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A. Ethambutol
A Study of the Evolution of Optic Neuritis caused by Ethambutol in Rabbits
INTRODUCTION Ethambutol, a white crystalline powder soluble in water, is the dextro-isomer of ethylene di-imino di-butanol. Together with rifampicin, it is now considered the second drug of choice in the treatment of pulmonary tuberculosis, specifically for INHresistant and streptomycin-resistant tubercle bacilli). Like all drugs, it may produce undesirable effects. Instances of impaired vision have been recognized shortly after the introduction of the racemic form of the drug. Subsequently, it has been shown that although most of the therapeutic effect resides in the dextroisomer, the levoisomer possesses most of the toxicity. As a result, ethambutol is now used only in the dextro form. However, even with the limited dosage, cases of visual impairment due to ethambutol continue to be reported.10,20,26,27 Data gathered from the literature present only case reports.9,10,20,22,27 One report11 suggests the relationship between zinc metabolism and loss of vision due to ethambutol. Other reports suggest the probable mechanism of enzyme action and demyelination as the causes of optic nerve injury and inflammation.9,24,25 Related studies suggest the possibility of relationship between vitamin levels and optic nerve diseases.4,14,21,23 The causes of optic neuritis due to ethambutol and the mechanisms for bringing this about are varied.1,11,12,15,16,19,24,25 However, the mechanism by which ethambutol exactly affects the nerve has not yet been elucidated; and so far, there has been no report on what is being done to prevent optic neuritis as a side effect of prolonged intake of ethambutol. This study, therefore, aims to determine histologically the sequence of events that lead to optic neuritis due to prolonged intake of ethambutol and to characterize biochemically the substances that could be involved, either directly or indirectly, in inducing the optic nerve injury. Results of this study would later be helpful in formulating the mechanism by which ethambutol produce injury to the optic nerve. Subsequent studies could thus look into the possibility of reversing or fin ding an inhibitor for the toxicity in the optic nerve. The first phase of the study, which was done at the Institute of Ophthalmology, was able to clinically induce optic neuritis in rabbits. Initial histological changes observed indicated changes in the myelin sheath structures following axonal swelling. Moreover, PAGE studies showed initial changes in the optic nerve protein pattern as neuritis developed. Further biochemical analyses showed decreased serum levels of both zinc and copper as the duration of intake of the drag progresses. This would indicate chelation of these ions by ethambutol causing their loss in the urine. This study is the second phase of the project and consists of ultrastructural examinations and further biochemical analyses of the products of the different states of demyelination leading to neuritis and/or optic nerve atrophy. DISCUSSION Although substantial literature3,18,20-22 have dealt with the relationship between optic neuritis and ethambutol, few studies biochemical parameters have been reported. Moreover, these studies have not attempted correlating the histological changes accompanying induction of optic neuritis with biochemical changes, which the present study did at regular 2 week intervals. The study is also innovative in its attempt to quantify the histological changes using electron micrographs (5 x 7) with uniform magnification of x 2,000. These were covered with plastic grid of the same size and using the principle of the WBC counting chamber, the number and diameter of the axons were measured in centimeter then divided by the magnification of the film (x 2,000) and multiplied by 1,000 to get the actual measurements in nanometer (nm). For every optic nerve sample submitted, five representative sections, which were free from folds, knife marks and other artifacts were chosen for micrography. To ensure uniformity, three films each of a cross-section of the nerve were chosen for quantitative determination. The values obtained are summarized in Table 1. It can therefore be appreciated that from the control values of 15 nm, the axonal dilatation gradually increased in the 50 mg sample to 19-28 nm; in the 100 mg sample to 19-21 nm; and in the 200 mg sample to 28 nm. If these values were further plotted against the duration of treatment (Figure 5), an upward trend in the graph was noted. A direct correlation of the axonal swelling to the duration rather than the case was therefore established in the 50 mg sample. This finding suggests that inspite of a clinically normal fundoscopic finding, there may be changes in the ultrastructure of the nerve in the form of axonal swelling, which may progress as treatment continues. The proposed mechanisms described in the literature on the cause of optic neuritis are varied.2,7 -10 These hypotheses have been categorized as either interference with metabolism of some vitamins and minerals3,11,16,22 or direct action on the optic nerve.9,19,20,21 Therefore, in determining the mechanism for the observed histological changes in the optic nerve structure following ethambutol therapy, several biochemical parameters have also been tested. Thus the observed decrease in serum Zn and Cu levels and decreased Vitamin B6

