Toxic Side Effects Are Determined Empirically

Toxic side effects are often difficult to predict solely from chemical structures, although some chemical groups, such as chlorines and fluorines, are often associated with toxicity. Instead, potential side effects are commonly determined experimentally by trial and error. Initial studies are performed with cultured human cells, and then animals are treated and examined. Finally, human volunteers are tested. Human trials usually involve hundreds to a few thousand persons; consequently, rare safety issues are not seen. The uncertainty of toxic side effects is an important factor in keeping doses low: A few patient deaths, even after a million successful treatments, can be enough to cause a compound to be withdrawn from the market. Consequently, consideration of both efficacy and safety leads to dose recommendations that are compromises—high enough to cure a large fraction of the patient population and low enough to do little immediate harm to most patients. As we point out in Chapter 5, “Emergence of Resistance,” this compromise dosing philosophy contributes to the emergence of antibiotic resistance.

An example with HIV and tuberculosis illustrates how some toxic effects come as a surprise. Antiretroviral drugs work well even after HIV has become firmly established; from the HIV perspective, treating immediately after infection with antiHIV antibiotics is unnecessary.93 Not only are the drugs expensive, but they also have side effects. However, when the patient is also infected with M. tuberculosis, a delay in HIV treatment can be catastrophic because HIV frees the bacterium from immune control. If treatment for HIV is Delayed, tuberculosis can progress rapidly. But as the antiretroviral drugs enable the immune system to rebuild, the presence of M. tuberculosis can lead to a severe inflammatory response called immune reconstitution inflammatory syndrome, which usually occurs in the first month of antiviral treatment. Thus, patients with both tuberculosis and HIV disease must be carefully monitored.

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