Amifostine, also known as Amifostinum or Amifostinum trihydricum, with trade name Ethyol, is a prescription drug with cell-protective effects established since 1995 and used in chemotherapy, radiotherapy, and prevention of dry mouth. For example, amifostine is used in advanced tumors of the ovaries or head and neck region by limiting potential tissue damage caused by cancer therapy. This protection does not extend to the cancerous tissue itself, since it lacks the prerequisites for introducing the radioprotector into the cell. Amifostine is characterized by high therapeutic breadth and good tolerability.
What is amifostine?
Amifostine is a prescription drug with cell-protective effects that has been established since 1995 and is used in chemotherapy, radiotherapy, and for the prevention of dry mouth. As early as 1948, U.S. radiologist Harvey Milton Patt discovered that the amino acid cysteine has radioprotective effects. During the Cold War, the Walter Reed Army Institute developed the – so far only – radioprotectant (WR2721) as protection against radioactive radiation in the event of nuclear war. However, because the substance is not available orally, but only by infusion, it is not used in the U.S. Army. The white, crystalline powder is water soluble. Before its intravenous use, sodium chloride solution (physiological saline) is added to the amifostine or ethyol powder, but no other drugs are added to avoid drug interactions. The infusion solution has a shelf life of six hours at up to 25°C or 24 hours between two and eight degrees Celsius, and 36 months in powder form at room temperature.
Pharmacologic effect
Chemically, amifostine (molecular formula C5H15N2O3PS) is a parent substance (prodrug) that is not converted to the active ingredient, enthanthiol, until it reaches tissues. Amifostine has a cell-protective effect, i.e. it protects against the blood-image-damaging, otherwise life-threatening toxicity (toxicity) of chemotherapy and repairs DNA attacked by cytostatics (cancer drugs). The drug protects healthy tissue, but not tumor cells, from the side effects of chemotherapy and radiation (selective cytoprotection) by scavenging free radicals, aggressive oxygen compounds. Due to the better blood supply in healthy tissue, amifostine can concentrate there fifty to one hundred times higher than in tumor tissue and reaches this tissue concentration after ten to 30 minutes. Only a maximum of four percent of the amount injected is excreted in the urine. However, amifostine is unable to protect the central nervous system because it cannot cross the blood–brain barrier.
Medical application and use
Tissue-protective amifostine is used as part of chemotherapy or radiotherapy for advanced tumors of the ovaries, lung cancer, head and neck tumors, and also for prostate cancer. Patients with ovarian cancer (ovarian carcinoma) undergoing combination therapy with cisplatin/cyclophosphamide receive a single dose of 910 mg/m KO Ethyol solution at the beginning of the chemotherapy cycle under the supervision of a physician experienced in chemotherapy or radiotherapy. Amifostine or Ethyol solution is administered as a 15-minute short-term intravenous infusion, with the actual chemotherapy again starting 15 minutes afterwards. In the aforementioned patients with ovarian cancer, the active ingredient reduces the risk of infection caused by the combination therapy, triggered by the decrease in white blood cells. In addition, amifostine also reduces renal toxicity in other tumors treated via combination therapy (with cisplatin) – care must be taken to ensure adequate fluid intake. In addition, amifostine protects patients with head and neck tumors from the toxic effects of radiation treatment.
Risks and side effects
The active ingredient amifostine or the agent ethyol should not be given in cases of hypersensitivity to aminothiol compounds, low blood pressure, fluid deficiency, renal or hepatic insufficiency, and also to children and patients over 70 years of age. Pregnancy and lactation are also excluded, as ethyol is always administered in conjunction with fertility and mutagenic drugs. The most common side effects include nausea, vomiting, increased liver enzyme levels, drop in blood pressure, decrease in blood calcium concentration, feeling of heat and drowsiness.Skin reactions occur frequently (105 in 10,000) in patients receiving radiation therapy and rarely (7 in 10,000) in patients receiving chemotherapy. Allergic reactions may present as rash, chills, chest pain, and shortness of breath, sometimes weeks after infusion. To minimize side effects, ensure adequate hydration before infusion and monitor blood pressure during and following treatment. The patient should lie on his or her back during the infusion. If the blood pressure drops, his pelvis should be elevated (Trendelenburg positioning) and physiological saline solution given. If specific chemotherapy (such as with cisplatin) induces emesis, the physician will combine ethyol administration with antiemetic agents and closely monitor fluid balance. The treating physician is required to give the infusion only for the maximum period of 15 minutes, because the rate of side effects increases with the duration of infusion.
