Drug administration therapeutic window

With regard to the systemic administration of smaller proteins (<20 kDa), the development of insulin for inhalation has shown that the pulmonary route is a feasible route of administration. However, advanced inhalation devices and formulations were required to obtain a reproducible lung deposition. It will be especially necessary to deal with the problems that occur when drugs with a small therapeutic window are administered. To enable widespread use of the lung as port of entry for these small proteins, future developments should be directed towards more simple inhalation devices which still give a high and reproducible lung deposition. The formulations that will be required for these proteins are likely to be much more complex and advanced than those that are currently used. Examples are formu-... 

Rnally, pharmacokinetic and pharmacokinetic/pharmacodynamic modelling can be used for the purpose of prediction of the concentration-time profile of the drug and drug-carrier conjugate after repeated administration from single dose data, as well as for the prediction of the dose needed to maintain the concentration at the target site within a therapeutic window. 

Pharmacokinetic principles, in addition to clinical factors such as the state of the patient, are utilized in determining dosage regimens. Factors that relate to the safety and efficacy of the drug, such as activity-toxicity relationships (therapeutic window and side effects), and pharmaceutical factors, such as dosage form and route of administration, must be considered.16... 

The rate of elimination is an important characteristic of a drug. Too rapid an elimination necessitates frequent repeated administration of the drug if its concentration is to reach its therapeutic window. Conversely, too slow an elimination could result in the accumulation of the drug in the patient, which might give an increased risk of toxic effects. Most drug eliminations follow first order kinetics (equations (8.1) and (8.2)), no matter how the drug is administered, but there are some notable exceptions, such as ethanol which exhibits zero order kinetics where ... 

Scopolamine was the first drug to be marketed as a transdermal delivery system (Transderm-Scop) to alleviate the discomfort of motion sickness. After oral administration, scopolamine has a short duration of action because of a high first-pass effect. In addition, several side-effects are associated with the peak plasma levels obtained. Transderm-Scop is a reservoir system that incorporates two types of release mechanims a rapid, short-term release of drag from the adhesive layer, superimposed on an essentially zero-order input profile metered by the microporous membrane separating the reservoir from the skin surface. The scopolamine patch is able to maintain plasma levels in the therapeutic window for extended periods of time, delivering 0.5 mg over 3 days with few of the side-effects associated with (for example) oral administration. 

Administration For myocardial infarction, intracoronary delivery of the drugs is the most reliable in terms of achieving recanalization. However, cardiac catheterization may not be possible in the 2 to 6 hour therapeutic window, beyond which significant myocardial salvage becomes less likely. Thus thrombolytic agents are usually administered intravenously, since this route is rapid, inexpensive, and does not have the risks of catheterization. 

Concentration time courses can be simulated by the model and the demographic parameters for different dose regiments. The final administration of the drug has to be adjusted so that e.g. 95% of the target population falls into the therapeutic window. If sub-populations differ too much, adjusted administration regiments have to be considered. 

Currently, the only treatment of patients with acute ischemic stroke is thrombolysis and restoration of blood flow [3,6,7]. Only a fraction of stroke patients benefits from this therapy [3,6,7], Therapeutic recanalization of an occluded cerebral artery is a risky option that can be applied only in the case of selected patients. The main limitation of cerebral thrombolysis is the narrow, 3-hour therapeutic window during which the thrombolytic agent has to be administered to be effective. Beyond this time limit, its effectiveness is neutralized by the high risk of cerebral hemorrhage [7], In acute stroke, only a small fraction of patients benefit from intravenous administration of recombinant tissue plasminogen activator, which is the only drug with proven effectiveness in reducing the size of infarct in humans [6],... 

The transdermal route provides an alternative route to oral administration. Drugs delivered by this route avoid digestion in the gastrointestinal tract (GI), local metabolism related to the GI route, and hepatic first pass metabolism. It can provide controlled drug delivery with the possibility of zero order (continuous) release. Thus, it is most suitable for short half-life therapeutic agents and drugs with narrow therapeutic windows. The use of transdermal patches is more... 

Theophylline is a classic example. Its bronchodi-lator effects are related to plasma concentrations in the range of 5-20 mg l-1, while higher concentrations are associated with tachyarrythmias and other serious adverse effects. This is a drug with a narrow therapeutic window . Elderly patients commonly have several risk factors that can lead to unexpectedly high serum concentrations after administration of standard doses reductions in renal clearance, reduced volume of distribution and an increased probability of concomitant disease and other therapies (Ohnishi et al., 2003). Monitoring plasma levels is thus helpful in avoiding the adverse effects of theophylline. 

Figure 1 Schematic presentation of the therapeutic window of a drug and potential drag concentration-time profiles upon administration of oral immediate- and controlled-release dosage forms thin and bold curve) (c denotes the drag concentration at the site of action in the living body, t the time after administration).

In most clinical situations, drugs are administered in a series of repetitive doses or as a continuous infusion to maintain a steady-state concentration of drug associated with the therapeutic window. Calculation of the appropriate maintenance dosage is a primary goal. To maintain the chosen steady-state or target concentration, the rate of drug administration is adjusted such that... 

Since TTX was found to effectively block sodium channel, it has been conducted for the possible therapeutic applications. One possible application is a neuroprotective drug in the treatment of ischemic damage of the brain that follows stroke. Whereas the onset of stroke is accompanied by a rapid local damage in the brain, infarction spreads from the point of damage slowly. Thus, there is a therapeutic window during which damages to the peri-infarct area can be prevented or minimized by administration of a neuroprotective drug (Koroshetz and Moskowitz, 1996). 

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