Initial pharmacological evaluation

Phase I Initial Pharmacological Evaluation. Determines the safe dosage level for humans. The medication is given to volunteers at gradual doses. The first sign of toxicity is noted. Dosage levels below the toxic dose level are considered safe. 

Phase I, which is the Initial Pharmacological Evaluation, determines the safe dosage level by administering gradual doses to volunteers and noting the first sign of toxicity. 

Toxicology studies are conducted to define the safety profile of a candidate and include definition of the no-toxic-effect dose, MTD, potential organs of toxicity, and potential biochemical markers to detect and track toxic events. Most developmental compounds that do not become therapeutic products have unacceptable toxicity in animals or humans. Before the definitive toxicology studies needed to support an IND submission are initiated, a number of animal experiments can be conducted to characterize the potential toxicity of the candidate. These early toxicology evaluations are usually conducted in the same species as used in pharmacology evaluations. As mentioned earlier, the lowest dose that has no toxicity or an acceptable level of toxicity is compared with the dose that gives the desired pharmacologic response in the same animal species to obtain a therapeutic ratio or index for that species. 

Pharmacologic Evaluation. The denervated iris sphincter in Adie s pupil shows cholinergic hypersensitivity. This response is expected according to the principle of denervation hypersensitivity. The hypersensitivity does not seem to correlate with either the amount of sphincter denervation, the duration of the Adie s pupil, or the amount of light-near dissociation. Occasionally, an acute Adie s pupil shows very little hypersensitivity during the first few weeks after onset but gradually becomes increasingly hypersensitive several months after the initial episode. 

Initially, we evaluated the pharmacological activities of insulin and its acyl derivatives by measuring plasma glucose levels after their intravenous injection [58]. As shown in Fig. 5.7, mono- or dicaproyl insulin (Cap-1, Cap-2) and monolauroyl insulin (Lau-1) still possessed relatively high pharmacological activities, although the potencies of the new derivatives was reduced as their molecular weight increased. 

As synthesis intermediates are chemically connected to final products, and as they often present some common groupings with them, it is not inconceivable that they share some pharmacological properties. For this reason, it is always prudent also to submit these compounds to a pharmacological evaluation. Among drugs discovered in this way are the tuberculostatic semicarbazones they were initially used in the synthesis of antibacterial sulfathiazoles. Subsequent testing of isonicotinic acid hydrazide, destined for the synthesis of a particular thiosemicarbazone, revealed the powerful tuberculostatic activity of the precursor which has since become a major antitubercular drug (isoniazide). 

Despite stmctural similarities, the pharmacological consequences of excesses of these substances are quite different. Due to the interest in the effects of nicotinic acid on atherosclerosis, and in particular its use based on its abiUty to lower semm cholesterol, the toxicity of large doses of nicotinic acid has been evaluated. Eor example, in a study designed to assess its abiUty to lower semm cholesterol, only 28% of the patients remained in the study after receiving a large initial dose of 4 g of nicotinic acid due to intolerance at these large doses (70). 

Pharmacologic neuroprotection, which might be expected to prevent tissue necrosis or apoptosis until tissue reperfusion can be achieved with rt-PA, is a theoretically attractive adjunct to rt-PA treatment. Despite positive studies in animals, all evaluations of neuroprotective agents in humans have failed. Most recently, the promising initial results for intravenous NXY-059, a ffee-radical-trapping agent, were not replicated in a confirmatory phase III trial (unpublished data). 

The underlying cause of anemia (e.g., blood loss iron, folic acid, or vitamin B12 deficiency or chronic disease) must be determined and used to guide therapy. As discussed previously, patients should be evaluated initially based on laboratory parameters to determine the etiology of the anemia (see Fig. 63-3). Subsequently, the appropriate pharmacologic treatment should be initiated based on the cause of anemia. 

Hanson, L.A., Bass, A.S., Gintant, G., Mittelstadt, S., Rampe, D. and Thomas, K. (2006) ILSI-HESI cardiovascular safety subcommittee initiative evaluation of three non-clinical models of QT prolongation. Journal of Pharmacological and Toxicological Methods, 54, 116—129. 

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