멜팔란 C화학적 특성, 용도, 생산
개요
Melphalan is a nitrogen mustard derivative of the large neutral
amino acid L-phenylalanine. It was first synthesized in 1953 by
Bergel and Stock and is the active L-isomer of the compound.
The D-isomer, known as medphalan, is less active against
certain animal tumors, and the dose needed to produce effects
on chromosomes is larger than that required with the L-isomer.
The racemic (DL-) form is known as merphalan or sarcolysin.
화학적 성질
Melphalan forms solvated crystals from methanol.
용도
Melphalan USP (Alkeran) is used to treat multiple myeloma; plasmacytic myeloma; cancer of breast and ovary.
Indications
Melphalan (Alkeran) is an amino acid derivative of
mechlorethamine that possesses the same general spectrum
of antitumor activity as do the other nitrogen mustards.
However, the bioavailability of the oral preparation
is quite variable (25–90%) from one patient to
another.
The major indications for melphalan are in the palliative
therapy of multiple myeloma and cancers of the
breast or ovary. Because it does not produce alopecia,
melphalan is occasionally substituted for cyclophosphamide
in the CMF regimen for breast cancer.
Melphalan produces less nausea and vomiting than
does cyclophosphamide; however, its bone marrow suppression
tends to be more prolonged and affects both
white cells and platelets. Peak suppression of blood
counts occurs 14 to 21 days after a 5-day course of drug
therapy; recovery is generally complete within 3 to 5
weeks.
정의
ChEBI: A phenylalanine derivative comprising L-phenylalanine having [bis(2-chloroethyl)amino group at the 4-position on the phenyl ring.
일반 설명
Melphalan is available in 2-mg tablets and 50-mg vials fororal and IV administration, respectively in the treatment ofmultiple myeloma, breast and ovarian cancer, and in highdosetherapy when bone marrow transplant is being utilized.The mechanisms of resistance are the same as those seen formechlorethamine. The agent is poorly absorbed when givenby the oral route. Melphalan is highly plasma protein bound(80%–90%) and inactivated in the blood by water to givethe hydroxy metabolites. Elimination occurs primarily in thefeces with an elimination half-life of 38 to 108 minutes. Thecommonly seen adverse effects are myelosuppression, nausea,and vomiting. Nausea is normally mild with normal doses butbecomes severe when high doses are used during bone marrowtransplant. Less commonly seen adverse effects are hypersensitivityreactions, skin rash, and alopecia. Secondarycancers are also of concern with the use of the agent.
공기와 물의 반응
Insoluble in water.
반응 프로필
Melphalan is a nitrogen mustard. May be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen may be generated in combination with strong reducing agents, such as hydrides.
위험도
Strong irritant to eyes and mucous membranes. Confirmed carcinogen.
화재위험
Flash point data are not available for Melphalan; however Melphalan is probably combustible.
Mechanism of action
Melphalan is orally active, but absorption can be erratic. Absorption is decreased with food, but dosing regimens do not demand an empty stomach. The drug can be formulated for IV administration, but the risk of serious side effects is higher. Melphalan distributes into body water, so toxicity can be pronounced in dehydrated patients or in those with renal dysfunction. Dehydration can be corrected, but dosage adjustments should be considered in patients with renal disease.
Clinical Use
This aromatic mustard, used primarily in the treatment of multiple myeloma, is able to stabilize the lone pair of electrons on the mustard nitrogen through resonance with the conjugated phenyl ring, slowing the formation of the reactive aziridinium ion.
부작용
Because the lone pair of electrons of melphalan (and other aromatic mustards) is less reactive, there is a greater opportunity for distribution to cancer cells and a decreased incidence of severe side effects. There is a lower incidence of nausea and vomiting compared to mechlorethamine, but patients still experience myelosuppression, which can be severe. This drug also is mutagenic and can induce leukemia.
Safety Profile
Confirmed human carcinogen producing leukemia and Hodgkin's disease. Poison by ingestion, intravenous, and intracerebral routes. Human systemic effects by ingestion: nausea, hypermothty, diarrhea, agranulocytosis, thrombocytopenia. Human reproductive effects by ingestion: menstrual changes. Mutation data reported. A skin irritant. Used as a poison gas. When heated to decomposition it emits toxic fumes of ClandNOx.
잠재적 노출
An alkylating agent. Healthcare workers may be exposed. As a drug it is an immunosuppressant,
used in the treatment of multiple myeloma and cancer of
the ovary. It is also used in investigation of other types
of cancer and as an antineoplastic in animals. Human
exposure to melphalan occurs principally during its use in
cancer treatment. Melphalan is administered orally or intravenously. Adult dosage is 6 mg/day, 5 days per month. Has
been used as a military poison gas (a nitrogen mustard,
alkaline, crystals).
Carcinogenicity
Melphalan is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.
운송 방법
UN2811 Toxic solids, organic, n.o.s., Hazard
Class: 6.1; Labels: 6.1-Poisonous materials, Technical
Name Required. UN3249 Medicine, solid, toxic, n.o.s.,
Hazard Class: 6.1; Labels: 6.1-Poisonous materials
Purification Methods
Purify melphalan by recrystallisation from MeOH, and its solubility is 5% in 95% EtOH containing one drop of 6N HCl. It is soluble in EtOH and propylene glycol but is almost insoluble in H2O. The RS-form has m 180-181o, and the R-form crystallises from MeOH with m 181.5-182o and [] D21 -7.5o (c 1.26, 1.0 N HCl). [Bergel & Stock J Chem Soc 2409 1954, Beilstein 14 IV 1689.]
폐기물 처리
Consult with environmental
regulatory agencies for guidance on acceptable disposal
practices. Generators of waste containing this contaminant
(≥100 kg/mo) must conform to EPA regulations governing
storage, transportation, treatment, and waste disposal. It is
inappropriate and possibly dangerous to the environment to
dispose of expired or waste drugs and pharmaceuticals by
flushing them down the toilet or discarding them to the
trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds,
double-bagged in plastic, discard in trash. Larger quantities
shall carefully take into consideration applicable DEA,
EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being
careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be
labeled, securely packaged, and transported by a state
licensed medical waste contractor to dispose by burial
in a licensed hazardous or toxic waste landfill or
incinerat
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