Contraindications Hypersensitivity to the preparation. Two other mechanisms need to be investigated. Moreover. central or periaxial scotoma with visual field restriction. that Zn and Cu form a complex with ethambutol and its metabolites. in combination with rifampicin and isoniazid. We conclude that these observations are due to both histochemical and biochemical changes coincident to demyelination displayed histologically. These complexes may enter the axons and the increased influx of ions causes a corresponding increased hydration resulting in axonal swelling. Ethambutol may act on this protein by releasing it and thereby causing it to induce influx of polymorphonuclease leading to subsequent inflammation. visual nerve disorders and other ocular diseases. One of these is related to an activity associated with basic proteins. headache. They become apparent 2-3 mounts after the treatment commencement and usually are reversible. Special warnings and precautions During the treatment with Ethambutol the serum creatine level and creatine clearance should be monitored. the following observations were shown: 1) Ultrastructural changes were demonstrated earlier than the clinical appearance of the optic neuritis. Indications Ethambutol is indicated in patients with all forms of the pulmonary tuberculosis. acting by inhibition of the biosynthesis of the arabinogalactan and arabinomanan. Described side effects are seen with doses higher than 25 mg /kg body weight/ 24 hours. which are encephalitogenic and present in the optic nerve. 2) As early as 2 weeks. it is possible to propose 2 mechanisms consistent with observed results. viruses. Adverse reactions In about 30% of the cases Ethambutol leads to development of retrobulbar neuritis of the ophthalmic nerve. CONCLUSION Based on the foregoing results and discussions. . axonal dilatation was shown in the 50 mg sample. It formats also helate complexes with the bivalent ions. 3) At 4 weeks duration. a "myelin-like" structure within the axonal cytoplasm appeared in the samples given 100 mg dose. in order to prevent the visual side effects. because of disturbing function of the cell polyamines (spermidine and spermine).R . It is advisable to administer concomitant Vitamin A therapy. dizziness. No cross-resistance to other anti-tuberculosis medicines is registered so far. First. While the results determined are not extensive enough to formulate a definite mechanism for the toxicity associated with ethambutol intake. It shows no activity on the fungus. and other bacteria. Rarely allergy reactions. It is effective in some extrapulmonary forms of tuberculosis also (except renal and ophthalmic). Its anti-microbial activity is evident on proliferating cells. Ethanbutol possesses bacteriostatic effect both on the sensitive and resistant to the other tuberculostatics tubeculous bacteria. arthralgia. due to inhibition of the decaprenil .levels in the optic nerve and retina could mean possible involvement of these metabolites. 4) Biochemical analysis of the retina and the optic nerve showed proportionate increase in proteins and lipids.arabinose activity. The degree of axonal dilatation appears to be directly related to duration rather than the dose. as well as on the photochromogene non-typical mycobacterium. The inflammatory response of consequent influx of lymphocytes and its extracellular enzymes can damage the optic nerve resulting in demyelination The other possible mechanism is the effect of ethambutol on enzymes such as 7-dehydrocholesterol reductase which when inhibited causes demyelination. A deficiency of Vitamin B6 similar to that observed in INH therapy remits in demyelination with nerve atrophy. gastrointestinal disorders. the appearance of the "myelin-like" structure may be related to the irreversibility of the axonal damage. Pharmacological mechanisms Ethambutol is an anti-tuberculosis medicine. and hyperuricemia may appear. Second: that ethambutol and/or its metabolites can assume a conformation similar to pyridoxine and thus compete with the absorption of this vitamin resulting in decreased absorption of the latter. In concomitant treatment with isoniazid Ethambutol reduces the risk of development of resistance. participating in biosynthesis and stabilization of the DNA. severe renal failure. pregnancy and nursing. Usually the retina remains intact.

It affects the spine often enough to be a factor in back pain. A person's susceptibility to gout may increase because of the inheritance of certain genes or from being overweight and eating a rich diet. sharp urate crystals build up in the synovial fluid of the joints. According to some medical experts. Women more typically develop gout later in life. and. a substance that is produced by the body and is also found in high concentrations in some foods. because it takes 20 years of hyperuricemia to cause gout symptoms. needle-like urate crystals gradually accumulate in the joints. shiny. and tendons. While normal uric acid levels don't necessarily rule out gout and high levels don't confirm it. the presence of hyperuricemia increases the likelihood of gout. regular excessive alcohol intake. is formed as the body breaks down waste products. In many cases. and can keep recurring. Diagnosis Usually. physicians can diagnose gout based on the physical examination and medical history (the patient's description of symptoms and other information). tenderness. Excess body weight. last longer. Over the course of years. liver. ankle. The . surgery. and dried peas and beans. some precipitating event. Often. drinking too much. These symptoms may go away in about a week and disappear for months or years at a time. Infection. this effect is confined to the ortho-hydroxybenzoic acid (salicylic acid). another disease (such as lymphoma. hyperuricemia can also cause kidney stones. flood into the joint and surround the crystals. estrogen protects against hyperuricemia. or even a heavy drinking binge can cause inflammation. and swelling of the joint. hand. leukemia. or eating the wrong kinds of foods may suddenly bring on the symptoms.) Gout affects an estimated one million Americans. a condition known as hyperuricemia. mistaking the urate crystals for a foreign invader. Hyperuricemia doesn't always cause gout. ligaments. urate crystals can begin to build up in the joints. The pain is often so excruciating that the sufferer cannot bear weight on the joint or tolerate the pressure of bedcovers. there was a twofold increase in the incidence of gout over the 20 years between 1977 and 1997. over the course of time. and it builds up in the blood stream. it is now known that chronic exposure to high levels of lead decreases the body's excretion of urates. According to a study published