Dose level labeling

Now, finally, the significance of all this. Because, as a practical matter, it is difficult to conduct bioassays with more than 100-150 animals per dose level (usually split evenly between males and females), it can be seen from the above table that in the best of circumstances, with a zero or very low incidence outcome in control animals, it would be necessary for a tested compound to induce something like an 8-15% tumor incidence before we could fairly label it a carcinogen. This is a fairly large risk, yet our typical cancer bioassay has what might be called a limit of detection at about this level. Like chemical assays, bioassays are limited in their ability to detect effects - in this case, the carcinogenicity of a chemical substance. 

In an open-label dose-escalation phase I study, 26 patients with advanced or metastatic cancer received doses ranging between 180 and 1000 mg. Dose levels up to 800 mg were well tolerated with adverse events being hypertension, fatigue, and dizziness. The agent produced partial responses in two patients, while three patients were presented with stable disease of over 6 months. 

Secretions from bile duct cannulated rats given a dose of 100 mg/kg hexachlorobutadiene were infused directly into the bile duct of nonexposed rats (Payan et al. 1991). The levels of label in the urine, bile, and feces of both the donor and recipient rats were measured 30 hours after dosing. The label in the urine and bile of the recipient rats represented label that was reabsorbed from the gastrointestinal tract. It was determined that 80% of the biliary metabolites were reabsorbed and only 20% remained in the feces and gastrointestinal tract. 

An example and model for enlightened labelling policy is the US labelling for cholestyramine (Anon., 1995a). This is based on the results of the Lipid Research Clinics Coronary Primary Prevention Trial (LRC CPPT) (1984), and includes estimates of drug efficacy at four different dosing levels ... 

By the use of radioactively labelled precursor chemicals, the cell s ability to synthesize macromolecules such as DNA, RNA, and proteins, after treatment with the drug, can be measured. A typical result is shown in Fig. 5, for exposure of the cells to the equivalent level of drug found in tumor tissue of a treated animal. The synthesis of new total DNA is selectively and persistently inhibited. Total RNA and protein syntheses are not markedly affected until much higher drug-dose levels, which are frankly toxic to... 

Nonetheless, it has been shown to elute immediately after the PC peak. LysoPC, if present, would elute between the PAF and sphingomyelin (Sph) peak. The latter component often shows a double peak, and this can be attributed to the separation of distinct fatty acyl species. It is well to emphasize again that compounds such as PAF and lysoPC have very low levels of unsaturated bonds present, and hence a detector other than an ultraviolet monitor would have to be used. An alternate approach would be to use tritiated PAF or tritiated lysoPC as examples and assay the eluates by liquid scintillation counting. Since the labeled compounds are at tracer dose levels, one could still assay for biological activity associated with the compounds. 

Clinical studies of the safety and efficacy of Hb-PHP (Apex) as a septicemia therapy are continuing. In a Phase I/II open label, ascending-dose study, patients with volume-refractory, vasopressor-dependent shock secondary to sepsis or presumed sepsis received a bolus infusion of Hb-PHP (25, 50, or lOOmgHb/kg body weight) over 30 min and were observed for cardiovascular changes and adverse effects. Hb infusion was well tolerated and permitted a decrease in vasopressor utilization while maintaining an increasing MAP. No adverse effects on pulmonary, cardiac, renal, or hepatic fimctions have been noted at this dose level Hb-PHP infusion increased SVR and decreased HR. These results supported further study of Hb-PHP in this indication. 

