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Chlormethine

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Chlormethine
Skeletal formula of chlormethine
Space-filling model of the chlormethine molecule
Names
IUPAC name
Bis(2-chloroethyl)methylamine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.110 Edit this at Wikidata
EC Number
  • 200-120-5
KEGG
MeSH Mechlorethamine
RTECS number
  • IA1750000
UNII
UN number 2810
  • InChI=1S/C5H11Cl2N/c1-8(4-2-6)5-3-7/h2-5H2,1H3 checkY
    Key: HAWPXGHAZFHHAD-UHFFFAOYSA-N checkY
  • CN(CCCl)CCCl
Properties
C5H11Cl2N
Molar mass 156.05 g·mol−1
Appearance Colorless liquid
Odor Fishy, ammoniacal
log P 0.91
Pharmacology
D08AX04 (WHO) L01AA05 (WHO)
  • Intracavitary
  • Intrapericardial
  • Intravenous
  • Topical
Pharmacokinetics:
<1 minute
50% (renal)
Legal status
  • In general: ℞ (Prescription only)
Related compounds
Related amines
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Chlormethine (INN, BAN), mechlorethamine (widely used in the US, not the USAN, however) also known as mustine and HN2 and in former USSR known as Embichin is a nitrogen mustard sold under the brand name Mustargen. It is the prototype of alkylating agents, a group of anticancer chemotherapeutic drugs. It works by binding to DNA, crosslinking two strands and preventing cell duplication. It binds to the N7 nitrogen on the DNA base guanine. As the chemical is a blister agent, its use is strongly restricted within the Chemical Weapons Convention where it is classified as a Schedule 1 substance.

Mechlorethamine belongs to the group of nitrogen mustard alkylating agents.[1][2][3]

Uses

It has been derivatized into the estrogen analogue estramustine, used to treat prostate cancer. It can also be used in chemical warfare where it has the code-name HN2. This chemical is a form of nitrogen mustard gas and a powerful vesicant. Historically, some uses of mechlorethamine have included lymphoid malignancies such as Hodgkin’s disease, lymphosarcoma, chronic myelocytic leukemia, polycythemia vera, and bronchogenic carcinoma [4] Mechlorethamine is often administered intravenously,[5] but when compounded into a topical formulation it can also be used to treat skin diseases. There have been studies demonstrating that topical administration of mechlorethamine has efficacy in mycosis fungoides-type cutaneous T cell lymphoma.[6][7][8]

Another important use of chlormethine is in the synthesis of meperidine.

Side effects and toxicity

Mechlorethamine is a highly toxic medication, especially for women who are pregnant, breastfeeding, or of childbearing age.[9][10] At high enough levels, exposure can be fatal.[3]

The adverse effects of mechlorethamine depend on the formulation.[11] When used in chemical warfare, it can cause immunosuppression and damage to mucous membranes of the eyes, skin, and respiratory tract. Mucous membranes and damp or damaged skin are more affected by exposure to HN-2. Though symptoms of exposure are generally delayed, the DNA damage it causes occurs very quickly. More serious exposures cause symptoms to develop sooner. Eye symptoms develop first, in the first 1–2 hours (severe exposure) or 3–12 hours (mild to moderate exposure) followed by airway (2-6/12–24 hours) and skin symptoms (6–48 hours). Hot, humid weather shortens the latent (symptom-free) period.[3]

Symptoms of toxic exposure to HN-2 vary based on the route of exposure. Eye exposure causes lacrimation (tear production), burning, irritation, itching, a feeling of grittiness or dryness, blepharospasm (spasms of the eyelid), and miosis (pinpoint pupils). More severe cases cause edema (swelling from fluid accumulation) in the eyelids, photophobia (extreme sensitivity to light), severe pain, corneal ulceration, and blindness.[3]

Inhalation of chlormethine damages the upper and lower airways sequentially, with more severe exposures causing faster damage that afflicts lower parts of the respiratory tract. Early symptoms include rhinorrhea (runny nose), epistaxis (nosebleed), toneless voice, sneezing, barking cough, and dyspnea (in smokers and asthmatics). Later symptoms include pain in the nose/sinuses and inflammation of the airway. In severe cases, there may be epithelial necrosis throughout the respiratory tract, causing pseudomembrane formation, which can obstruct the airway. Pneumonia may develop and prove fatal.[3]

