Amifostine

Repeated peroral administration of melatonin and ascorbic acid in a dose of 200 mg/kg 30 min before treatment with gammafos reduced its cumulative toxic effect. Succinic acid in a dose of 100 mg/kg was ineffective under these conditions. The cumulative death time for 50% animals receiving gammafos alone or in combination with melatonin, ascorbic acid, and succinic acid was 3.08, 4.29, 4.06, and 2.97 days, respectively.

Amifostine may temporarily produce hypotension; antihypertensive or other potentially hypotension-producing medications should be discontinued 24 hours prior to amifostine administration; patients receiving antihypertensive therapy that cannot be discontinued should not receive amifostine.

/SIGNS AND SYMPTOMS/ The maximum single dose of amifostine was 1300 mg/sq m . No information is available on single doses higher than this in adults. In the setting of a clinical trial, pediatric patients have received single amifostine doses of up to 2700 mg/sq m. At the higher doses, anxiety and reversible urinary retention occurred. ... Administration of amifostine at 2 and 4 hours after the initial dose has not led to increased nausea and vomiting or hypotension. The most likely symptom of overdosage is hypotension...

/CASE REPORTS/ ... A 56-year-old Caucasian man who received concomitant chemotherapy and radiation for head and neck cancer developed fever concurrent with the administration of amifostine. ...This is the first case report that demonstrates the occurrence of fever with low-dose amifostine therapy without the manifestation of accompanying rash or hypotension. Patients receiving amifostine who develop only fever should be evaluated for an adverse drug reaction, as well as for sepsis and fevers of neutropenia, and it may be necessary to discontinue the drug. ...

/CASE REPORTS/ The most common side effects associated with amifostine are nausea, vomiting, hypotension, hypocalcemia and allergic reactions. /The authors/ describe the case of a man with dermatomyositis and stage IV nasopharyngeal cancer treated with chemoradiotherapy and sc amifostine. The patient suffered a life-threatening anaphylactoid reaction to amifostine.

/CASE REPORTS/ Amifostine is a phosphorylated aminothiol prodrug that can selectively protect normal tissues against the toxic effects of chemotherapy and radiotherapy. In clinical use amifostine is well tolerated and may rarely cause allergic reactions. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two closely related entities that present with severe acute mucocutaneous reactions most often triggered by drugs. There are only two case reports related to the use of amifostine during radiotherapy, one case with SJS and the other with SJS-TEN overlap. In this paper, a case with amifostine-induced TEN during radiotherapy is presented.

/OTHER TOXICITY INFORMATION/ Although hypocalcemia occurs only rarely during cytoprotective therapy with amifostine, serum calcium concentrations should be monitored in patients at risk of hypocalcemia, such as those with nephrotic syndrome or those receiving multiple doses of amifostine, and calcium supplementation initiated as necessary.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Amifostine

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Acute Exposure/ ... A total of 32 rats were treated by ip administration of 0.9% saline solution (group 1), 5 mg/kg cisplatin (group 2), 25 mg/kg amifostine (group 3), and 25 mg/kg amifostine followed by 5 mg/kg cisplatin (group 4) after 30 min. /Investigators/ recorded elevation of N-acetyl-beta-D-glucosaminidase (NAG) in 24 hr pooled urine as a specific marker for tubular lesions, renal leakage of magnesium as an unspecific nephrotoxicity marker, and survival over a 10-day observation period. A significant (P < 0.002) increase in urinary NAG after treatment was documented only in cisplatin-treated group 2 [day 2 (mean+/-SE), 93+/-2.1 units/gram creatinine; day 4, 70.6+/-16 units/gram creatinine; normalization at day 8]. Treatment with amifostine before cisplatin administration resulted in a slight urinary NAG leakage (day 2, 2.8+/-1.8 units/gram creatinine; day 4, 13.8+/-13 units/gram creatinine; normalization at day 6). No increase in urinary enzyme levels was seen in the other groups, and there were no significant differences in urinary magnesium between all groups. Four of eight rats in the cisplatin-treated group and one of eight rats in the amifostine plus cisplatin-treated group died.

/LABORATORY ANIMALS: Acute Exposure/ Daily treatment of outbred albino mice with gammafos in radioprotective doses of 300 and 500 mg/kg for 4 days produced a cumulative toxic effect. This effect was not observed after decreasing the dose of gammafos to 100 mg/kg. Repeated peroral administration of melatonin and ascorbic acid in a dose of 200 mg/kg 30 min before treatment with gammafos reduced its cumulative toxic effect. Succinic acid in a dose of 100 mg/kg was ineffective under these conditions. The cumulative death time for 50% animals receiving gammafos alone or in combination with melatonin, ascorbic acid, and succinic acid was 3.08, 4.29, 4.06, and 2.97 days, respectively.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Amifostine has been shown to be embryotoxic in rabbits at doses of 50 mg/kg, approximately sixty percent of the recommended dose in humans on a body surface area basis.

/GENOTOXICITY/ Amifostine demonstrated no mutagenic effects in the Ames test and in the mouse micronucleus test. However, the free thiol metabolite demonstrated mutagenic effects in the Ames test and in in vitro mouse studies. This metabolite demonstrated no mutagenic effects in the mouse micronucleus test and did not demonstrate clastogenicity in human lymphocytes. Data from in vitro and in vivo studies indicate that amifostine may protect against the mutagenic effects of chemotherapeutic agents.

While data specific to amifostine were not located(SRC, 2007), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soil(1).

Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

Rat(ip): LD50: 418 mg/kg

Rat(im): LD50: 396 mg/kg

Mouse(po): LD50: 842 mg/kg

Mouse(ip): LD50: 321 mg/kg

Mouse(iv): LD50: 557 mg/kg

Mouse (im): LD50: 514 mg/kg