クロラムフェニコール

外観

白色〜わずかにうすい黄色, 結晶〜結晶性粉末

溶解性

水, エーテルに難溶。エタノール, 酢酸エチルに可溶。メタノール, エタノールに易溶、水, エーテルに難溶。エタノールに溶けやすく、水に溶けにくい。

解説

クロラムフェニコール，くろらむふぇにこーる，1947年に南アメリカのベネズエラの土壌から発見されたストレプトミセス・ベネゼエレStreptomyces venezuelaeという放線菌の培養液から得られた抗生物質で、「クロロマイセチン」（クロマイと略称）の商品名で有名である。合成に初めて成功した抗生物質としても知られる。白色ないし黄白色の結晶または結晶性粉末で、においはなく味は苦い。グラム陽性菌、グラム陰性菌、スピロヘータ、リケッチア、クラミジアに有効で、広域性抗生物質の一つである。以前は繁用されたが、悪性貧血など重篤な副作用のため、現在では点眼液など外用のほかは、内服では腸チフスなど特定の感染症のみにしか適応されず、使用量は激減した。

用途

作用機序の研究用。

用途

クロラムフェニコール系抗生 物質です。細菌リボソーム 50S に結合し、タ ンパク質合成阻害作用を示します。抗菌スペ クトルは広く、多くの細菌やリケッチケアな どに抗菌力を示します。

用途

クロラムフェニコール系抗生 物質です。細菌リボソーム 50s に結合し、タ ンパク質合成阻害作用を示します。抗菌スペ クトルは広く、多くの細菌やリケッチケア等 に抗菌力を示します。

用途

クロラムフェニコール (Chloramphenicol) は、バクテリア Streptomyces venezuelae 由来の抗生物質であり、現在は化学合成によって作られている。 類似化合物にフロルフェニコールがあるが、こちらは動物のみでヒトには用いられていない。 クロラムフェニコールはグラム陽性、陰性にかかわらず、多くの微生物に対して有効であるが、再生不良性貧血を含む骨髄の損傷など人体に重大な副作用があるため、先進国においては腸チフスなど重大で生命の危機がある感染症、もしくは多剤耐性のため本剤以外に選択肢がない場合にのみ用いられる。

用途

培地添加剤、食品中の残留クロラムフェニコールの分析、耐性菌の研究。

効能

抗生物質, 抗リケッチア, タンパク質合成阻害薬

商品名

クロマイ (アルフレッサファーマ); クロラムフェニコール (富士製薬工業); クロラムフェニコール (日東メディック); クロロマイセチン (アルフレッサファーマ); クロロマイセチン (アルフレッサファーマ); クロロマイセチン (アルフレッサファーマ); クロロマイセチン (アルフレッサファーマ); ハイセチン (富士製薬工業)

確認試験

(１) 本品の定量法で得た試料溶液につき，紫外可視吸光度 測定法〈2.24〉により吸収スペクトルを測定し，本品のスペ クトルと本品の参照スペクトル又はクロラムフェニコール標 準品について同様に操作して得られたスペクトルを比較する とき，両者のスペクトルは同一波長のところに同様の強度の 吸収を認める．
(２) 本品につき，赤外吸収スペクトル測定法〈2.25〉の臭 化カリウム錠剤法により試験を行い，本品のスペクトルと本 品の参照スペクトル又はクロラムフェニコール標準品のスペ クトルを比較するとき，両者のスペクトルは同一波数のとこ ろに同様の強度の吸収を認める．

定量法

本品及びクロラムフェニコール標準品約0.1g(力価)に 対応する量を精密に量り，それぞれをメタノール20mLに溶 かし，水を加えて正確に100mLとする．この液20mLずつを 正確に量り，それぞれに水を加えて正確に100mLとする． 更に，この液10mLずつを正確に量り，それぞれに水を加え て正確に100mLとし，試料溶液及び標準溶液とする．試料 溶液及び標準溶液につき，紫外可視吸光度測定法〈2.24〉に より波長278nmにおける吸光度AT及びASを測定する．
クロラムフェニコール(C₁₁H₁₂C_l2N₂O₅)の量[μg(力価)] ＝MS × AT／AS × 1000
MS：クロラムフェニコール標準品の秤取量[mg(力価)]