Skin exposure mainly causes erythema (redness) and vesication (blistering) at first, but absorption through the skin causes systemic toxicity. In cases where more than 25% of the skin is affected, fatal exposure is likely to have occurred.[3]

Though ingestion is uncommon, if mechlorethamine is swallowed it causes severe chemical burns to the gastrointestinal tract and concomitant nausea, vomiting, diarrhea, abdominal pain, and hemorrhage.[3]

Long-term effects of acute or chronic chlormethine exposure are caused by damage to the immune system. White blood cell counts drop, increasing the risk of infection, and red blood cell and platelet counts may also drop due to bone marrow damage. Chronic eye infections may result from exposure, but blindness is temporary. Long-term effects on the respiratory system include anosmia (inability to smell), ageusia (inability to taste), inflammation, chronic infections, fibrosis, and cancer. Skin that has been damaged by HN2 can change pigmentation or become scarred, and may eventually develop cancer.[3]

History

Successful clinical use of chlormethine (mechlorethamine) resulted in development of the field of anticancer chemotherapy, led by Cornelius P. Rhoads at Memorial Sloan-Kettering. The drug is a nitrogen-based analogue of mustard gas (which is sulfur-based) and was derived from chemical warfare research. Secret clinical trials of the agent for Hodgkin's disease and several other lymphomas and leukemias in humans began in December 1942. Because of wartime secrecy restrictions, it was not until 1946 that the results of these trials were published openly.[12]

Chemistry

Chlormethine is combustible and under extreme conditions becomes explosive. It can react with metals to form gaseous hydrogen.[3]

See also

References

  1. ^ Rappeneau S, Baeza-Squiban A, Jeulin C, Marano F (March 2000). "Protection from cytotoxic effects induced by the nitrogen mustard mechlorethamine on human bronchial epithelial cells in vitro". Toxicol. Sci. 54 (1): 212–21. doi:10.1093/toxsci/54.1.212. PMID 10746948.
  2. ^ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
  3. ^ a b c d e f g h i "CDC - The Emergency Response Safety and Health Database: Blister Agent: NITROGEN MUSTARD HN-2 - NIOSH". www.cdc.gov. Retrieved 2016-04-20.
  4. ^ Bunn Jr, P. A.; Hoffman, S. J.; Norris, D; Golitz, L. E.; Aeling, J. L. (1994). "Systemic therapy of cutaneous T-cell lymphomas (mycosis fungoides and the Sézary syndrome)". Annals of Internal Medicine. 121 (8): 592–602. doi:10.7326/0003-4819-121-8-199410150-00007. PMID 8085692.
  5. ^ Medline (2012). Mechlorethamine. Retrieved from http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682223.html
  6. ^ Lindahl LM, Fenger-Gron M, Iversen L. Topical nitrogen mustard therapy in patients with mycosis fungoides or parapsoriasis. J Eur Acad Dermatol Venereol. 2013 Feb;27(2):163-8.
  7. ^ Galper SL, Smith BD, Wilson LD. Diagnosis and management of mycosis fungoides. Oncology (Williston Park). 2010 May;24(6):491-501.
  8. ^ Lessin SR, Duvic M, Guitart J, Pandya AG, Strober BE, Olsen EA, Hull CM, Knobler EH, Rook AH, Kim EJ, Naylor MF, Adelson DM, Kimball AB, Wood GS, Sundram U, Wu H, Kim YH. Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides. JAMA Dermatol. 2013 Jan;149(1):25-32.
  9. ^ Recordati Rare Diseases Inc. (2013). Mustargen Package Insert. Retrieved from http://www.drugs.com/pro/mustargen.html
  10. ^ Actelion Pharmaceuticals Ltd. (2013) Valchlor Package Insert. Retrieved from http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202317lbl.pdf
  11. ^ Mustargen and Valchlor
  12. ^ Gilman A. (1963). "The initial clinical trial of nitrogen mustard". Am J Surg. 105 (5): 574–578. doi:10.1016/0002-9610(63)90232-0. PMID 13947966.
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