Pharmacologically active dose

Epinephrine has a narrow benefit-to-risk ratio. Along with its therapeutic effects, when administered in recommended doses by any route, it potentially causes transient anxiety, fear, restlessness, palpitations, pallor, tremor, and headache. Although usually perceived as adverse effects, such symptoms indicate that a pharmacologically active dose of the medication has been absorbed. The desirable pharmacologic effects of epinephrine cannot be separated from the undesirable pharmacologic effects [10]. 

Since toxicity usually arises from exaggerated pharmacological effects, sometimes combined with a narrow therapeutic range and/or a steep dose-response relationship from the NOAEL to toxicity, the pharmacologically active dose is often a more sensitive indicator of potential toxicity for biotechnology-derived pharmaceuticals (compared to the preclinical NOAEL adjusted by a safety... 

Male Sprague-Dawley rats weighing 180-240 g are fed a commercial laboratory with low concentrations of thyroid hormones, containing constant amount of unlabelled iodine. The animals are treated for at least seven days with the test compound to be evaluated, at a pharmacologically active dose determined by a previous biological studies. On the morning of the test day, rats are injected with a test dose of 131-1 (intravenously or intraperitoneally), and the concentration of radioactivity in the thyroid glands is measured after 1 1 hours. The blood concentration of 131-1 at these time points is measured, and the tissue to blood ratios are calculated for individual animals. 

Evaluate in vivo dose-response range, including dose-response comparison of lead candidates calculation of pharmacologically active doses, e.g., ED50 or ED)0 and therapeutic ratio when combined with no effect or minimum toxic effect dose level. 

The most widely used technique for the evaluation of hERG channel interaction is the voltage clamp. A detailed description of the experimental setup has been described elsewhere [119]. The hERG interaction is measured and reported as the % inhibition of the hERG current compared to the vehicle control at various concentrations of the NCE. The concentration that inhibits 50% (IC50) is calculated, whenever possible. The concentrations of NCE used in the assay are carefully selected based on the expected maximum plasma concentration (Cmax) at the pharmacologically active dose (usually based on studies in animal models) and the human plasma protein binding for the NCE. 

EFFECTS ON THE BODY. A pharmacologically active dose of caffeine is about 200 mg, depending upon the individual. In the body, caffeine demonstrates the following actions ... 

Nicardipine is almost completely absorbed after po adrninistration. Administration of food decreases absorption. It undergoes extensive first-pass metaboHsm in the Hver. Systemic availabiHty is dose-dependent because of saturation of hepatic metaboHc pathways. A 30 mg dose is - 35% bioavailable. Nicardipine is highly protein bound (>95%). Peak plasma concentrations are achieved in 0.5—2.0 h. The principal path of elimination is by hepatic metaboHsm by hydrolysis and oxidation. The metaboHtes are relatively inactive and exert no pharmacological activity. The elimination half-life is 8.6 h. About 60% of the dose is excreted in the urine as metaboHtes (<1% as intact dmg) and 35% as metaboHtes in the feces (1,2,98,99). 

Absorption after po dosing is fairly complete. It undergoes extensive first-pass metaboHsm in the Hver and is 60% bioavailable. It is extensively bound (99%) to a -acid glycoproteins. Bepridil is almost completely metaboli2ed in the Hver. Seventeen metaboHtes have been identified but only the 4-hydroxy-A/-phenyl-bepridil has some pharmacological activity. The elimination half-life is 33—42 h (107). 

According to Georgadze the three sophora alkaloids sophocarpine (a), sophocarpidine (h) and sophoridine (c) only differ in degree and not in character of their pharmacological activity thus on intravenous injection each causes a rise and then a fall i i blood pressure and their activity in this direction is in decreasing order (a), (c), (b). In small doses they stimulate, and in larger doses depress, the isolated heart of either cold- or warm-blooded animals and then their decreasing order of activity is (c), (b), (a). 

The pharmacological activities of the isomers should be compared in vitro and in vivo in both animals and humans. Separate toxicological evaluation of the enantiomers would not usually be required when the profile of the racemate was relatively benign but unexpected effects - especially if unusual or near-effective doses in animals or near planned human exposure - would warrant further studies with the individual isomers. 

In this review, we will describe the pharmacologic activity of epinephrine in anaphylaxis, the evidence base for its use, epinephrine dosing and routes of administration, epinephrine autoinjector use in first-aid treatment, reasons for failure to inject epinephrine promptly, reasons for occasional apparent lack of response, and future directions in epinephrine research. 

Vitamin K content of enteral nutrition formulas may affect pharmacological activity. Monitor and titrate dose to maintain therapeutic international normalized ratio (INR)... 

Subsequent clinical studies provided additional evidence that GTN exerts antiplatelet activity in vivo and offered insight into the nature of GTN s anti-aggregatory pharmacology. A dose-effect relationship between intravenous GTN and inhibition of platelet aggregation was uncovered in healthy male subjects, in whom plasma... 

Some biotechnologically derived pharmaceuticals will cross-react with species that can be evaluated toxicologically, while others cross-react only with nonhuman primates such as the chimpanzee, a protected species. In this case, a well-designed safety, or Phase 0 study at doses higher than the proposed clinical dose may provide valuable safety information. However, a lack of cross-reactivity with any nonhuman species does not necessarily make preclinical safety evaluation impossible, not does it limit toxicity testing to species in which the protein lacks relevant pharmacological activity. Some alternative possibilities are summarized in Table 12.9. 

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