Amifostine (ethiofos) is a cytoprotective adjuvant used in cancer

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

and radiotherapy involving DNA-binding chemotherapeutic agents. It is marketed by Clinigen Group under the trade name Ethyol.

Indications

Amifostine is used therapeutically to reduce the incidence of neutropenia-related fever and infection induced by DNA-binding chemotherapeutic agents including

alkylating agent Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effectin ...

s (e.g. cyclophosphamide) and platinum-containing agents (e.g.

cisplatin Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, ...

). It is also used to decrease the cumulative

nephrotoxicity Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxin ...

associated with platinum-containing agents. Amifostine is also indicated to reduce the incidence of

xerostomia Xerostomia, also known as dry mouth, is dryness in the mouth, which may be associated with a change in the composition of saliva, or reduced salivary flow, or have no identifiable cause. This symptom is very common and is often seen as a side eff ...

in patients undergoing radiotherapy for head and neck cancer. Amifostine was originally indicated to reduce the cumulative renal toxicity from cisplatin in non-small cell

lung cancer Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissue (biology), tissues of the lung. Lung carcinomas derive from tran ...

. However, while nephroprotection was observed, the probability that amifostine could protect tumors could not be excluded. Additional data have shown that amifostine-mediated tumor protection, in any clinical scenario, is unlikely.

Pharmacokinetics

Amifostine is an organic thiophosphate prodrug which is hydrolysed ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'' by alkaline phosphatase to the active cytoprotective

thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...

metabolite, WR-1065. The selective protection of non-malignant tissues is believed to be due to higher alkaline phosphatase activity, higher pH, and vascular permeation of normal tissues. Amifostine can be administered intravenously or subcutaneously after reconstitution with

normal saline Saline (also known as saline solution) is a mixture of sodium chloride (salt) and water. It has a number of uses in medicine including cleaning wounds, removal and storage of contact lenses, and help with dry eyes. By injection into a vein i ...

. Infusions lasting less than 15 minutes decrease the risk of adverse effects. The patient should be well-hydrated prior to administration.

Mechanism of action

Inside cells, amifostine detoxifies reactive metabolites of platinum and alkylating agents, as well as scavenges free radicals. Other possible effects include accelerated

DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...

, induction of cellular hypoxia, inhibition of apoptosis, alteration of gene expression and modification of enzyme activity. Amifostine is believed to radioprotect normal tissue via

Warburg Warburg (; Westphalian: ''Warberich'' or ''Warborg'') is a town in eastern North Rhine-Westphalia, central Germany on the river Diemel near the three-state point shared by Hessen, Lower Saxony and North Rhine-Westphalia. It is in Höxter distri ...

-type effects.

Adverse effects

Common

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s of amifostine include

hypocalcemia Hypocalcemia is a medical condition characterized by low calcium levels in the blood serum. The normal range of blood calcium is typically between 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L) while levels less than 2.1 mm ...

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

, sneezing, somnolence, and

hiccups A hiccup (scientific name ''singultus'', from a Latin word meaning "to catch one's breath while sobbing"; also spelled hiccough) is an involuntary contraction ( myoclonic jerk) of the diaphragm that may repeat several times per minute. The hi ...

. Serious side effects include: hypotension (found in 62% of patients),

erythema multiforme Erythema multiforme (EM) is a skin condition that appears with red patches evolving into target lesions, typically on both hands. It is a type of erythema possibly mediated by deposition of immune complexes (mostly IgM-bound complexes) in th ...

Stevens–Johnson syndrome Stevens–Johnson syndrome (SJS) is a type of severe skin reaction. Together with toxic epidermal necrolysis (TEN) and Stevens–Johnson/toxic epidermal necrolysis (SJS/TEN), it forms a spectrum of disease, with SJS being less severe. Erythema ...

and

toxic epidermal necrolysis Toxic epidermal necrolysis (TEN) is a type of severe skin reaction. Together with Stevens–Johnson syndrome (SJS) it forms a spectrum of disease, with TEN being more severe. Early symptoms include fever and flu-like symptoms. A few days later ...

, immune

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune s ...

syndrome,

erythroderma Erythroderma is an inflammatory skin disease with redness and scaling that affects nearly the entire cutaneous surface.Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. p. 436. . This term applie ...

anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the foll ...

, and loss of consciousness (rare).

Contraindications

Contraindications to receiving amifostine include

to amifostine and aminothiol compounds like WR-1065. Ethyol contains

mannitol Mannitol is a type of sugar alcohol used as a sweetener and medication. It is used as a low calorie sweetener as it is poorly absorbed by the intestines. As a medication, it is used to decrease pressure in the eyes, as in glaucoma, and to lo ...

References

{{Detoxifying agents for antineoplastic treatment Chemotherapeutic adjuvants Prodrugs Amines