in November 2002. it accounts for about 5% of all cases of arthritis. Gout Definition Gout is a form of acute arthritis that causes severe pain and swelling in the joints. and affect more joints. Gout is different from other forms of arthritis because it occurs when there are high levels of uric acid circulating in the blood. goes away after 5-10 days. which include pain. allowing uric acid to accumulate in the blood. redness. and the inflammation may be accompanied by a mild fever. however. but may also affect the heel. An additional factor is occupational or environmental. leading to permanent joint deformity and decreased motion. which can cause urate crystals to settle in the tissues of the joints. swelling. Urate crystals may be present in the joint for a long time without causing symptoms. including brains. It is not yet known whether this increase is the result of improved diagnosis or whether it is associated with risk factors that have not yet been identified. stone-like deposits known as tophi may build up in the joints. the body produces too much uric acid or the kidneys aren't efficient enough at filtering it from the blood. causing inflammation—in other words. Salicylates belong in this category. warmth. which is found naturally in the blood stream. Eventually. It occurs more often in men than in women. the use of blood pressure medications called diuretics. and dry. Normally. the redness. or hemolytic anemia) may be the underlying cause of the uric acid buildup that results in gout.Salicylates The desirability of detailed information regarding the drugs which enter most commonly into the therapeutic equipment of the practitioner of medicine is manifest. or elbow. According to Rockwood's experiments1 on man. the sex ratio is about 4:1. a stubbed toe. In some cases. Uric-acid levels tend to increase in men at puberty. Doctors can also administer a test that measures the level of uric acid in the blood. Gout appears to be on the increase in the American population. (In addition to causing the tophi associated with gout. and high levels of certain fatty substances in the blood (serum triglycerides) associated with an increased risk of heart disease can all increase a person's risk of developing gout. wrist. attacks of gout recur more and more frequently. It most commonly affects the big toe. and when estrogen levels fall during menopause. surgery. according to the National Institutes of Health. and pain that are the hallmarks of a gout attack. It has long been known that salicylates will provoke a significant increase in the output of uric acid. the stress of hospitalization. also called renal calculi or uroliths. Causes and symptoms As a result of high levels of uric acid in the blood. starting in their Description Uric acid. White blood cells. the kidneys filter uric acid out of the blood and excrete it in the urine. Gout usually comes on suddenly. Sometimes. Salts of salicylic acid form the essential ingredient of many of the secret remedies for these conditions. sardines. They are employed widely—perhaps not always wisely— especially as "specifics" in acute inflammatory rheumatism or acute arthritis. injury to the joint. men commonly develop gout in their late 30s or early 40s. such as an infection. 60s. The inflamed skin over the joint may be red. and is not obtained by the isomeric parahydroxybenzoic and metahydroxybenzoic acids. anchovies. However. however. the gout attack begins in the middle of the night. mainly those containing purine.

The potential side effects of allopurinol include rash. Alternative treatment Alternative approaches to gout focus on correcting hyperuricemia by encouraging weigt loss and limiting the intake of alcohol and purine-rich foods. . which tends to go away once the patient stops taking it.) Lowering uric acid in the blood also helps to prevent or improve the kidney problems that may accompany gout. people having gout attacks are encouraged to rest and to increase the amount of fluids that they drink. doctors try to prevent future attacks of gout and long-term joint damage by lowering uric acid levels in the blood. or indomethacin (Indocin). However. a skin condition known as dermatitis. Once an acute attack has been successfully treated. however. Prognosis Gout cannot be cured but usually it can be managed successfully. such as organ meats. In addition to taking pain medications as prescribed by their doctors. If you are using diuretics for BP control. beer. Diuretic for gout patients? Q: Since hydrochlorothiazide can increase the risk of attacks in patients with gout. nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen sodium (Aleve). Colchicine may causediarrhea. they are used for only about 48 hours and are not likely to cause major problems. The most definitive way to diagnose gout is . and preventing longterm joint damage. Doctors sometimes also use colchicine (Colbenemid). it may also be helpful to avoid foods high in purine. Prevention For centuries. While all of these drugs have the potential to cause side effects. Increasing fluid intake. contrast hydrotherapy (alternating three-minute hot compresses with 30-second cold compresses) can help dissolve the crystals and resolve the pain faster. gravies. losing weight and limiting alcohol intake can help ward off gout. so people taking diuretics or "water pills" may be better off switching to another type of blood pressure medication. While this view is perhaps a little overstated and oversimplified. attacks become a problem. During an acute attack. For congestive heart take a sample of fluid from the joint and test it for urate crystals. Treatment The goals of treatment for gout consist of alleviating pain. anchovies. medicines alone do not dissolve the tophi and they must be removed surgically. blocks the production of urate in the body. and liver dysfunction. Everyone should be sure to drink at least six to eight glasses of water each day. beans. Dehydration may also promote the formation of urate crystals.Corticosteroids such as prednisone (Deltasone) and adrenocorticotropic hormone (Acthar) may be