John B. Marshall

Quality in the technical performance of colonoscopy and the continuous quality improvement process for colonoscopy: recommendations of the U.S. Multi-Society Task Force on Colorectal Cancer

Gastrointestinal and peritoneal tuberculosis remain common problems in impoverished areas of the world, but is relatively infrequent in the United States. A resurgence of tuberculosis in America since the mid-1980s means that clinicians will continue to see cases. Immigrants and AIDS patients are two population groups at particular risk for abdominal tuberculosis in this country; the urban poor, the elderly, and Indians on reservations are others. The symptoms and signs of GI and peritoneal tuberculosis are nonspecific, and unless a high index of suspicion is maintained, the diagnosis can be missed or delayed resulting in increased morbidity and mortality. Only 15-20% of patients have concomitant active pulmonary tuberculosis. Tuberculous peritonitis needs to be considered in all cases of unexplained exudative ascites. Laparoscopy with directed biopsy currently is the best way to make a rapid specific diagnosis. The measurement of ascites adenosine deaminase levels represents a major diagnostic advance in tuberculous peritonitis, particularly in underdeveloped areas where the affliction is common and laparoscopy may not be available. With greater experience, this testing procedure could also supersede invasive studies in western countries, particularly in high-risk patient groups. The commonest sites of tuberculous involvement of the GI tract are the ileocecal area, the ileum and the colon, although any area of the gut can be involved. If the area of affected gut is within reach of the flexible endoscope, rapid diagnosis may be possible with biopsy (if acid-fast bacilli or caseating granulomas are seen). Not infrequently, the disease is not considered until it is diagnosed at the time of surgery. In countries with a high prevalence of intestinal tuberculosis, a therapeutic trial of antituberculous drugs may be reasonable if the clinical picture is compatible. The diagnosis of tuberculous enteritis can be taken as highly probable if the patient responds to treatment and this is followed by no recurrence. Serologic tests for diagnosing tuberculosis are being improved and evaluated in intestinal tuberculosis. Gastrointestinal and peritoneal tuberculosis are treated with antituberculous drugs. Surgery is reserved for complications or uncertainty in diagnosis. Six-, 9-, and 18- to 24-month regimens are all effective for extrapulmonary tuberculosis. Standard therapy of at least 9 months duration is also effective in most AIDS patients who are started on appropriate treatment in a timely fashion and who are compliant. The potential for multidrug resistance needs to be kept in mind and accounted for.

PURPOSE: This phase I study was performed to evaluate the safety and pharmacokinetics of escalating doses of Marimastat (British Biotech, Inc, Oxford, United Kingdom) in patients with advanced malignancies and to determine the phase II recommended dose to be used in subsequent studies. PATIENTS AND METHODS: A standard phase I design was used in this study, in which consecutive groups of three patients were treated with escalating doses of the study drug. Marimastat was administered orally at 25, 50, or 100 mg twice daily to consecutive groups of patients with advanced lung cancer. An additional three patients were added at the highest dose studied (100 mg orally twice daily) to assess whether the inflammatory polyarthitis observed at that dose level can be prevented by a concurrent administration of nonsteroidal antiinflammatory drugs (NSAIDS) and/or low-dose corticosteroids. Blood was drawn for safety monitoring, pharmacokinetic analysis, and plasma levels of metalloproteinase (MMP)-2 and MMP-9 (determined by zymography). A total of 12 patients were studied. RESULTS: The most significant toxicity at the highest dose studied (100 mg orally twice daily) was a symptomatic inflammatory polyarthritis that persisted for up to 8 weeks after discontinuation of the study drug and was dose-limiting. The estimated plasma elimination half-life of Marimastat was 4 to 5 hours. The mean maximum concentration (Cmax) at a reasonably well-tolerated dose (50 mg orally twice daily) was 196 ng/mL and was reached within 1 to 2 hours (Tmax) after administration. Areas under the curve (AUC) tended to correlate with the dose of Marimastat. Zymographic analysis of peripheral-blood ratios of activated proenzymatic forms of MMP-2 and -9 did not show any consistent patterns of change in MMP levels or in a degree of their activation during the course of treatment. CONCLUSION: Marimastat was well absorbed from the gastrointestinal tract, with high levels of the study drug detected in plasma within hours after drug administration. Plasma concentrations of Marimastat achieved at dose levels 2 and 3 (50 mg and 100 mg orally twice daily) were substantially higher than those required for MMP inhibition in vitro. The dose-limiting toxicity (DLT) was severe inflammatory polyarthritis, which seemed to be a cumulative toxicity.