Pancreatic replacement enzymes have been used for treatment of cystic fibrosis since shortly after the disease was first described in 1938. These enzymes were introduced into medical practice before the passage of the Food, Drug, and Cosmetics Act. In addition, because they were derived from """"""""food"""""""" and were therefore thought to be intrinsically safe, no rigorous formal studies of efficacy and safety, such as would be needed now to fulfill the requirements of an FDA new drug application, were ever performed. The use of this class of therapeutic agents was governed by the Department of Agriculture rather than by the Food and Drug Administration. Over the first few decades of use, the only major toxicity reported was symptomatic allergy to inhaled powdered enzymes (almost always in caregivers [e.g., parents and nurses]) and a rise in serum uric acid in some patients who required high doses. Both of these problems were rare, and neither represented a clinically important threat to cause irreversible injury or death. Relatively unsupervised use of these drugs continued. In recent years, however, very high-dose enteric coated preparations were introduced. These drugs were much more effective for many patients. New technology allowed production of very high-dose capsules (each containing 25000 or more units of lipase, compared to the 4000 units in previous preparations; the amount of proteases was also increased). Some patients who took very high doses (usually >5000-10000 units/lipase per kg per meal) developed severe colonic strictures (with obstruction) and many required surgery, including some who underwent subtotal colectomy. Although the exact pathophysiology of this toxicity is not known with certainty, there is little doubt that it hss been associated with the introduction of the high-dose capsules (and usually with the consumption of large amounts of them). With this occurrence of a new major toxicity the FDA was compelled to review the status of these drugs, and ruled that the very high-dose preparation (i.e., any capsule containing more than 20000 units of lipase) be removed from the market immediately, and that all other pancreatic enzymes must be expeditiously processed as new drugs. The study proposed here is one of many which are not necessary to establish efficacy (to the standards of an FDA new drug application) of pancreatic enzymes for treatment of CF.
The specific aim of the study is to compare fat and protein absorption (as determined by a 3-day stool fat and protein determination) in CF patients during a three day period of administration of pancreatic enzyme replacement (Ultrase MT12) with meals with the same patient's data during a three-day period of administration of a placebo preparation with meals. """"""""
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