Oral tolerance, definition

Of 206 postmenopausal women who took the oral combination of estradiol valerate plus norethisterone (5) eight withdrew because of bleeding during year 1 during years 2 and 3 there were no withdrawals because of bleeding. By the end of year 3, 133 patients had completed the study. There were serious adverse effects in 24, but there was no definite relation to therapy. The numbers of adverse events reported each year by the patients who completed the study are shown in Table 1. The authors concluded that this combination was effective in the majority of patients and was well tolerated. 

The safety and efficacy of oral cyclodextrin itraconazole (5 mg/kg/day) as antifungal prophylaxis has been assessed in an open trial in 103 neutropenic children (median age 5 years range 0-15 years) (53). Prophylaxis was started at least 7 days before the onset of neutropenia and continued until neutrophil recovery. Of the 103 patients, only 47 completed the course of prophylaxis 27 withdrew because of poor compliance, 19 because of adverse events, and 10 for other reasons. Serious adverse events (other than death) occurred in 21 patients, including convulsions (n = 7), suspected drug interactions (n = 6), abdominal pain (n — 4), and constipation n — 4). The most common adverse events considered definitely or possibly related to itraconazole were vomiting (n = 12), abnormal liver function (n — 5), and abdominal pain (n = 3). Tolerabihty of the study medication at end-point was rated as good (55%), moderate (11%), poor (17%), or unacceptable (17%). There were no unexpected problems of safety or tolerability. 

Three published controlled trials of the use of vitamin C in treating nitrate tolerance in 77 subjects overall have been reviewed (76). Vitamin C (3-6 g/day orally or by intravenous infusion) reduced nitrate tolerance for up to 3 days, without causing adverse reactions. However, before making definitive recommendations, studies of longer duration should be done in a larger number of patients. 

For example, NCEP-ATP uses waist circumference to define obesity, while other expert committees use the body mass index (BMI). The ATP guidelines base glucose intolerance on a fasting glucose while others prefer the results of an oral glucose tolerance test (OGTT). As we are better able to quantify the relationship between these factors and the development of cardiovascular disease, the definition of the syndromes and the individual component values will no doubt continue to be refined. 

By definition, sustained release formulations differ pharmaceutically and pharmacokinetically from the innovator drug. Delayed or sustained release oral formulations are used for chronic therapy, and may have two principal advantages (a) reduction in dose frequency (and thus, hopefully, improved compliance see Chapter 21) and (b) reduction of Cmax for a standard AUC, which can improve tolerability when adverse events are plasma concentration-related. The demonstration of bioequivalence usually hinges on the following factors (a) equivalence of AUC to an innovator drug at steady state (b) the absence of any chance of dose dumping (c) consistency of performance from dose to dose [see 21CFR320.25(f)]. 

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