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Biomedical subjects

Robert L Wortmann

Publications and source records attributed to Robert L Wortmann.

15 recordsLinked to original sources
PubMed2007

Myotoxicity associated with lipid-lowering drugs.

PURPOSE OF REVIEW: Lipid-lowering drugs are associated with myotoxicity, which ranges in severity from myalgias to rhabdomyolysis resulting in renal failure and death. Although rhabdomyolysis is rare, muscle symptoms and serum creatine kinase elevations are sufficiently frequent during the course of lipid-lowering drug therapy to pose diagnostic challenges for the clinician. Progress in our understanding of this form of myotoxicity is reviewed. RECENT FINDINGS: Muscle pain and weakness are the cardinal symptoms and often interfere with vigorous exercise. These symptoms may occur with or without serum creatine kinase elevations. The risk of myotoxicity is increased by combination statin-fibrate therapy as well as by factors that elevate tissue levels of the lipid-lowering drug, including the dose, drug-drug interactions, and host factors. Underlying neuromuscular diseases may become clinically apparent during statin therapy and may predispose to myotoxicity. The pathophysiology of myotoxicity most probably involves metabolic effects of the statins on the isoprenoid pool and on mitochondrial function. SUMMARY: Management of myotoxicity requires an evaluation of risk factors prior to prescribing lipid-lowering drugs, attention to muscle symptoms, and withdrawal of drug in the event of significant abnormalities.

Creatine Kinase↗
PubMed2007

Management of gout in older adults: barriers to optimal control.

Gout, a common inflammatory arthritis, can be diagnosed with absolute certainty. Gout results from the body's reaction to urate crystals deposited in tissues, and this pathophysiology is well understood. If used appropriately, available therapies can be entirely effective in not only treating the symptoms of gout, but also in eliminating the excess urate from the body, thereby eradicating the disease. Because of these facts, management of patients with gout should be successful. However, management of gout is particularly challenging in the elderly, even though the principles of management are the same for all age groups. The purpose of this article is to review these principles and discuss them as they pertain to the elderly. The classic gout attack is acute in onset, extremely painful and associated with marked swelling, warmth, erythema and tenderness of a single joint. However, the diagnosis of gout may be challenging in the elderly because atypical presentations are more common in this group. Treatment of acute gout involves the use of NSAIDs, colchicine, corticosteroids or corticotropin (adrenocorticotropic hormone). Unfortunately, co-morbid conditions such as chronic kidney disease, peptic ulcer disease and congestive heart failure may make the use of these agents dangerous or contraindicated. Thus, it is important to try to treat an acute flare of gout at the earliest sign, because the sooner treatment is initiated, the faster the inflammation will resolve. Urate-lowering agents include allopurinol and uricosuric agents. These also must be used judiciously in the elderly. However, if used at the lowest dose that maintains the serum urate level below 5.0-6.0 mg/dL, the excess urate in the body will be eliminated, acute flares will no longer occur and tophi will resolve. Gout is often seen in association with hypertension, excessive alcohol consumption, obesity and hypertriglyceridaemia. These conditions and the medications used to treat them may contribute to the hyperuricaemia. Treating these conditions and using medications that do not promote hyperuricaemia will aid in the management of gout. Despite the challenges that often complicate the management of gout in the elderly, an understanding of the pathophysiology of the disease and both the indications and limitations of the medications used should allow successful treatment.

Aged↗
PubMed2006

Genetic risk factors associated with lipid-lowering drug-induced myopathies.

Lipid-lowering drugs produce myopathic side effects in up to 7% of treated patients, with severe rhabdomyolysis occurring in as many as 0.5%. Underlying metabolic muscle diseases have not been evaluated extensively. In a cross-sectional study of 136 patients with drug-induced myopathies, we report a higher prevalence of underlying metabolic muscle diseases than expected in the general population. Control groups included 116 patients on therapy with no myopathic symptoms, 100 asymptomatic individuals from the general population never exposed to statins, and 106 patients with non-statin-induced myopathies. Of 110 patients who underwent mutation testing, 10% were heterozygous or homozygous for mutations causing three metabolic myopathies, compared to 3% testing positive among asymptomatic patients on therapy (P = 0.04). The actual number of mutant alleles found in the test group patients was increased fourfold over the control group (P < 0.0001) due to an increased presence of mutation homozygotes. The number of carriers for carnitine palmitoyltransferase II deficiency and for McArdle disease was increased 13- and 20-fold, respectively, over expected general population frequencies. Homozygotes for myoadenylate deaminase deficiency were increased 3.25-fold with no increase in carrier status. In 52% of muscle biopsies from patients, significant biochemical abnormalities were found in mitochondrial or fatty acid metabolism, with 31% having multiple defects. Variable persistent symptoms occurred in 68% of patients despite cessation of therapy. The effect of statins on energy metabolism combined with a genetic susceptibility to triggering of muscle symptoms may account for myopathic outcomes in certain high-risk groups.

AMP Deaminase↗
PubMed2005

Febuxostat compared with allopurinol in patients with hyperuricemia and gout.