given orally or may be injected directly into the joint for a more concentrated effect. In 2004. and they may not work for all patients. As tophi dissolve.development of a tophus can confirm the diagnosis of gout. these drugs can aggravate a peptic ulcer or existing kidney disease and cannot be used. the latter approach may be essential. These drugs may promote the formation of kidney stones. since diuretic therapy is a mainstay of treatment (N Engl J Med. A 2004 study revealed that eating more low-fat dairy products could reduce risk of developing gout. (In some cases. There are two types of drugs for correcting hyperuricemia. and wine. Acute attacks of gout can be treated with nonaspirin. The aim of the guidelines was to prevent repeat gout attacks and to reduce medication errors associated with intravenous colchicine in hospitals. what diuretic is safe and effective for these patients? A: Because they increase serum uric acid levels by reducing intravascular volume (as well as by direct renal mechanism). especially in cases where nonsteroidal antiinflammatory drugs cannot be used. lifestyle factors clearly influence a person's risk of developing gout. all diuretics can potentially precipitate gouty attacks. Allopurinol (Zyloprim). the FDA was seeking trial data on a new drug called oxypurinol (Oxyprim) for treating chronic gout. red meat. especially those with kidney disease. sardines. New quality of care indicators were released in 2004 to improve care for patients with gout. joint mobility generally improves. is also recommended. avoiding severe attacks in the future. aspirin and closely related drugs (salicylates) should be avoided because they can ultimately worsen gout. 2003. In some cases. Since purine is broken down in the body into urate. ibuprofen (Advil). Such uricosuric drugs as probenecid (Benemid) and sulfinpyrazone (Anturane) lower the levels of urate in the blood by increasing its removal from the body (excretion) through the urine. consuming garlic (Allium sativum) has been recommended to help prevent gout. you can either switch to other agents or use drugs that lower the serum uric acid level (allopurinol) if it is elevated and repeated gouty. These medications may have to be taken for life to prevent further gout attacks. gout has been known as a "rich man's disease" or a disease caused by overindulgence in food and drink.349:1647-1655). a type of drug called a xanthine-oxidase inhibitor. Since obesity and excessive alcohol intake are associated with hyperuricemia and gout. and can dissolve kidney stones as well as treating gout. especially by drinking water. In addition. however.

OR of recurrent gout attacks were 3.6-10 and few have explored factors that trigger recurrent attacks among individuals already diagnosed with gout. thought to trigger recurrent gout attacks. investigations have concentrated on risk factors for initial occurrence of gout3. respectively. ranking seventh among the most prescribed medications in the US in 200322. Patients were recruited online and asked to provide access to medical records. We examined the relation of all diuretic use and use of specific diuretics. Detection. including thiazide and loop diuretics use. such as thiazide and loop. to the risk of recurrent gout attacks using a conditional logistic regression model adjusting for alcohol consumption and purine intake. both increasing prevalence of hypertension20 and use of thiazide diuretic prescriptions are likely to lead to further increases in recurrent gout attacks. The casecrossover study uses each subject as his/her own control and compares the frequency of exposure to a suspected precipitating factor immediately prior to disease onset (hazard period) to that during the control periods. A similar effect was also later found for loop diuretics12. the relation of diuretic use as well as use of specific diuretics. To assess several putative risk factors. Further.Recent Diuretic Use and the Risk of Recurrent Gout Attacks: The Online Case-Crossover Gout Study ABSTRACT. to the risk of recurrent gout attacks has not been formally investigated. The median time between onset of gout attack and logging on to the website was 2 days. and the magnitude of association. many patients with gout have recurrent attacks3. patients with gout often have comorbidities including hypertension and coronary heart disease16. One hundred ninety-seven subjects completed both control and hazard period questionnaires.4 per 1000 persons in the US1.. The association between hyperuricemia and diuretic therapy has been known since 195811-13. Data were obtained on specific diuretic use on each day over the 2-day period prior to an acute gout attack (hazard period) and on each day of 2 days during the intercritical period (control period). thiazide and loop. if existing. is unknown. Although much is known about the pathophysiology of gout and clinically effective drug treatments are available. and this number does not include the use of thiazides in combination therapy. In addition to the burden of gout-related arthritis itself.2 and 3. Results. Conclusion. hypertension itself is an independent risk factor for the development of gout17.6 (95% confidence interval 1.8 for use of thiazide and loop. Adjusting for alcohol consumption and purine intake. In a small case-control study of hypertensive patients who developed gout. Such an . Objective.e. such as repeated gout attacks.7). Thus.4–9. In a retrospective cohort study of enrollees in the New Jersey Medicaid DISCUSSION Our results suggest that recent use of diuretics within 48 hours is associated with a significantly increased risk of recurrent gout attacks among persons with preexisting gout. the odds ratio (OR) for recurrent gout attacks from all diuretic use over the last 48 h was 3. these medications were observed to raise serum uric acid levels. program. Shortly after discovery of the thiazide class of diuretics. While knowledge of the association with hyperuricemia is clear. The Joint National Commission Seventh Report on Prevention. We conducted an internet-based casecrossover