gout secondary to psoriasis also was exacerbated by psoralen and UV-A (PUVA) photochemotherapy (23). 

Since the drug tolerance to this compound is high, it may be of interest as a medicine for treatment of gout and hyperuricemia, as well as an antihypertensive agent. IbP and its 1- and 3-substituted derivatives containing 3- and 4-pyridinyl moieties in the pyridine ring exhibited pronounced cardiotonic activity (81USP4276293). 

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