Therapeutic range design

A patient with heart failure developed a serious abnormal heart rhythm, ventricular tachycardia, and it was decided to treat this with lig-nocaine (also known as lidocaine) by the intravenous route. He was given a loading dose designed to raise the plasma concentration to an effective 2 mg/1, and then given a constant-rate intravenous infusion aimed at maintaining that concentration. In about an hour he was observed to be tremulous and then had a brief generalized convulsion (a fit). The plasma lig-nocaine concentration was found to be 8 mg/1 (desired therapeutic range 1 - no more than 5 mg/1). 

Withdrawal of antiseizure drugs, whether by accident or by design, can cause increased seizure frequency and severity. The two factors to consider are the effects of the withdrawal itself and the need for continued drug suppression of seizures in the individual patient. In many patients, both factors must be considered. It is important to note, however, that the abrupt discontinuance of antiseizure drugs ordinarily does not cause seizures in nonepileptic patients, provided that the drug levels are not above the usual therapeutic range when the drug is stopped. 

Besides animal studies, in vitro studies give information about the doses and concentrations that show antitumor activity and concentration-response relationships can be established. Knowing the therapeutic range of concentration from the concentration-response relationship, and being able to predict the behavior of the drug in humans from the allometric equations, an optimal design may be implemented for the FTIH study. 

Based on the observation that chloramphenicol (CAP)-imprinted polymer possessed a modest affinity for chloramphenicol-methyl red (CAP-MR), Levi et al. [65] designed an intriguing MIP sensor to monitor the change of CAP in patients blood (Fig. 6). The presence of CAP in blood leads to a competitive displacement of CAP-MR from the imprinted cavities. The displaced composite is subsequently monitored at 460 nm. After optimizing the flow rate and concentration of CAP-MR in acetonitrile mobile phase, the response of this system to CAP, thiamphenicol (TAM), and chloramphenicol diacetate (CAP-DA) was determined (Fig. 7). As observed for CAP, there was a linear correlation over the range 1-1000 pg/mL. However, for CAP-DA almost no appreciable response was achieved, even if it was injected to 1000 pg/mL. As also observed, the value for CAP was about 40% higher than that for TAM at the same concentration. This revealed that CAP could compete more efficiently with the bound CAP-MR than TAM did. Further information showed that this method was adequate for detection below and above the recommended therapeutic range (10-20 pg/mL serum, potentially toxic above 25 pg/mL). 

Various methods have been designed for clinical use to predict doses that remain within the therapeutic range. These are as follows ... 

Figure 11.6 Plasma drug concentration (Cp) versus time profile following the intravenous bolus administration of many equal doses at an identical dosing interval (t). In this representation, the dosing regimen has been designed so that the plasma drug concentrations will fall within the therapeutic range at steady state.

ImmunO lSS iy. Chemiluminescence compounds (eg, acridinium esters and sulfonamides, isoluminol), luciferases (eg, firefly, marine bacterial, Benilla and Varela luciferase), photoproteins (eg, aequorin, Benilld), and components of bioluminescence reactions have been tested as replacements for radioactive labels in both competitive and sandwich-type immunoassays. Acridinium ester labels are used extensively in routine clinical immunoassay analysis designed to detect a wide range of hormones, cancer markers, specific antibodies, specific proteins, and therapeutic dmgs. An acridinium ester label produces a flash of light when it reacts with an alkaline solution of hydrogen peroxide. The detection limit for the label is 0.5 amol. 

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