study involving subjects who had a gout attack within the past year. Evaluation. Because of the favorable cost profile and efficacy. epidemiologic data obtained from the last 4 decades are consistent with an increasing incidence and prevalence of gout in Western industrialized countries2. Methods. Gurwitz. Thus. Self-matching of each subject eliminates bias in control selection and removes confounding effects of factors that are constant over time. Diuretics raise uric acid levels through a combination of volume depletion and decreased renal tubular secretion of uric acid14.4. Key Indexing Terms: DIURETICS GOUT TRIGGERS Gout affects about 8. While a central therapeutic strategy in management of gout is avoidance of triggering events. we conducted an internetbased case-crossover study to assess the relation of diuretic use to the risk of recurrent gout attacks and evaluated whether the effect varies according to types of diuretic use. thiazide diuretics are commonly prescribed. et al14 found a 2-fold increased risk for initiation of anti-gout medication in patients receiving thiazide diuretics. and Treatment of Hypertension recommends thiazide-type diuretics as initial therapy in most patients either alone or in combination with another agent21. Several investigators have hypothesized that significant increases over the last 2 decades in the prevalence of hypertension and concomitant diuretic therapy may contribute to the increased prevalence and incidence of gout in Western countries18-20. Considering the relatively high prevalence of hypertension among gout patients and the widespread use of diuretics for the treatment of hypertension. it is an optimal study design for examining the effect of risk factors triggering recurrent attacks. Participants were predominantly male (80%) and over half had a college education. gout was more strongly related to the use of loop diuretics than thiazides15. Recent use of diuretics is associated with a significantly increased risk for recurrent gouty arthritis. These attacks cause progressive disability and can lead to cumulative joint damage5. i. The increased risk of gout attacks from either thiazide or possibly loop diuretic therapies represents an important modifiable risk factor in patients with gout.

Thus. Clarification of the effect of diuretic use on the risk of recurrent gout attacks has important clinical implications. and the effect of these diuretics on recurrent gout attacks was not trivial. clinicians have ample ability to individualize management for this population. Self-matching of each subject eliminates bias in control selection and removes confounding effects of factors that are constant over time. . While the association of diuretics with hyperuricemia has been known for years. Detection. We hypothesize that abrupt changes in diuretic use may lead to acute increases in uric acid concentration. and renal insufficiency. Such misclassification. We did not collect information on dosages of medications used.g. Further. betablockers. Evaluation and Treatment of Hypertension recommended thiazide-type diuretics as initial therapy in most patients either alone or in combination with another agent21. The case-crossover study design uses each subject as his/her own control and compares the frequency of exposure to a suspected precipitating factor immediately prior to disease onset to that during the control periods. Recently. participants in our study were recruited from 40 states and the District of Columbia. we applied 2 innovative approaches. it is still possible that misclassification of risk factors may have occurred. First. although the effect for the latter was not statistically significant. our study design was not immune to “confounding by indication” for diuretic use. would be very low in our study participants. such as congestive heart failure or renal insufficiency. Despite the well known association of gout and diuretics. There are a number of alternative effective agents for the treatment of hypertension and congestive heart failure in persons with gout that are unlikely to predispose to recurrent gout attacks.. Also. In our study. is likely to be nondifferential. low-dose aspirin use. Indeed.4. the Joint National Commission 7th Report on Prevention. In our study. the association between hypertension and gout is further compounded by the administration of diuretic therapy. about 28% of participants with a history of gout were taking diuretics. such as developing or worsening of hypertension. While it is possible these risk factors may occur differently during the hazard period compared to the control period. the number of subjects using diuretics in our study was relatively small. One explanation for such an increase is the increases in the prevalence of hypertension and concomitant diuretic therapy18-20.g. to examine whether diuretic use could trigger recurrent gout attacks. and allopurinol). weight and body mass index) and use of other medications known to affect serum urate levels (e. we showed that both risk factors and disease occurrence can be assessed in real time. Our study has some limitations as well. a relatively large proportion of our patient population with preexisting gout was prescribed this class of antihypertensive therapy. In summary. we believed the frequency of these risk factors. and can potentially lead to cumulative joint damage5. Third. including diuretic use. Many persons with gout continue to have recurrent gout attacks3. this was especially the case for loop users. this is the first study to find and quantify the effect of diuretics on the risk of recurrent gout attacks. if it occurred. Both prevalence and incidence of gout have increased over the last 2 decades in industrialized countries2. thus increasing the appropriate conditions for crystal formation or precipitation and modulating their phlogistic potential through perturbation of the local synovial microenvironment27. Several characteristics of our study are noteworthy. and would bias the results toward the null. we were able to reach patients with gout in the entire