サリドマイド 化学特性,用途語,生産方法
外観
白色～ほとんど白色, 結晶～粉末
溶解性
ジオキサン及びN,N-ジメチルホルムアミドに溶け、水,アセトン及びエタノールにほとんど溶けない。
解説
サリドマイド，C13H10N2O4(258.23)．1950年代末から市販された非バルビツール酸系の睡眠導入剤であるが，強い催奇性(四肢の短縮症)により，数年で市場から姿を消すことになった．グルタミン酸イミドがそのアミノ基でフタルイミドを形成しており，1個の不斉炭素がある．市販されたのはラセミ体であり，その後，薬効の強いR体は催奇性がないとの研究結果も出たが，容易にラセミ化するため，臨床使用はされていない．現在では，立体異性体の存在する薬剤については，有効な異性体を特定し，単一異性体として使用されるのが標準となっている．白色の針状晶．(±)-体は融点269～271 ℃．ジオキサンに可溶，ほかの有機溶媒に不溶．
用途
薬理研究用。
効能
抗生物質, 抗悪性腫瘍薬
商品名
サレド (藤本製薬)
来源
サリドマイド（thalidomide）鎮静・催眠薬の一種。1957年に西ドイツで開発。妊娠初期に服用するとあざらし肢症奇形児の出産が多くなることが明らかになり、各国で製造・販売が禁止された。日本での発売開始は昭和33年（1958）、昭和37年（1962）に出荷・発売停止、回収となった。その後、血液癌がんの一種、多発性骨髄腫に薬効があるところから、平成20年（2008）10月に厚生労働省が製造・発売を再承認。ハンセン病にも効果があるとされるが、その仕組みは不明。
化学的特性
White Powder
使用
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.
適応症
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.
定義
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.
世界保健機関（WHO）
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.
一般的な説明
Needles or white powder.
空気と水の反応
Insoluble in water.
反応プロフィール
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).
健康ハザード
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.
火災危険
Flash point data for Thalidomide are not available; however, Thalidomide is probably combustible.
生物活性
Teratogen, sedative-hypnotic with inherent anti-inflammatory properties. A selective inhibitor of tumor necrosis factor α (TNF- α ) synthesis.
作用機序
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.
臨床応用
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.
副作用
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.
安全性プロファイル
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.
サリドマイド 上流と下流の製品情報
原材料
準備製品