Some drugs currently available or in pre-licensure clinical trials appear to protect tissue against radiation-induced injury. Amifostine, a free radical scavenger, is the only drug currently licensed as a radioprotectant. Its use is limited to cancer radiation therapy and chemotherapy, because in its approved formulation, it is unsuitable for first responders due to incapacitating side effects. Its use in the general population is also untenable because of its side effects, the need for intravenous administration, and the need to administer it one hour prior to radiation exposure. Limited data suggest that lower doses might be useful in reducing the long-term effects of radiation exposure, such as mutagenesis and carcinogenesis. Other potential radioprotectants include Tempol, a drug that is currently in clinical trials as a topical radiation protector to prevent hair loss during cancer radiotherapy; a steroid that enhances survival shortly after radiation exposure in a mouse model; and antioxidants, such as vitamin E analogs, isoflavones, and benzylsulfone analogs.
Cytokines and growth factors, particularly those of the hematopoietic system, can also protect against radiation-induced injury, in part by increasing tissue cellularity and thus ensuring a larger number of surviving cells. Granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF) are used to partially reconstitute the immune system in cancer patients after destruction of the bone marrow during cancer treatment, and may be effective both as radioprotectants and radiation-injury mitigators.
Some drugs are known to prevent uptake of specific radioactive isotopes. Potassium iodide (KI), for example, can block radioactive iodine uptake by the thyroid. Radioactive iodine is present in waste from nuclear reactors and in fallout from nuclear weapons, and is used for diagnostic and therapeutic purposes. To be effective, KI must be taken several hours before or shortly after exposure to radioactive iodine; it is only 7 percent as effective when given 24 hours after exposure. KI does not protect against radioactive isotopes other than iodine, and does not remove radioactive iodine once it has entered the thyroid. KI tablets are currently in the Strategic National Stockpile (SNS), and efforts are underway to produce a liquid/oral formulation suitable for young children. Aluminum hydroxide limits the uptake of strontium-90, a radioactive isotope that is also found in radioactive waste and fallout, but it must be given immediately after the radioactive material is internalized in order to be effective.
Still other compounds accelerate excretion of specific radioactive materials. Prussian blue, a pigment recently licensed for use as a radioprotectant under the brand name Radiogardase, enhances the excretion of cesium and thallium; radioactive cesium is found in spent nuclear fuel and waste and in nuclear fallout, and it is widely used for medical purposes.
Chelating agents, such as calcium diethylenetriaminepentaacetate (Ca-DTPA) and zinc diethylenetriaminepentaacetate (Zn-DTPA), promote the excretion of the radioactive transuranic elements such as plutonium, americium, californium, and curium produced by nuclear explosives and nuclear reactors. Ca- and Zn-DTPA are currently in the SNS, but must be administered intravenously and usually require multiple doses, limiting their utility in a mass-casualty setting. In addition, Ca-DTPA is not considered safe for children or pregnant women; the data on Zn-DTPA are insufficient to determine safety in these populations.
Other drugs have shown some ability to help heal radiation-induced injuries. Certain cytokines and growth factors, for example, may facilitate faster recovery of cell populations damaged by radiation; GM-CSF and G-CSF are used to partially reconstitute the hematopoietic and immune systems in cancer patients and others after myeloablation or intensive chemotherapy. G-CSF is included in the SNS, but only for emergency use under an Investigational New Drug (IND) application and with the informed consent requirements as generally applied to investigational agents.
Keratinocyte growth factor facilitates recovery in epithelial tissues and shows promise for use in radiation injury. Radiation-induced damage of the gastrointestinal tract results in breakdown of the epithelial barrier, thus causing diarrhea, inability to properly absorb nutrients, hemorrhage, bacterial translocation, and increased susceptibility to infection. Although post-exposure infection and sepsis are major causes of mortality, little information is available regarding the antibiotics most likely to be useful in managing such infections; proper antibiotic selection may be critical in maintaining the appropriate intestinal flora when there is denudation of the mucosa. Compounds that have a trophic effect on the gut epithelium (e.g., growth factors and intestinal peptide hormones), enhance the mucosal immune system (e.g., beta glucan), or minimize epithelial barrier breakdown or the consequences thereof (e.g., octreotide) may also be effective in pre-exposure prophylaxis or post-exposure mitigation. A combination of pentoxifylline and tocopherol has shown early promise in treating radiation fibrosis, as have angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers.
Ideally, products will be easily administered, safe for repeated doses, have a long shelf life, and be inexpensive to manufacture. With the exception of products intended for patients undergoing radiation therapy, efficacy testing of these products cannot be ethically carried out in humans. Therefore, such products will be licensed as radiation countermeasures only after meeting stringent requirements under the FDA animal rule.
The National Institutes of Health will provide support services to facilitate and accelerate product development research conducted by academia, industry, and federal laboratories. One goal of this support is to enable academic and industry scientists to more quickly bring their products to the acquisition stage under Project Bioshield. Examples of such services include the support of
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Last Updated March 19, 2007