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Steps of drug development (cont'd...)

Median Effective dose (ED50)

This is the dose of a drug required to produce therapeutic action on 50\% of the population, drug applied on. This is also called the minimum effective dose. These two doses are determined to calculate the safety margin (therapeutic index) of the molecule.

Therapeutic index (TI)

This is the ratio of LD50 and ED50. Therefore, TI= LD50/ ED50, from this equation, we can say that if the ratio is greater, the safety margin of the drug is greater that is if LD50>>> ED50, the drug is safe. To go to the next step of the screening the ration LD50/ ED50 must be >10.

Eg. Benzodiazepines are safer class of sedatives compared barbiturates, as the as the LD50/ ED50 is high for the previous class [Rang MP et. al., 2007].

However, The TI can not be the only parameter, taken into account to determine the safety profile of a new molecule.

Limitations of acute toxicity study to determine risk benifit ration of drug include:

a. LD50 can not determine the toxicity (unwanted adverse drug reactions) of a drug in therapeutic dose. The dry mouth is the unwanted action of anti-cholinergic drugs, which can not be evaluated by this study [Rang MP et. al., 2007]

b. ED50 is dependant on the clinical uses of a drug. The method can not determine the different doses of the drug, based on it's clinical uses. eg. dose of aspirin for the treatment of migraine is much more higher than it's dose as anti-platelet agent [Rang MP et. al., 2007]

c. The non predictable adverse drug reactions (idiosyncrasy, intolerance etc.) can not be determined evaluating TI. eg. Anaphylactic shock due to use of penicillin is the serious adverse drug reaction to very few patients that can not be measured by TI [Rang MP et. al., 2007]

d. The toxicity of a molecule, influenced by a disease condition or by the drugs, used together with, can not be determined by this method. eg. NSAIDs are contraindicated for the asthmatic patients, but it can not be measured through TI measuring.

Therefore, the conclusion is that TI measurement is a good method to determine usefulness of a new molecule and to determine the lethal dose, but all the toxicity profile cannot be evaluateded measuring only TI [Rang MP et. al., 2007].

The LD50 data, obtained in the preclinical screening is fused with the number needed to treat (NNT) value, determined on clinical trial, to calculate the risk/benefit ratio of the molecule.

Reference

[Rang MP et. al., 2007] Rang HP, Dale MM, Ritter J M, Moore P K, Pharmacology, 5th Edition, Elsevier, 2-752, 2007.

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