BACKGROUND: Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia and gout. METHODS: We randomly assigned 762 patients with gout and with serum urate concentrations of at least 8.0 mg per deciliter (480 micromol per liter) to receive either febuxostat (80 mg or 120 mg) or allopurinol (300 mg) once daily for 52 weeks; 760 received the study drug. Prophylaxis against gout flares with naproxen or colchicine was provided during weeks 1 through 8. The primary end point was a serum urate concentration of less than 6.0 mg per deciliter (360 micromol per liter) at the last three monthly measurements. The secondary end points included reduction in the incidence of gout flares and in tophus area. RESULTS: The primary end point was reached in 53 percent of patients receiving 80 mg of febuxostat, 62 percent of those receiving 120 mg of febuxostat, and 21 percent of those receiving allopurinol (P<0.001 for the comparison of each febuxostat group with the allopurinol group). Although the incidence of gout flares diminished with continued treatment, the overall incidence during weeks 9 through 52 was similar in all groups: 64 percent of patients receiving 80 mg of febuxostat, 70 percent of those receiving 120 mg of febuxostat, and 64 percent of those receiving allopurinol (P=0.99 for 80 mg of febuxostat vs. allopurinol; P=0.23 for 120 mg of febuxostat vs. allopurinol). The median reduction in tophus area was 83 percent in patients receiving 80 mg of febuxostat and 66 percent in those receiving 120 mg of febuxostat, as compared with 50 percent in those receiving allopurinol (P=0.08 for 80 mg of febuxostat vs. allopurinol; P=0.16 for 120 mg of febuxostat vs. allopurinol). More patients in the high-dose febuxostat group than in the allopurinol group (P=0.003) or the low-dose febuxostat group discontinued the study. Four of the 507 patients in the two febuxostat groups (0.8 percent) and none of the 253 patients in the allopurinol group died; all deaths were from causes that the investigators (while still blinded to treatment) judged to be unrelated to the study drugs (P=0.31 for the comparison between the combined febuxostat groups and the allopurinol group). CONCLUSIONS: Febuxostat, at a daily dose of 80 mg or 120 mg, was more effective than allopurinol at the commonly used fixed daily dose of 300 mg in lowering serum urate. Similar reductions in gout flares and tophus area occurred in all treatment groups.

Allopurinol↗
PubMed2005

Frequency of myopathy in patients receiving lovastatin.

Lovastatin (Mevacor) 20 mg is being considered for nonprescription availability. Because the most severe untoward consequence of therapy with any statin is rhabdomyolysis, the clinical data for lovastatin pertaining to this adverse event were reviewed. Evidence to date, based on almost 2 decades of experience, points to an extremely low risk for myopathy and rhabdomyolysis associated with lovastatin.

Anticholesteremic Agents↗
PubMed2005

Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout.

OBJECTIVE: Gout affects approximately 1-2% of the American population. Current options for treating hyperuricemia in chronic gout are limited. The purpose of this study was to assess the safety and efficacy of febuxostat, a nonpurine selective inhibitor of xanthine oxidase, in establishing normal serum urate (sUA) concentrations in gout patients with hyperuricemia (>or=8.0 mg/dl). METHODS: We conducted a phase II, randomized, double-blind, placebo-controlled trial in 153 patients (ages 23-80 years). Subjects received febuxostat (40 mg, 80 mg, 120 mg) or placebo once daily for 28 days and colchicine prophylaxis for 14 days prior to and 14 days after randomization. The primary end point was the proportion of subjects with sUA levels <6.0 mg/dl on day 28. RESULTS: Greater proportions of febuxostat-treated patients than placebo-treated patients achieved an sUA level <6.0 mg/dl at each visit (P < 0.001 for each comparison). The targeted sUA level was attained on day 28 in 0% of those taking placebo and in 56% of those taking 40 mg, 76% taking 80 mg, and 94% taking 120 mg of febuxostat. The mean sUA reduction from baseline to day 28 was 2% in the placebo group and 37% in the 40-mg, 44% in the 80-mg, and 59% in the 120-mg febuxostat groups. Gout flares occurred with similar frequency in the placebo (37%) and 40-mg febuxostat (35%) groups and with increased frequency in the higher dosage febuxostat groups (43% taking 80 mg; 55% taking 120 mg). During colchicine prophylaxis, gout flares occurred less frequently (8-13%). Incidences of treatment-related adverse events were similar in the febuxostat and placebo groups. CONCLUSION: Treatment with febuxostat resulted in a significant reduction of sUA levels at all dosages. Febuxostat therapy was safe and well tolerated.

Adult↗
PubMed2005

Recent advances in the management of gout and hyperuricemia.

PURPOSE OF REVIEW: To review the recent advances in the management of gout and hyperuricemia. RECENT FINDINGS: The first quality indicators for gout management have been proposed. Selective COX II inhibitors, as well as traditional NSAIDs, are effective in acute gout. A new xanthine oxidase inhibitor, febuxostat, and pegylated uricases are in clinical trials. SUMMARY: The therapeutic aims in gout include termination of the acute attack as promptly and gently as possible, prevention of future attacks, prevention or reversal of complications of the, and prevention or reversal of associated features such as obesity, hypertriglyceridemia, hypertension, or alcoholism.

