Triethylenethiophosphoramide

Описание

Thiotepa, a tertiary aziridine, is less reactive than quaternary aziridinium compounds and is classified as a weak alkylator. It is possible for the nitrogen atoms to be protonate before reacting with DNA (a positively charged aziridine is more reactive than the un-ionized aziridine), but the electron-withdrawing effect of the sulfur atom decreases the pKa to approximately six, which keeps the percentage ionized at pH 7.4 relatively low. Thiotepa undergoes oxidative desulfuration, forming an active cytotoxic metabolite known as TEPA (triethylenephosphoramide).

Химические свойства

white crystals or powder

Использование

Tri(1-aziridinyl)phosphine sulfide is useful for the treatment of cancers, especially cancers resistant to chemotherapy. Antineoplastic. Thio-TEPA (N,N?N?-triethylenethiophosphoramide) is used as a cancer chemotherapeutic, alkylating agent. It is used to treat various kinds of cancer such as breast, ovarian and bladder cancer. It is also used as conditioning treatment prior to hematopoietic progenitor cell transplantation (HPCT)

Показания

Although thiotepa is chemically less reactive than the nitrogen mustards, it is thought to act by similar mechanisms. Its oral absorption is erratic. After intravenous injection, the plasma half-life is less than 2 hours. Urinary excretion accounts for 60 to 80% of eliminated drug.
Thiotepa has antitumor activity against ovarian and breast cancers and lymphomas. However, it has been largely supplanted by cyclophosphamide and other nitrogen mustards for treatment of these diseases. It is used by direct instillation into the bladder for multifocal local bladder carcinoma.
Nausea and myelosuppression are the major toxicities of thiotepa. It is not a local vesicant and has been safely injected intramuscularly and even intrathecally.

Общее описание

Odorless white crystalline solid.

Реакции воздуха и воды

Water soluble.

Профиль реактивности

Triethylenethiophosphoramide polymerizes readily upon exposure to heat or moisture, especially at acidic pH.

Опасность

Confirmed carcinogen.

Пожароопасность

Flash point data for Triethylenethiophosphoramide are not available. Triethylenethiophosphoramide is probably combustible.

Механизм действия

Thiotepa and the TEPA metabolite readily enter the CNS after systemic administration, leading to dizziness, blurred vision, and headaches. More critically, these agents also are severe myelosuppressants and can induce leukopenia, thrombocytopenia, and anemia. Patients treated with thiotepa are at high risk for infection and hemorrhage.

Клиническое использование

This antineoplastic agent is most commonly employed in the treatment of ovarian and breast cancers, as well as papillary carcinoma of the bladder.

Побочные эффекты

Patients have died from myelosuppression after intravesically administered thiotepa. The drug also causes damage to the hepatic and renal systems. Dose and/or administration frequency should be increased slowly, even if the initial response to the drug is sluggish, or unacceptable toxicity may result.

Профиль безопасности

Confirmed human carcinogen producing leukemia. Poison by ingestion, intraperitoneal, intravenous, and subcutaneous routes. Experimental teratogenic data. Human systemic effects by parenteral route: paresthesia, bone marrow changes, and leukemia. Experimental reproductive effects. Human mutation data reported. When heated to decomposition it emits very toxic fumes of POx, SOx, and NOx.

Возможный контакт

Used in the treatment of cancers resistant to chemotherapy. Antineoplastic: thiotepa has been prescribed for a wide variety of neoplastic diseases: adenocarcinomas of the breast and the ovary; superficial carcinoma of the urinary bladder; controlling intracavitary or localized neoplastic disease; lymphomas, such aslymphosarcomas and Hodgkin’s disease; as well as bronchogenic carcinoma.

Канцерогенность

Thiotepa is known to be a human carcinogen based on sufficient evidence from studies in humans. Thiotepa was first listed in the Second Annual Report on Carcinogens in 1981 as reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals and insufficient evidenceof carcinogenicity from studies in humans. Thiotepa was reclassified as known to be a human carcinogen in the Eighth Report on Carcinogens in 1998.

Перевозки

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.

Несовместимости

Tris(aziridinyl)phosphine sulfide polymerizes readily upon exposure to heat or moisture, especially at acidic pH. Incompatible with strong oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides.

Утилизация отходов

It is inappropriate and possibly dangerous to the environment to dispose of expired or waste 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 incinerator.