Pyramiding dose study

FIGURE 5.14. Example of pyramiding dose study for acute toxicity testing in a nonrodent species. 

If one uses a novel chemistry, a pyramiding dose escalation type of study in primates may provide useful information for dose selection. However, the class similarities in the toxicity profile, short of using a novel chemistry, suggest that such study would be of limited value for most PS ODN therapeutics. 

Pyramid or — rolling acute and/or two or four week study Thirteen — weeks in two species Tolerance, PK -> and efficacy with human dosing up to one month in length DELAY — ... 

Toxicity is remarkably low for a compound of such activity. In mice, the LDso value is about three times that of chlorpromazine [166] while none of the effects of the latter drug on the myocardium, liver, skin or eye have appeared in the studies of oxypertine. It is, however, still too early to appraise its chronic toxicity in man. As indicated earlier, dangerous interactions are likely to follow concurrent use of a MAO inhibitor, though simultaneous use of anti-Parkinsonism drugs, for example, to control the relatively minor extra-pyramidal symptoms seems to present no unusual problems. Hypotension may occasionally occur with high doses. 

As a comparison, haloperidol (Haldol) is generally considered to be among the most potent neuroleptics and the most likely to cause extra-pyramidal reactions. In a double-blind study of first-episode patients diagnosed with schizophrenia, the subjects were randomly assigned to take 1, 2, 3, or 5 mg/day (Kapur et al., 2000). If the patients did not respond to the lower doses, they were raised to the limit of 5 mg/day. These are relatively small doses. The recommended initial dose for moderate symptoms or geriatric or debilitated patients is 1-6 mg/day (Drug Facts and Comparisons, 2007). For severe or chronic patients, it is 6-15 mg/day, with higher doses for prompt control. 

Ascending the pyramid, step 3 is the place for first-in-human pilot studies, in which an exploratory dose, a specific biomarker for a physiological response, or tracer studies will be examined. For most true superfruits in advanced research, this is the current level of progress. 

In early 2009, a phase II clinical trial sponsored by a company aptly named CherryPharm was launched to determine the effects of drinking cherry juice on pain perception in subjects with severe knee osteoarthritis. This human research was based on laboratory studies charting inflammation-induced pain behavior in rats. Results showed that tart cherry extracts reduce inflammation-induced pain and edema similarly to a dose of the pain-relief drug indomethacin. Although these studies indicate that tart cherry anthocyanins may have a beneficial role in the treatment of inflammatory pain, most of this research is based on test-tube or rat studies, meaning that progress remains within the lower half of the research pyramid. 

In contrast to the aforementioned cannabinoid neuroprotection, some studies have reported a neurotoxic effect of THC. Thus, morphological changes in the hippocampus, decreases in the mean volume, synaptic density and dendritic length of CA3 pyramidal neurons, and reduced neuronal density in rat hippocampus associated with chronic THC oral administration have been described (Scallet et al. 1987). However, others could not find any significanthistopathological alteration in the brains of rats and mice treated orally with very high doses of THC for 2 years (Chan et al. 1996). Likewise, direct intracranial administration of THC or WIN 55,212-2 to rats for 1 week did not induce neural cell apoptosis (Galve-Roperh et al. 2000). 

In a study of the effects of hyperthyroidism on the developing granule cell-pyramidal cell pathway (Lauder and Mugnaini, 1977, 1980) we found that thyroxine could stimulate the growth of the mossy fibers, in a dose-dependent manner, causing them to sprout collaterals which grew down into the infrapyramidal region and synapsed with the basal dendrites of pyramidal cells. Normally, the mossy fibers innervate only the apical pyramidal cell dendrites where they synapse on... 

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