A subtherapeutic international normalized ratio despite increasing doses of warfarin: could this be malabsorption?

OBJECTIVE: To describe a case of warfarin resistance apparently caused by malabsorption and to review the literature regarding warfarin resistance. CASE SUMMARY: A 28-year-old renal transplant patient with systemic lupus erythematosus was admitted for upper extremity thrombophlebitis. Resistance to oral warfarin was demonstrated. Potential causes were investigated. The trapezoidal rule was used to compare the area under the curve for intravenous versus oral dosing of warfarin. The usual bioavailability of warfarin should be 100%. In this patient, warfarin bioavailability after oral dosing was 1.5%. Three potential causes, malabsorption (FF), enzymatic degradation (FG), and first-pass extraction in the portal circulation (FH), are discussed. CONCLUSION: This case demonstrates resistance to warfarin presumably caused by malabsorption.

Nicotine: does it have a role in the treatment of ulcerative colitis?

OBJECTIVES: To review the epidemiology, pathophysiology, diagnosis, clinical manifestations, and treatment of ulcerative colitis, with emphasis on the relationship between smoking, nicotine, and ulcerative colitis, and the most recent clinical trials on the use of nicotine in the treatment of ulcerative colitis. DATA SOURCES: A MEDLINE search (1966 to present) of English language literature regarding the use of various nicotine dosage forms in the treatment of ulcerative colitis. Additional literature was obtained from bibliographic literature searches of appropriate articles identified through this search. DATA SELECTION: All appropriate journal articles focusing on ulcerative colitis and current treatment options, with emphasis on clinical trials involving the use of nicotine, were considered by the authors for inclusion. DATA SYNTHESIS: Ulcerative colitis is a chronic inflammatory disease state of unknown etiology. Its progression is erratic, with patients experiencing periods of exacerbations and remissions. Current therapeutic options have yielded less than satisfactory results. With the discovery of the potential relationship between nonsmoking status and the onset of ulcerative colitis and the development of various nicotine dosage forms came the hypothesis that nicotine may play a protective role against the development of ulcerative colitis and maintenance of remission. Hence, investigators began conducting clinical trials on the use of available nicotine dosage forms in the management of ulcerative colitis. The most recent clinical trials on the use of nicotine in the management of ulcerative colitis have suggested that nicotine, in combination with conventional pharmacologic therapy, may result in clinical improvement in some patients. The use of nicotine as a single agent cannot be recommended at this time. Clinical trials have also revealed poor patient tolerability and long-term compliance due to nicotine's significant adverse effect profile. Overall, investigation of nicotine in the treatment of ulcerative colitis has yielded disappointing results. CONCLUSION: Nicotine cannot be recommended as adjunctive or single therapy for the treatment of ulcerative colitis and will not alter current treatment options. Further research in this area is necessary with focus on enhancing understanding of disease pathophysiology, therapeutic effects of nicotine, and reducing nicotine's adverse effect profile.

Ketoconazole to prevent acute respiratory distress syndrome in critically ill patients.

Ketoconazole appears to be an effective prophylactic measure in surgical patients at risk of developing ARDS. The beneficial effects may be caused by thromboxane synthetase inhibition because thromboxane B2 concentrations were decreased by ketoconazole in both studies. Two studies were unable to demonstrate a beneficial effect with the selective thromboxane synthetase inhibitor dazoxiben. Both studies consisted of a small number of subjects with already established ARDS, not prophylaxis in patients at risk of ARDS. Although the effects of ketoconazole on mortality in patients at risk of ARDS are conflicting, there may be reduced mortality in patients with sepsis. Several issues must be considered before ketoconazole is used in this setting. First, the studies to date have excluded patients at risk of hepatotoxicity, which is probably wise considering the potential hepatotoxicity with ketoconazole and the unknown benefit/risk ratio in these patients. Also, therapies that reduce gastric acidity should be avoided to ensure bioavailability. If ketoconazole is administered through a jejunostomy tube, it probably should be given with a dilute acid to enhance absorption. Furthermore, ketoconazole is a known inhibitor of the cytochrome P450 system, which results in a number of drug interactions. If ketoconazole is used, the patient's current drug therapy should be reviewed for potential interacting drugs. In light of the current studies, ketoconazole may be considered for surgical patients at risk of developing ARDS (especially patients with sepsis) with the previously noted considerations. Future research should seek to confirm ketoconazole's role for the prevention of ARDS in all critically ill patients. Additional studies also should clarify the role of various inflammatory mediators in the pathophysiology and therapy of ARDS.

Use of fish oil to prevent coronary angioplasty restenosis.

OBJECTIVE: To review the literature investigating the use of fish oil in preventing restenosis postangioplasty (RPA). DATA SOURCES: An Index Medicus and bibliographic search of the English-language literature pertaining to the use of fish oil in preventing RPA. The key terms used were fish oil, angioplasty, and eicosapentaenoic acid. STUDY SELECTION AND DATA EXTRACTION: The results of all trials, including abstracts, that were obtained are reviewed and critiqued. DATA SYNTHESIS: Restenosis of a coronary vessel at the site of angioplasty occurs 30-40 percent of the time. Because fish oil has been theorized to prevent atherosclerosis and because atherosclerotic-like processes are theorized to be involved in RPA restenosis, fish oil has been studied to determine whether it can prevent RPA. Results of such trials have been mixed. Some have observed a reduction in the number of patients with angiographic or clinical evidence of restenosis. Two trials have failed to observe such an effect. Reasons for the differences are unknown. Possible explanations include differences in study design, endpoint parameters, definition of restenosis, and dosing methods of the fish oil. Bleeding was not of significant concern in any of the trials, even when fish oil was combined with antiplatelet therapy. CONCLUSIONS: Fish oil may be considered for use in patients to prevent RPA. It probably should be continued for only six months following the procedure. Current data suggest that at least 3 g/d of eicosapentaenoic acid and 1 g/d of docosahexaenoic acid should be used. If possible, therapy should be started as soon as it is known that angioplasty will be performed or at least as soon as possible following the procedure. Many patients may not be able to tolerate fish oil because of its gastrointestinal effects.