In contrast, in a drug development setting TI is calculated based on plasma exposure levels.
TDM is recommended for use in the treatment of psychiatric disorders with lithium due to its narrow therapeutic range.
It is desirous for the value of LD50 to be as large as possible, to decrease risk of lethal effects and increase the therapeutic window.
) is still useful as it can be considered an upper bound of the protective index, and the former also has the advantages of objectivity and easier comprehension.
However, to convert a calculated TI into something useful, the nature and limitations of pharmacological and/or toxicological endpoints must be considered.
For example, at the same dose there may be marked inter-individual variability in exposure due to polymorphisms in metabolism, DDIs or differences in body weight or environmental factors.
Some antibiotics and antifungals require monitoring to balance efficacy with minimizing adverse effects, including: gentamicin, vancomycin, amphotericin B (nicknamed 'amphoterrible' for this very reason), and polymyxin B. Radiotherapy aims to shrink tumors and kill cancer cells using high energy.
The therapeutic ratio in radiotherapy for cancer treatment is determined by the maximum radiation dose for killing cancer cells and the minimum radiation dose causing acute or late morbidity in cells of normal tissues.
Both direct and indirect radiation induce DNA mutation or chromosomal rearrangement during its repair process.
Indirect radiation occurs from radiolysis of water, creating a free hydroxyl radical, hydronium and electron.
p53, a tumor suppressor protein that plays a role in G1 and G2/M arrest, enabled the understanding of the cell cycle through radiation.
For example, irradiation of myeloid leukemia cells leads to an increase in p53 and a decrease in the level of DNA synthesis.
Irradiation at G2 phase showed increased radiosensitivity and thus G1 arrest has been a focus for therapeutic treatment.
However, the high energy radiation can override the ability of damaged normal cells to repair, leading to additional risk of carcinogenesis.
Employing IG-IMRT, protons and heavy ions are likely to minimize the dose to normal tissues by altered fractionation.
Direct inhibitors target proteins (PARP family) and kinases (ATM, DNA-PKCs) that are involved in DNA repair.
For example, in radiation therapy for cancerous tumors, shaping the radiation beam precisely to the profile of a tumor in the "beam's eye view" can increase the delivered dose without increasing toxic effects, though such shaping might not change the therapeutic index.
Similarly, chemotherapy or radiotherapy with infused or injected agents can be made more efficacious by attaching the agent to an oncophilic substance, as in peptide receptor radionuclide therapy for neuroendocrine tumors and in chemoembolization or radioactive microspheres therapy for liver tumors and metastases.
Sometimes the term safety ratio is used, particularly when referring to psychoactive drugs used for non-therapeutic purposes, e.g. recreational use.
For example, the risk associated with benzodiazepines increases significantly when taken with alcohol, opiates, or stimulants when compared with being taken alone.
[medical citation needed] Therapeutic index also does not take into account the ease or difficulty of reaching a toxic or lethal dose.
[18] Medication with a small therapeutic window must be administered with care and control, frequently measuring blood concentration of the drug, to avoid harm.
Medications with narrow therapeutic windows include theophylline, digoxin, lithium, and warfarin.
[19][20] The purpose of administering MTD is to determine whether long-term exposure to a chemical might lead to unacceptable adverse health effects in a population, when the level of exposure is not sufficient to cause premature mortality due to short-term toxic effects.
All modern healthcare systems dictate a maximum safe dose for each drug, and generally have numerous safeguards (e.g. insurance quantity limits and government-enforced maximum quantity/time-frame limits) to prevent the prescription and dispensing of quantities exceeding the highest dosage which has been demonstrated to be safe for members of the general patient population.
Such examples include emotional "blunting" with antidepressants, pruritus with opiates, and blurred vision with anticholinergics.