Amifostine is a cytoprotective adjuvant used in cancer chemotherapy

Chemotherapy

Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

 and radiotherapy involving DNA

DNA

Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

-binding chemotherapeutic agents. It is marketed by MedImmune

MedImmune

MedImmune, LLC, headquartered in Gaithersburg, Maryland, became a wholly owned subsidiary of AstraZeneca in 2007. Since being acquired, MedImmune has remained a Maryland-based biotechnology development enterprise...

 under the trade name Ethyol.

Indications

Amifostine is used therapeutically to reduce the incidence of neutropenia

Neutropenia

Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...

-related fever and infection induced by DNA-binding chemotherapeutic agents including alkylating agent

Alkylating antineoplastic agent

An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group to DNA.The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring....

s (e.g. cyclophosphamide

Cyclophosphamide

Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....

) and platinum-containing agents (e.g. cisplatin

Cisplatin

Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...

). It is also used to decrease the cumulative nephrotoxicity associated with platinum-containing agents. Amifostine is also indicated to reduce the incidence of xerostomia

Xerostomia

Xerostomia is the medical term for the subjective complaint of dry mouth due to a lack of saliva. Xerostomia is sometimes colloquially called pasties, cottonmouth, drooth, or doughmouth. Several diseases, treatments, and medications can cause xerostomia. It can also be exacerbated by smoking or...

 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

Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...

. However, while nephroprotection was observed, the fact that amifostine could protect tumors could not be excluded. Given better treatment options for non-small cell lung cancer, this indication for non-small cell lung cancer was withdrawn in 2005.

Pharmacokinetics

Amifostine is an organic thiophosphate prodrug

Prodrug

A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...

 which is hydrolysed in vivo

In vivo

In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

by alkaline phosphatase

Alkaline phosphatase

Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...

 to the active cytoprotective thiol

Thiol

In organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...

 metabolite, WR-1065. The selective protection of non-malignant tissues is believed to be due to higher alkaline phosphatase activity, higher pH

PH

In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...

, and vascular permeation of normal tissues.

Amifostine can only be administered intravenously, after reconstitution with normal saline

Saline (medicine)

In medicine, saline is a general term referring to a sterile solution of sodium chloride in water but is only sterile when it is to be placed intravenously, otherwise, a saline solution is a salt water solution...

. 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

DNA repair refers to 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 UV light and radiation can cause DNA damage, resulting in as many as 1...

, induction of cellular hypoxia, inhibition of apoptosis, alteration of gene expression and modification of enzyme activity.

Adverse effects

Common side effect

Adverse drug reaction

An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

s of amifostine include hypocalcemia, diarrhea

Diarrhea

Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

, nausea

Nausea

Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

, vomiting

Vomiting

Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...

, sneezing, somnolence, and hiccoughs.
Serious side effects include: hypotension (found in 62% of patients), erythema multiforme

Erythema multiforme

Erythema multiforme is a skin condition of unknown cause, possibly mediated by deposition of immune complex in the superficial microvasculature of the skin and oral mucous membrane that usually follows an infection or drug exposure...

, Stevens–Johnson syndrome and toxic epidermal necrolysis

Toxic epidermal necrolysis

Toxic epidermal necrolysis is a rare, life-threatening dermatological condition that is usually induced by a reaction to medications...

, immune hypersensitivity

Hypersensitivity

Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...

 syndrome, erythroderma

Erythroderma

Erythroderma is an inflammatory skin disease with erythema and scaling that affects nearly the entire cutaneous surface....

, anaphylaxis

Anaphylaxis

Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...

, and loss of consciousness (rare).

Contraindications

Contraindications to receiving amifostine include hypersensitivity

Hypersensitivity

Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...

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

Mannitol

Mannitol is a white, crystalline organic compound with the formula . This polyol is used as an osmotic diuretic agent and a weak renal vasodilator...

.