Gout↗
PubMed2004

Treatment of acute gouty arthritis: one physician's approach and where this management stands relative to developments in the field.

An attack of acute gouty arthritis is one the most painful episodes that can be experienced by humans. Fortunately, there are three classes of agents that can effectively terminate the acute attack. These include colchicine, nonsteroidal anti-inflammatory drugs, and glucocorticoids. If therapy with any one of these is initiated promptly after the onset of symptoms, relief should occur quickly. Recent observations have increased the knowledge of crystal-induced acute inflammatory responses. These observations allow a better understanding of the mechanisms of action of these agents and provide the rationale for using them in combination in severe or refractory cases.

Acute Disease↗
PubMed2002

Differentiating idiopathic inflammatory myopathies from metabolic myopathies.

The metabolic myopathies are a heterogeneous group of diseases, including glycogenoses, disorders of lipid metabolism, and mitochondrial myopathies, that result primarily from inborn errors of metabolism. Most of these metabolic defects cause medical conditions that manifest early in life. Nevertheless, clinical presentations during the teenage years and adulthood are increasingly being recognized. Many of the clinical manifestations of these diseases are difficult to differentiate from those observed in the idiopathic inflammatory myopathies, especially polymyositis. A directed evaluation using the clinical, laboratory, and genetic approaches summarized in this article, however, should allow for the differentiation of most metabolic myopathies from polymyositis and other forms of idiopathic inflammatory myopathy. The diagnosis of a metabolic myopathy should be considered in patients who appear to have polymyositis but lack the characteristic changes of inflammation found on EMG, MRI, or muscle histology, or in such patients who are refractory to immunosuppressive therapy. The forearm ischemic exercise test is especially useful to screen for some inborn errors of glycogen metabolism or glycolysis and for myoadenylate deaminase deficiency. Thorough analysis of muscle tissue, including histology, histochemistry, biochemistry, and occasionally electron microscopy, is often necessary to make the diagnosis of a metabolic myopathy. Advances in molecular biology methods and knowledge of the precise genetic defects associated with these metabolic defects are dramatically increasing our capacity to diagnose patients with a widening range of myopathies. It is expected that, with further understanding of the mechanisms of the metabolic and idiopathic inflammatory myopathies, the differentiation of these disorders into their pathogenetic components, and the capacity to diagnose them will continue to improve. These are essential factors in improving genetic counseling and eventually the therapy of these serious, and currently incurable, disorders.

Diagnosis, Differential↗
PubMed2002

Gout and hyperuricemia.

Gout continues to be a health problem around the world despite the availability of effective therapies. Although the prevalence is influenced by genetic factors, the associations of alcohol consumption, obesity, and hypertension appear to be partially responsible for the increased prevalence of gout and hyperuricemia in African and Oriental countries. The association between hyperuricemia and cardiovascular disease seems linked to insulin resistance. This relation, in part, explains the common coexistence of hyperlipidemia and glucose intolerance in patients with gout. Accordingly, it is recommended that one pay more attention to dietary manipulation in patients with gout in addition to managing hypertension, obesity, and other medical problems. Although acute gout attacks can be treated, eliminating gout requires effective removal of urate from the body. Allopurinol remains a dominant urate-lowering agent, however its use may be limited by allergic reactions. Uricosuric agents are also effective urate-lowering agents and provide an alternative to allopurinol. Strategies to treat patients who are sensitive to allopurinol continue to evolve.

Africa↗
PubMed2002

Lipid-lowering agents and myopathy.

Each of the lipid-lowering agents available today can cause myopathy. The severity of the muscle disorder may vary from trivial myalgias or elevations of creatine kinase in asymptomatic individuals to rhabdomyolysis with myoglobinuria, renal failure, and death. Fortunately, significant myopathy occurs at a low rate. However, the large number of individuals taking these medications renders it a significant problem. Although the pathophysiology of the myopathy remains speculative, its occurrence appears to be dose related. Consequently, the total dosage of lipid-lowering drug consumed, the concomitant use of other medications that affect their blood levels, and the individual's specific drug-metabolizing enzyme profile may contribute to this toxicity.

Creatine Kinase↗
PubMedDate not supplied

Dermatomyositis.

Dermatomyositis is one of the idiopathic inflammatory myopathies. It is characterized clinically by progressive symmetrical proximal muscle weakness and a characteristic rash. There are patients with rash who have little or no muscle disease. Although the process primarily attacks the skin and the muscles, it is a systemic disease with frequent manifestations in the gastrointestinal tract and pulmonary system. Dermatomyositis has been linked to internal malignancy in somewhere between 15% and 25%. Therapy for the muscle disease includes systemic corticosteroids with or without an immunosuppressive agent. Therapy of the skin disease begins with photoprotection and topical corticosteroids, but also includes the use of antimalarial agents and immunomodulatory therapies.

Adrenal Cortex Hormones↗