PubMed · 908820
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J L Colaizzi. 1977. Digoxin.. https://doi.org/10.1016/s0003-0465(16)34485-8
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In bioavailability studies of two formulations of a drug, the standard two-sequence, two-period crossover design is usually considered to assess bioequivalence. The standard two-sequence, two-period crossover design, however, may not be useful when differential carryover effects are present. In addition, it does not provide independent estimates of intrasubject variabilities for the two formulations. To overcome these problems, alternatively, a higher-order crossover design may be considered. In this paper, we derive statistical methods based on Schuirmann's two one-sided tests procedure for assessing bioequivalence for some commonly used higher-order crossover designs. Four designs, including Balaam's design, the two-sequence dual design, and two four-period designs (with two and four sequences), are considered. The relative merits of these designs as compared to the standard two-sequence, two-period design are discussed. Two examples concerning bioequivalence are used to illustrate the use of these methods.
The pathogenesis of extrapancreatic tumor hypoglycemia has been related to the secretion of big insulin-like growth factor (IGF) II by the tumor. In 25 of 28 patients with this type of hypoglycemia we found 1.5-8-fold elevated serum levels of immunoreactive big (15-25 kD), but decreased levels of normal IGF II. After removal of the tumor, big IGF II disappeared and normal IGF II increased. Tumors contained elevated levels of IGF II, 65-80% in the big form. The insulin-like bioactivity of big IGF II and its affinity towards IGF-binding proteins (IGFBP)-2 and -3 are similar to those of normal IGF II, but two- to threefold higher on a molar basis. Big IGF II is mainly bound to the 50-kD IGFBP complex. The latter contains approximately 10 times more of this peptide than in normal serum and displays three- to fourfold increased insulin-like bioactivity. The formation of the 150-kD IGFBP complex with 125I-recombinant human IGFBP-3 is impaired in tumor serum. This results in sequestration of IGFBP-3 and predominant association of big IGF II with IGFBP-2 and -3 in the 50-kD complex. Increased bioavailability of big IGF II in this complex due to unrestricted capillary passage and enhanced insulin bioactivity of this big IGF II pool provide a continuous increased insulin-like potential available to insulin and type 1 IGF receptors of insulin-sensitive tissues and thus may lead to sustained hypoglycemia.
Increasing knowledge about the risk of toxic effects caused by anthropogenic mercury accumulation in ecosystems has resulted in a growing pressure for reduction of the discharge of mercury waste. Consequently, the mercury waste problems of dental clinics have been given increased attention, and restrictions on handling and discharge of contaminated waste have been established in several countries. Major amalgam particles from trituration surplus of those produced during the carving and burnishing of new amalgam restorations are generally collected in coarse filters and sold for refinement. Minor amalgam particles released by production of new fillings or by removal of old restorations partly sediment in tubes and drains. The remaining particles are carried with the waste water stream to the local purifying plant. In Scandinavia, the industrial discharge of mercury-contaminated waste water has been reduced to a minimum. According to recent investigations, dental clinics appear to be responsible for the major amount of mercury collected in the sludge generated in purifying plants. If threshold values for heavy metal content, including mercury, are exceeded, the sludge is not allowed to be recycled as fertilizer. Installation of an approved amalgam-separating apparatus in dental clinics is now mandatory in several countries--for example, Switzerland, Germany, Sweden, and Denmark. Approval of amalgam separators is based on national testing programs, including clinical or laboratory tests demanding 95-99% separating efficiency.