US. Second. we were unable to assess a dose-response relationship between diuretic use and risk of recurrent gout attacks. Neither case-control nor cohort studies are ideal study designs for such research questions. we found that recent use of thiazide and possibly loop diuretics was associated with a significantly increased risk for recurrent gouty arthritis. congestive heart failure. the prevalence of hypertension in the US has increased from 25. While we used validated questionnaires to assess risk factors for gout. For instance. Clinicians have ample ability to individualize management for special populations28 and could reduce the risk of gout attacks by avoiding the use of diuretics in persons with preexisting gout. we showed that the majority of subjects’ history of gout could be verified by their medical records and these subjects can be efficiently followed over time.0% during 1991-98 to 28. and subjects were asked to recall these putative risk factors occurring within the last 48 hours. a case-crossover study design and use of the Internet. These attacks are painful. that may also trigger recurrent gout attacks.effect was observed for both thiazide and loop diuretics. studying the triggering effect of diuretics on the risk of recurrent gout attacks is challenging.7% during 1999200020. which should minimize the potential recall bias. we postulate that the true effect of diuretics may actually be larger than we observed. increase functional limitation. Given the wide availability of alternative effective agents for the treatment of hypertension and congestive heart failure. Further. Developing or worsening of hypertension is likely to be a chronic process and could therefore occur during either a hazard or control period. and could reduce risk of recurrent gout attacks by avoiding the use of thiazide and possibly loop diuretics in persons with preexisting gout. There are other potential important confounders that could have varied between control and hazard periods including adiposity (e.. Since hypertension impairs urate secretion and promotes hyperuricemia26. using the Internet as a medium.

Benemid.Zyloprim) is prescribed for chronic gout or gouty arthritis and works by affecting the system that manufactures uric acid in the body. 5% women. which has anti-gout properties. In severe cases. The big toe is eventually affected in 90% of cases. and medications to reduce hyperuricemia. Probalan) is prescribed for chronic gout and gouty arthritis. It acts on the kidneys to help the body eliminate uric acid. The medication should be continued until pain and inflammation are non-existent for at least 48 hours. Colchicine does not cure gout or take the place of other medicines that lower the amount of uric acid in the body. it becomes more of a challenge if other conditions exist along with gout or if there is poor patient compliance to recommended lifestyle changes or a medication regimen. Time Required: Here's How: Variable 1. It is used to prevent gout attacks. NSAIDS are initially prescribed at maximum dosage and reduced as symptoms subside. . 4. 3. and avoiding complications (formation oftophi. or if the kidneys do not eliminate excess uric acid. then it is tapered gradually over one to two weeks. Gout is often related to an inherited abnormality in the body to process uric acid. NSAIDS. Typically. It prevents or relieves gout attacks by reducing inflammation. 5. preventing future attacks. which is a uricosuric agent. Medications for gout include:  non-steroidal anti-inflammatory drugs (NSAIDS)  colchicine  corticosteroids  adrenocorticotropic hormone (ACTH)  allopurinol  probenecid  sulfinpyrazone 2. 7.GOUT usually attacks a single joint suddenly and intensely. rapid and safe relief of pain and inflammation. Probenecid (brand names . NSAIDS which are COX-2 inhibitors may be useful for patients with gastrointestinal concerns but their use for acute gout has not been specifically reported yet. Subsequent attacks may not occur for weeks. Corticosteroids or adrenocorticotropic hormone can be used for patients who cannot take NSAIDS or colchicine. Allopurinol (brand name . gout patients are about 95% men. years. ACTH is administered as an intramuscular injection (an initial dose and subsequent doses over several days as needed). while others take large amounts of colchicine during a short period of time (several hours). repeated attacks occurring over a long period may cause damage to the joints and loss of mobility. 2. months. or not at all. 6. 5. kidney stones. Probenecid is known as a uricosuric agent. not treat them once they occur. Treatment goals include terminating acute gout attacks. such as avoiding a purine-rich diet. reduction in alcohol consumption. 6. specifically indomethacin. Dietary alterations are recommended. not to treat them once they occur. and Colchicine. ColBenemid (other brand names are Col-Probenecid and Proben-C) is a gout medication that contains Probenecid. An initial attack of gout (50% of initial attacks involve the big toe) may last several days and disappear even if untreated. weight reduction. Colchicine is used to treat acute flares of gouty arthritis and to prevent recurrent acute attacks. Other NSAIDS may be equally effective. are commonly the first medication prescribed to treat acute gout. Uric acid levels can become elevated by eating a lot of purine-rich foods such as meats. Though gout treatment is most often treated successfully and without complications. most commonly the first metatarsophalangeal (big toe). 3. Patients with acute gout typically receive daily doses of prednisone (20-40mg) or its equivalent for 3 to 4 days. 4. by the overproduction of uric acid by the body. Knowing how to treat gout is important for preventing attacks. Other preventive measures include maintaining adequate fluid intake. It is used to prevent attacks related to gout. and joint destruction). Colchicine may be used in 2 ways: some people take small amounts of it regularly for months or years. Gouty joints show the most visibly red signs of inflammationof any of the 100 types of arthritis.