純度試験

(１) 重金属〈1.07〉 本品1.0gをとり，第2法により操作し， 試験を行う．比較液には鉛標準液2.5mLを加える(25ppm以 下)．
(２) ヒ素〈1.11〉 本品2.0gをとり，第4法により検液を調 製し，試験を行う(1ppm以下)．
(３) 類縁物質 本品0.10gをメタノール10mLに溶かし， 試料溶液とする．この液1mLを正確に量り，メタノールを 加えて正確に100mLとし，標準溶液(1)とする．標準溶液 (1)10mLを正確に量り，メタノールを加えて正確に20mLと し，標準溶液(2)とする．これらの液につき，薄層クロマト グラフィー〈2.03〉により試験を行う．試料溶液，標準溶液 (1)及び標準溶液(2)20μLずつを薄層クロマトグラフィー用シ リカゲル(蛍光剤入り)を用いて調製した薄層板にスポットす る．次にクロロホルム／メタノール／酢酸(100)混液(79： 14：7)を展開溶媒として約15cm展開した後，薄層板を風乾 する．これに紫外線(主波長254nm)を照射するとき，試料溶 液から得た主スポット及び原点のスポット以外のスポットは， 標準溶液(1)から得たスポットより濃くない．また，試料溶 液から得た主スポット及び原点のスポット以外のスポットの合計は，2.0％以下である．

貯法

容器 気密容器．

乾燥減量

0.5％以下(1g，105℃，3時間)．

強熱残分

0.1％以下(1g)．

説明

Chloramphenicol was originally produced by fermentation of Streptomyces venezuelae, but its comparatively simple chemical structure soon resulted in several efficient total chemical syntheses. With two asymmetric centers, it is one of four diastereomers, only one of which (1R,2R) is significantly active. Because total synthesis produces a mixture of all four, the unwanted isomers must be removed before use. Chloramphenicol is a neutral substance that is only moderately soluble in water, because both nitrogen atoms are nonbasic under physiologic conditions (one is an amide and the other a nitro moiety). It was the first broad-spectrum oral antibiotic used in the United States and was once very popular. Severe potential blood dyscrasia has greatly decreased its use in North America. Although its cheapness and efficiency makes it still very popular in much of the rest of the world where it can often be purchased over-the-counter without a prescription

化学的特性

Chloramphenicol is a white to grayish-white or yellowish-white crystalline solid.

使用

Chloramphenicol is unusual nitroaromatic metabolite produced by Streptomyces venezuelae, first published in 1947. Chloramphenicol is a broad spectrum antibiotic with good activity against Gram negative and anaerobic bacteria. Although restricted to ocular use, antibiotic resistance to other classes has refocused attention on this class. Chloramphenicol acts by binding to the 23S sub-unit of the 50S ribosome, inhibiting protein synthesis. Chloramphenicol has been extensively studied with over 35,000 literature citations.

定義

ChEBI: Chloramphenicol is an organochlorine compound that is dichloro-substituted acetamide containing a nitrobenzene ring, an amide bond and two alcohol functions. It has a role as an antimicrobial agent, an antibacterial drug, a protein synthesis inhibitor, an Escherichia coli metabolite, a Mycoplasma genitalium metabolite and a geroprotector. It is an organochlorine compound, a diol, a C-nitro compound and a carboxamide.

適応症

Resistance to chloramphenicol is usually explained by the presence of a plasmid that determines the production of chloramphenicol acetyltransferase. This enzyme acetylates the drug, giving it unable to bind with 50 S subunits of bacterial ribosomes.
Chloramphenicol is a potentially toxic drug and has a few indications for use. It is the drug of choice for treating typhoid fever, and it is used for treating brain abscesses. Until recently, it was the drug of choice for therapy of bacterial meningitis in children (in combination with ampicillin). However, third-generation cephalosporins are currently preferred for such purposes. Chloramphenicol is an effective alternative for a number of infections in situations, where drugs of choice cannot be used for one reason or another. However, it should never be used for infections that can readily be treated with other antimicrobial drugs. Synonyms of this drug are levomycetin, amindan, aquamycetin, chloromycetin, ophthoclor, opulets, leukomycin, and many others.

世界保健機関（WHO）

Chloramphenicol, an antibiotic isolated from Streptomyces venezuelae in 1947, first became available for general clinical use in 1948. By 1950 it was evident that its use could cause serious, sometimes fatal, blood dyscrasias. However, it remains one of the most effective antibiotics for treating invasive typhoid fever and salmonellosis, some rickettsioses and serious infections caused by Haemophilus influenzae or anaerobic organisms. This is considered to justify its retention in the WHO Model List of Essential Drugs. (Reference: (WHTAC1) The Use of Essential Drugs, 2nd Report of the WHO Expert Committee, 722, , 1985)

一般的な説明

Synthetic bacteriostatic antibiotic that inhibits the translation of RNA by blocking the peptidyltransferase reaction on ribosomes.