NSCLC patient with a 40% reduction in undefined measurable disease. A weekly schedule has also been evaluated and an MTD of 245 mg/m2 defined (167). Thirty patients were treated for a median of 6 weeks, and grade 3 DLTs included vomiting, diarrhea, dehydration, and transient elevations in creatinine and transaminases. As with the previous schedule, 80% FT inhibition in PBMCs was noted at the higher dose levels (168). In addition, FT inhibition by a mean of 80% was observed in 14 posttreatment tumor samples at 2 h and persisted at 30% inhibition at 24 h. In some tumor samples, assessment of apoptosis by a DNA break labeling assay revealed induction of apoptosis after dmg exposure, for example, a refractory breast cancer patient with a 5-month minor response. Two other schedules (169, 170), weekly for 4 weeks followed by a 2-week rest and oral twice a day for 14 days every 21 days, have been evaluated with no objective responses reported. 

At a higher oral dose level, the amount of the et-carbon label led dose excreted in the urine of raLs fell and faecal excretion increased. Only 38% of a single oral dose of 500 mg kg was excreted in the urine (with 62% in faeces over a 7-day period. This may not necessarily signify a reduction in the amount of PBO absorbed, since biliary excretion of PBO metabolites has been shown to be the major route of elimination following intravenous administration (Fishbein el /., 1969). 

The excretion of nonionic iopamidol was studied in healthy subjects at several dose levels by use of two different solution concentrations of 200 and 300 mg I/mL, which were administered intravenously at a rate of 20 and 39 mL/min, respectively (760). Urinary elimination of iopamidol was rapid at all dose levels, with more than half of the dose excreted by the kidneys in the first 2 h after injection. Total urinary recovery within 72-96 h after injection was more than 90%, and the fecal recovery for the same period was about 1% of the administered dose. C-Labeled iopamidol was also included in this study for quantitation and the search for metabolic products of iopamidol, of which none was found. In dogs the urinary and fecal excretion of iopamidol at 72 h were 94.8 1.2 and 0.63 0.32%, respectively, of the injected dose at the dose level of 50 mg I/kg body weight. At a higher dose level of 200 mg I/kg, these excretions were 93.4 1.5 and 3.17 1.39%, respectively (195). The... 

Microemulsions of a series of polyiodinated triglycerides (ITG), labeled with iodine-125 and processed in a microfluidizer,were investigated for their contrast enhancement of the liver and the tumor in normal and tumor-bearing (Walker 256) rats, in rabbits bearing VX2 carcinoma, and in normal dogs in CT (911). The mean particle diameter of microemulsions was less than 300 nm. These preparations were stable and autoclavable. Thirty minutes after intravenous injection, from 66 to 78% of the injected dose remained in the liver of the rats. After 3 h the liver still retained from 46% to 93% of the dose. At dose levels ranging from 20 to 70 mg I/kg, the increase in density was reported to be about 40 HU in the rats. In a female pig, the contrast enhancement within 1 h of injection was 90 HU. The liver uptake of ITGs was partially dependent on the formulation vehicle, but the metabolism and clearance from the liver were... 

FIGURE 7.26 Shown are the observed probabilities for each category, given dose, plotted versus the corresponding predicted probabilities based on the wrong model. The solid diagonal line is the line of identity. The data points for each dose level are connected and each data point is labeled with the category number. 

Fig. 5. Effect of injected dose on peak TC of injected substance (all molecular sizes). Curves represent total and labeled molecules bound to tumor given a fixed number of labeled molecules (6 x 1010 mol) at all dose levels. Arrow shows the typical dose used in antibody scanning.

In an NAT experiment, similar to those for NNN and NNK, NAT was not carcinogenic at any of the three dose levels. lARC (1870) concluded that the TSNAs are the most abundant suspected carcinogens in tobacco smoke. It considered NNN and NNK to be proven carcinogens for laboratory animals. It considered the evidence limited for defining the carcinogenicity of NAB in laboratory animals and inadequate to label NAT as a carcinogen for laboratory animals. 

Prenner J L, Thompson J T, Miller D G, et al. (2005). An Open Label Study for the Evaluation of Tolerability of Five Dose Levels of Intravitreous VEGF siRNA (Cand5) in Patients With Wet Age-Related Macular Degeneration. American Academy of Ophthalmology Annual Meeting, poster 463. 

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