S. All of the aforementioned drugs can be used in (brand name . Sulfinpyrazone (brand name . is not specifically a gout medication but is an angiotensin II receptor antagonist.psmid. Be compliant with the treatment plan your doctor recommends.pdf http://medical-dictionary.sopharma. Fenofibrate.bumc. and maintain healthy uric acid levels. 3. Keep your weight under 5.phtml http://arthritis. The drug helps prevent attacks but is not used to treat an attack once it has started. Dietary changes can help prevent gout attacks. Sulfinpyrazone is not currently available in the U. Medication to control level of uric acid. preventing gout attacks. to control symptoms. prevent future is not a specific gout medication but it a lipid-lowering drug that may help uric acid levels. (brand names .htm http://www. Reference http://www. Losartan. Analgesic painkillers are also used to relieve the intense pain of gout.about. It works by lowering the amount of uric acid in your https://dcc2.bu. What You Need: • • • • Diet low in purines. Maintain adequate fluid intake. 10.cortlandtforum. 9. Medication to control pain.Anturane) is also known as a uricosuric agent and is used to treat gouty arthritis. Medication to control inflammation. Avoid a purine-rich diet. Tips: 1.8. Reduce alcohol http://www.thefreedictionary. Medications can help control pain and inflammation of a gout attack and help prevent future attacks by eliminating excess uric acid or affecting the production of excess uric acid. Obesity has been linked to gout.pdf . 4. antihypertensive drug that may help control uric acid levels.Cozaar and Hyzaar).

in part. uric acid inhibits the growth of pulmonary smooth muscle cells. lead to gouty arthritis. or both. Uric acid passes through the liver. We present evidence indicating. volume depletion appears to play an important role in this response. both reabsorption and secretion occur in this segment. but in addition it can be a contributing factor in the formation of calcium oxalate stones themselves . The mechanism of urate retention by the kidney is indirect. and second. where p44/42 and p38 MAPK are activated in addition to the activation of cyclooxygenase-2 and the transcription factor nuclear factor. with the net effect being the reabsorption of most of the filtered urate. Hyperurecimia may be induced during treatment with such drugs as diuretics. In addition ethanol and salicylates may result in a decrease in the tubular secretion of uric acid. this can occur either by enhanced reabsorption or by reduced secretion. there is evidence that soluble uric acid can induce vascular smooth muscle cells to proliferate in vitro. that the inhibitory effect of uric acid on DNA synthesis is mediated by at least two distinct signaling pathways. first. Hyperuricemia may occur because of an overall decrease in secretion. These reports suggest that uric acid is retained in renal proximal tubule epithelial cells (PTCs). without causing cell injury. However. monosodium urate monohydrate reportedly activates p38 MAPK in chondrocytes. Similarly. which are made inside the cells of . which is caused. including a polarized morphology. In vivo. which.0 mg/dL (male).B). and hormone responses. Normal Uric acid levels are 2. which occurs via the initial activation of PKC. and subsequent activation of p38 MAPK. one that involves the activation of NF. are deficient in the enzyme uricase. unlike other mammals. The proximal tubule is the major site of urate handling. Hyperuricemia (High Uric Acid) What is hyperuricemia? Hyperuricemia is an excess of uric acid in the blood. The primary rabbit renal PTC culture system utilized in this study retains in vitro the differentiated phenotype typical of the cells in the renal proximal tubule.0 mg/dL (female) and 3.4-7. by alterations affecting the proliferation of renal PTCs. hyperuricemia ultimately may result in renal disease. Diuretics decrease urate excretion by increasing net urate reabsorption. and finally postsecretory reabsorption.B (NF. HYPERURICEMIA HAS BEEN IMPLICATED in the development of diverse renal diseases. causing renal tubular dysfunction. Purines are nitrogen-containing compounds. Clinical investigations have revealed that the hyperuricemia that occurs following renal transplantation is primarily related to a reduction in the tubular secretion of uric acid.Hyperurecemia Diuretics Hyperuricemia is a relatively common finding in patients treated with a loop or thiazide diuretic and may. Regardless of the mechanism. The present study was performed to identify specific intracellular signaling pathways that are targeted by uric acid in particular under conditions of hyperuricemia and are responsible for the effects of uric acid on renal PTC growth. Uric acid is the end product of purine metabolism in humans. Uric acid is freely filtered by the glomerulus and is reabsorbed in the early renal proximal convoluted tubule via a uric acid transporter followed by secretion possibly in the S2 segment.4-6. A convenient means for defining the effects of uric acid on renal proximal tubule epithelial cells is through in vitro studies with differentiated cells in culture.B and another that