Талидомид

Химические свойства

White Powder

Использование

Inhibits FGF-induced angiogenesis. Inhibits replication of human immunodeficiency virus type 1. Teratogenic sedative. There is now a growing clinical interest in Thalidomide, and it is introduced as an immunomodulatory agent used primarily in combination with dexamethasone to treat multiple myeloma.

Показания

Thalidomide (Thalomid) is a derivative of glutamic acid that is chemically related to glutethimide. It exerts a number of biological effects as an immunosuppressive, antiinflammatory, and antiangiogenic agent, yet its mechanisms of action have not been fully elucidated. Thalidomide potently inhibits production of tumor necrosis factor (TNF) and interleukin (IL) 12, and its effect on these and other cytokines may account for some of its clinical effects.

Определение

ChEBI: A dicarboximide that is isoindole-1,3(2H)-dione in which the hydrogen attached to the nitrogen is substituted by a 2,6-dioxopiperidin-3-yl group.

Всемирная организация здравоохранения(ВОЗ)

Notwithstanding the highly potent teratogenic action of thalidomide, this drug retains a place in the treatment of reactional lepromatous leprosy and several serious dermatological conditions refractory to other treatment. In many countries, the competent authorities have granted exemption from licensing requirements to enable doctors to obtain limited supplies of thalidomide under strictly controlled circumstances for use in named patients. Arrangements have also been made by some national drug regulatory authorities for thalidomide to be used in institutions concerned with the treatment of leprosy.

Общее описание

Needles or white powder.

Реакции воздуха и воды

Insoluble in water.

Профиль реактивности

Organic amides/imides, such as Thalidomide, react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx).

Угроза здоровью

Thalidomide is a strong teratogen. Exposureto this compound during the first trimesterof pregnancy resulted in deformities inbabies. Infants born suffered from ameliaor phocomelia, the absence or severe shortening of limbs. Administration of thalidomide in experimental animals caused fetaldeaths, postimplantation mortality, and specific developmental abnormalities in theeyes, ear, central nervous system, musculoskeletal system, and cardiovascular system. Several thousand children were affected.The drug has been withdrawn from themarket.
Thalidomide is usually administeredorally. Its toxicity is dose dependent. Someother effects are drowsiness, constipation andrash and nerve damage in the arms and legs.
Interest in thalidomide resurged in recentyears because of its antitumor activity in thetreatment of multiple myeloma (Oxberry andJohnson 2006). The compound is an inhibitorof angiogenesis, that is, it prevents formationof new blood vessels in tumors. Also, it hasbeen found to be effective in treating AIDS-related Kaposis sarcoma.

Пожароопасность

Flash point data for Thalidomide are not available; however, Thalidomide is probably combustible.

Биологическая активность

Teratogen, sedative-hypnotic with inherent anti-inflammatory properties. A selective inhibitor of tumor necrosis factor α (TNF- α ) synthesis.

Механизм действия

Its absorption from the gastrointestinal tract is slow, with peak plasma levels being reached after 3 to 6 hours. It appears to undergo nonenzymatic hydrolysis in the plasma to a large number of metabolites.The elimination half-life is approximately 9 hours.

Клиническое использование

Thalidomide is approved for use in the United States for the treatment of cutaneous manifestations of erythema nodosum leprosum, a potentially lifethreatening systemic vasculitis that occurs in some patients with leprosy.Although not approved for other indications, thalidomide has also been shown to be very effective in the management of Beh?et’s disease, HIVrelated mucosal ulceration (aphthosis), and select cases of lupus erythematosus.

Побочные эффекты

Thalidomide is a highly teratogenic drug, characteristically causing phocomelia (aplasia of the midportions of the limbs). Even a single dose may cause fetal malformation. Thalidomide should be prescribed to women of childbearing potential only when no acceptable alternative exists. Because it is not known whether thalidomide is present in the ejaculate of males receiving the drug, male patients must use a latex condom when engaging in sexual activity with women of childbearing potential.
Other side effects of thalidomide may include sedation (in fact, thalidomide was originally marketed in Europe as a sleeping aid), constipation, and peripheral neuropathy, which may be permanent.

Профиль безопасности

Poison by ingestion. Moderately toxic by skin contact and intraperitoneal routes. Human teratogenic effects by ingestion: developmental abnormalities of the musculoskeletal and cardiovascular systems. Experimental reproductive effects. Questionable carcinogen with experimental tumorigenic and teratogenic data. Human mutation data reported. It was commonly used as a prescription drug in Europe in the late 1950s and early 1960s. Its use was dscontinued because it was lscovered to cause serious congenital abnormalities in the fetus, notably amelia and phocomelia (absence or deformity of the limbs, including hands and feet) when taken by a woman during early pregnancy. When heated to decomposition it emits toxic fumes of NOx. Used as a sedative and hypnotic.