Dose-dependent trends

Fig. 8. BB-10010 dose-dependent trend of better neutrophil recovery in patients receiving FAC chemotherapy. Mean neutrophil counts during cycle 6 of FAC chemotherapy, presented as a percentage of each patient s pretreatment neutrophil coimt.

Two studies found maprotiline to be clearly superior to placebo and two other studies found trends in the same direction ( p < 0.001, combined data) (Table 7-5) (105, 106, 107 and 108). More than 1,600 patients were randomly assigned to either maprotiline or a standard HCA 660 on maprotiline did well, and 247 showed minimal improvement, no change, or worsened. For the HCAs (usually imipramine or amitriptyline), 640 patients did well, and 255 showed minimal improvement, no change, or worsened. In summary, 73% did well with maprotiline, and 72% did well with a standard antidepressant. Combining these data with the Mantel-Haenszel test indicated no difference in efficacy (Table 7-6). Maprotiline has a dose-dependent risk of seizures. As with TCAs and amoxapine, overdoses of maprotiline can be lethal. %... 

Based on the pooled data from the three Phase 3 studies, there was a trend toward dose-dependent increases in the frequency of drug-related adverse events, particularly dyspepsia, myalgia, and back pain, although the overall absolute incidence was between 0.5% and 10%. This was dependent on the event and drug dose. 

To evaluate further the dose and time dependence of the blood NTE assay, we studied NTE inhibition in brain and blood short time (4 hr) after dosing hens with PrDChVP (0.32 - 1.0 mg/kg, im), as well as 24, 48, 72 and 96 hr after the maximal injected dose, 1.0 mg/kg [98], Brain and blood NTE were inhibited in a dose-responsive manner 4 hr after dosing (linear trend, P < 0.0001), and NTE inhibition was highly correlated between brain and blood (r = 0.997). 

None of the widely quoted statistics embrace all those individuals dependent on drugs and medicaments, but always only those who attract attention because of crime, their lifestyle, or their social environment. In the case of benzodiazepines, appetite-suppressants and combinations of analgesics with caffeine, the low-dose dependence of the patient is often associated with social conditions, so that the problem is often seen in the context of the particular decade in which the abuse occurs. The same is true of the experimental drug-taker who discontinues his or her consumption after a short time and is not noticed. For this reason, exact national statistics on consumption behavior are difficult to obtain. Moreover, it is possible to detect trends, e.g. the appearance of new dependence phenomena, patterns of abuse, drug combinations or methods of application, and the analyst must arrange his work accordingly. 

Erosions and dryness of mucous membranes were observed in 8 of 24 patients with severe psoriasis given etretinate at doses of 50-100 mg/day (Fredrikison and Petterssen, 1978). A trend toward a dose-related severity of side effects was observed for all the reported effects, but the differences were not statistically significant. Ruest and Rufli (1979) also observed dose-dependent adverse reactions at doses of 0.5-1 mg/kg/day. Beside these commonly observed side ef-... 

Polymeropoulos, E. E. (1993) QSAR analysis of time- and dose-dependent in vivo drag effects using artificial neural networks. Trends QSAR Mol. Modell. 92, Proc. Eur. Symp. Structure-Activity Relationships QSAR and Molecular Modeling 9th, pp. 546-549., Strasbourg, France. 

From the trend of concentration-dose dependence, conclusions can be drawn regarding the relative rates of radical generation and disappearance due to recombination. If the two rates are comparable, a linear dependence would be expected (cf. PA6 and LLDPE data), whereas in the case of recombination being faster than generation, a downward deviation from linearity would occur (cf. HOPE and LDPE data). For all examined blends, however, an upward deviation from linearity was observed, which meant that the process of radical formation (chain scission) was predominant. Based on quantitative determinations for aged samples, it has been concluded that radicals decay more rapidly in blends than in pure polymers, and this can be attributed to a higher chain mobility and facilitated... 

Interestingly, exceptions are possible. Stewart et al. [81] reported that the effect of magnesium stearate concentration on the dissolution of a model low-dose drug, riboflavin, from capsules was dependent in some manner on the type of filler. Soluble fillers exhibited the anticipated prolonged times with increasing lubricant levels. However, the trends with insoluble fillers were less predictable. In some cases insoluble fillers were only slightly affected by the concentration of magnesium stearate. For others, such as microcrystalline cellulose, there appeared to be an ideal intermediate concentration of lubricant at which the dissolution rate was maximized. 

Note that the testing for trend is seen as a more sensitive way of picking up a possible treatment effect than simple pairwise comparisons of treated and control groups. Attempting to estimate the magnitude of effects at low doses, typically below the lowest positive dose tested in the study, is a much more complex procedure, and is heavily dependent on the assumed functional form of the dose-response relationship. 

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