involves the activation of cPLA 2. an increase in uric acid production (resulting in an increase in the serum uric acid level). over a period of time. or passes through your intestines to regulate "normal" levels. Although generally uric acid has been considered inert. The mechanisms by which uric acid affects renal PTC growth may be similar to the reported effects of uric acid on such cell types as vascular smooth muscle cells. the mechanisms underlying the affects of uric acid on the proliferation of renal PTCs have not previously been elucidated. Uric acid may affect the function of renal PTCs via a similar spectrum of diverse signaling pathways. also reported that uric acid stimulates the growth of T cells and synovial fibroblasts. Di Giovine et al. Also important to blood uric acid levels are purines. including the formation of urinary stones. Included among the deleterious effects of hyperuricemia is interstitial renal disease. Not only is uric acid a frequent component of urinary stones. that uric acid inhibits DNA synthesis by the PTCs. Most of it is excreted (removed from your body) in your urine. Normal values will vary from laboratory to laboratory. Uric acid is also a contributing factor in the pathogenesis of essential hypertension. However. as well as tubular injury. and enters your bloodstream. as well as distinctive renal proximal tubule transport systems. since urate retention does not occur if the diuretic-induced fluid losses are replaced.

this may cause you to not be able to clear the uric acid out of your system. or none at all. or acidosis can cause hyperuricemia o Elevated uric acid levels may produce kidney problems. and tumor lysis syndrome may occur. or gouty arthritis from high uric acid levels in your blood. and secondary (high uric acid levels due to another disease or condition). • You may have fever. and your uric acid levels are elevated (caused by tumor lysis syndrome) • You may notice an inflammation of a joint (called "gout"). People may live many years with elevated uric acid levels. Sometimes. In a recent study4 30 per cent of 737 patients seen at a rheumatic-disease hospital were found to have serum urate levels greater than 6 mg. and some people with gout do not have significantly elevated uric acid levels in their blood. Purine breaks down into uric acid. especially in your toes and fingers). and gout (collection of uric acid crystals in the joints. per 100 ml. This is usually due to chemotherapy. This may cause high uric acid levels in the blood. No explanation could be found for the hyperuricemia in a quarter of . or chemotherapy agents may cause an increased turnover rate of cell death. .can cause increased levels of uric acid in the blood o Endocrine or metabolic conditions -certain forms of diabetes. if the uric acid crystals deposit in one of your joints. 3 may cause this problem to be more frequent than it need be. may occur. • If your blood uric acid levels are significantly elevated. (*Note. and you are undergoing chemotherapy for leukemia or lymphoma. fatigue if you have certain forms of cancer. What causes hyperuricemia? Causes of high uric acid levels (hyperuricemia) can be primary (increased uric acid levels due to purine). THE combination of an elevated serum urate level and joint symptoms that are atypical for classic gouty arthritis presents a familiar diagnostic problem to the clinician. the first 100 words appear below. chills.gout may occur with normal uric acid levels. • You may have kidney problems (caused by formation of kidney stones). resulting in high levels • Secondary hyperuricemia o Certain cancers. you may have symptoms kidney problems. from foods containing purine (exogenous). o Medications . or problems with urination Diagnostic Significance of Hyperuricemia in Arthritis This article has no abstract. . Causes of high uric acid levels include: • Primary hyperuricemia o Increased production of uric acid from purine o Your kidneys cannot get rid of the uric acid in your blood. Problems.your body (endogenous). o After chemotherapy. What are some symptoms of hyperuricemia to look for? • You may not have any symptoms. o Kidney disease . lymphoma. You may be at risk for tumor lysis syndrome if you receive chemotherapy for certain types of leukemia. Failure to consider the urate-retaining action of some commonly used drug such as salicylate in low doses1 or chlorothiazide or hydrochlorothiazide2 . if there is a large amount of disease present. Only about 20% of people with elevated uric acid levels ever develop gout. Uric acid formation may occur when the blood uric acid level rises above 7 mg/dL. or multiple myeloma. there is often a rapid amount of cellular destruction. and they do not develop gout or gouty arthritis (arthritis means "joint inflammation"). thus causing hyperuricemia. or come from outside of your body. but high uric acid levels can occur before chemotherapy is administered. Increased levels of uric acid from excess purines may accumulate in your tissues. . too). the body produces more uric acid than it is able to excrete. and form crystals. such as kidney stones.

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