危険性

Has deleterious and dangerous side effects. Must conform to FDA labeling requirements. Use is closely restricted. Probable carcinogen.

接触アレルゲン

This broad spectrum phenicol group antibiotic has been implicated in allergic contact dermatitis. Cross-sensitivity to thiamphenicol is possible, but not systematic.

作用機序

Chloramphenicol is bacteriostatic by virtue of inhibition of protein biosynthesis in both bacterial and, to a lesser extent, host ribosomes. Chloramphenicol binds to the 50S subparticle in a region near where the macrolides and lincosamides bind.
Resistance is mediated by several R-factor enzymes that catalyze acetylation of the secondary and, to some extent, the primary hydroxyl groups in the aliphatic side chain. These products no longer bind to the ribosomes and so are inactivated. Escherichi a coli frequently is resistant because of chloramphenicol's lack of intercellular accumulation.

安全性プロファイル

Confirmed human carcinogen producing leukemia, aplastic anemia, and other bone marrow changes. Experimental tumorigenic data. Poison by intravenous and subcutaneous routes. Moderately toxic by ingestion and intraperitoneal routes. Human systemic effects by an unknown route: changes in plasma or blood volume, unspecified liver effects, and hemorrhaging. Experimental teratogenic and reproductive effects. Human mutation data reported. An antibiotic. When heated to decomposition it emits very toxic fumes of NOx and Cl-. See also other chloramphenicol entries.

職業ばく露

An antibiotic derived from streptomyces venezuelae. A potential danger to those involved in the manufacture, formulation, and application of this antibiotic and antifungal agent

発がん性

Chloramphenicol is reasonably anticipated to be a human carcinogen, based on limited evidence of carcinogenicity from studies in humans.

環境運命予測

As an antibiotic, chloramphenicol enters the target cells by facilitated diffusion and binds reversibly to the 50S ribosomalsubunit. This prevents the interaction between peptidyl transferase and its amino acid substrate, which results in the inhibition of peptide bond formation. Indeed, it is an inhibitor of protein synthesis in the bacteria and to a lesser extent, in eukaryotic cells. Chloramphenicol can also inhibit mitochondrial protein synthesis in mammalian cells particularly erythropoietic cells, which are sensitive to the drug.

代謝経路

Six metabolites of chloramphenicol are identified, among which the sulfate conjugate is characterized in goat urine.

代謝

When given orally, it is rapidly and completely absorbed but has a fairly short half-life. It is mainly excreted in the urine in the form of its metabolites, which are a C-3 glucuronide, and, to a lesser extent, its deamidation product and the product of dehalogenation and reduction. These metabolites are all inactive. The aromatic nitro group also is reduced metabolically, and this product can undergo amide hydrolysis. The reduction of the nitro group, however, does not take place efficiently in humans but, rather, primarily occurs in the gut by the action of the normal flora. Chloramphenicol potentiates the activity of some other drugs by inducing liver metabolism. Such agents include anticoagulant coumarins, sulfonamides, oral hypoglycemics, and phenytoin.

輸送方法

UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials. UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1- Poisonous materials, Technical Name Required.

純化方法

Purify chloramphenicol by recrystallisation from H2O (solubility is 2.5mg/mL at 25o) or ethylene dichloride as needles or long plates, and by sublimation at high vacuum. It has A 1cm 298 at max 278nm, and it is slightly soluble in H2O (0.25%) and propylene glycol (1.50%) at 25o but is freely soluble in MeOH, EtOH, BuOH, EtOAc and Me2CO. [Relstock et al. J Am Chem Soc 71 2458 1949, Confroulis et al. J Am Chem Soc 71 2463 1949, Long & Troutman J Am Chem Soc 71 2469, 2473 1949, Ehrhart et al. Chem Ber 90 2088 1957, Beilstein 13 IV 2742.]

不和合性

Compounds of the carboxyl group react with all bases, both inorganic and organic (i.e., amines), releasing substantial heat, water, and a salt that may be harmful. Incompatible with arsenic compounds (releases hydrogen cyanide gas), diazo compounds, dithiocarbamates, isocyanates, mercaptans, nitrides, sulfides (releasing heat, toxic, and possibly flammable gases), thiosulfates, and dithionites (releasing hydrogen sulfate and oxides of sulfur).

廃棄物の処理

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.