ミノサイクリン 化学特性,用途語,生産方法
性質
ミノサイクリンの作用機序は、細菌のリボソームサブユニットへ結合しタンパク質合成を阻害することです。動物のリボソームサブユニットへは結合しないため、細菌に静菌的かつ特異的に作用します。
そのほか、リパーゼ活性抑制作用や白血球遊走抑制作用、活性酸素抑制作用があることから、尋常性ざ瘡 (ニキビ) に効果が期待できます。ミノサイクリンの発現頻度が高い副作用は、めまいと吐き気です。
服用後の車の運転など、危険な動作は避けてください。他の重大な副作用として、血液障害、急性腎障害、ショック・アナフィラキシー、肝機能障害などがあります。特に肝機能障害は、大量投与で引き起こされる可能性が高いです。
ただし、ミノサイクリンは肝臓で代謝される薬物です。そのため、腎機能に応じて投与量を減量する必要はありません。
解説
ミノサイクリンとは、で示されるテトラサイクリン系抗生物質です。
細菌内に入った後に、リボソームのサブユニット (30S) に結合し、 タンパク質合成を阻害します。
黄色の結晶性粉末で、N,N-ジメチルホルムアミドやに溶けやすいですが、水やには溶けにくいです。
用法用量
錠剤、注射剤共に、初回にミノサイクリンを100〜200mg投与したのち、12時間ごとあるいは24時間ごとに100mgを投与します。
優先的に使用するのは錠剤です。経口摂取が不可能な場合や緊急の場合は、注射剤から開始して、経口摂取可能になった時点で錠剤に移行することが推奨されています。
効能
抗生物質, タンパク質合成阻害薬
使用上の注意
錠剤を服用する際は、多めの水で服用してください。錠剤が食道に停留し崩壊すると食道潰瘍を起こす恐れがあります。特に就寝直前の服用や、服用後すぐ横になる行為は避けてください。
また、錠剤、注射剤に共通して、投与により尿が黄褐〜茶褐色、緑、青に変色した報告や甲状腺が黒色になった報告があります。
説明
An important antibiotic produced by semisynthesis from demeclocycline is minocycline. It is much more
lipophilic than its precursors, gives excellent blood levels following oral administration (90–100% available),and can be given once a day. Its absorption is lowered by approximately 20% when taken with food or milk.
It is less dependent on active uptake mechanisms and has a somewhat broader antimicrobial spectrum. It
also, apparently, is less painful on IM or IV injection, but it has vestibular toxicities (e.g., vertigo, ataxia, and
nausea) not generally shared by other tetracyclines.
使用
Minocycline is a semi-synthetic tetracycline prepared by sequential hydrogenolysis, nitration and reductive methylation. Minocycline, together with doxycycline, is regarded as a ‘third generation’ tetracycline largely replacing the natural products and pro-drugs produced in the early 1950s for mainstream antibiotic applications. Like all tetracyclines, minocycline shows broad spectrum antibacterial and antiprotozoan activity and acts by binding to the 30S and 50S ribosomal sub-units, blocking protein synthesis. Minocycline has been extensively cited in the literature with over 5,000 references.
定義
ChEBI: A tetracycline analogue having a dimethylamino group at position 7 and lacking the methyl and hydroxy groups at position 5.
適応症
The tetracycline antibiotic minocycline (Minocin) is
modestly effective in the treatment of rheumatoid
arthritis and is generally well tolerated. Radiographic
evidence of its efficacy as a DMARD is lacking, although
clinical symptoms do abate. It can be useful in
the treatment of early, mild disease.
世界保健機関（WHO）
Minocycline, a semi-synthetic tetracycline derivative was
introduced in 1967. It is used today in the treatment of bacterial, rickettsial and
amoebic infections. Symptoms described as dizziness or vertigo have been
recognized in association with minocycline administration, however, these
symptoms are usually not severe. Minocycline is registered in many countries and
the World Health Organization is not aware that registration has been refused
elsewhere.
抗菌性
It exhibits the broad-spectrum activity
typical of the group, but retains activity against some strains
of Staph. aureus resistant to older tetracyclines. It is active
against β-hemolytic streptococci and some tetracycline-
resistant
pneumococci. It is also active against some enterobacteria
resistant to other tetracyclines, probably because
some Gram-negative efflux pumps remove minocycline less
effectively
than other tetracyclines. Some strains of H. influenzae resistant
to other tetracyclines are susceptible. Sten. maltophilia
is susceptible, as are most strains of Acinetobacter spp.
and L. pneumophila.
It is notable for its activity against Bacteroides and
Fusobacterium spp., and is more active than other tetracyclines
against C. trachomatis, brucellae and nocardiae. It inhibits
Mycobacterium tuberculosis, M. bovis, M. kansasii and M. intracellulare
at 5–6 mg/L. Candida albicans and C. tropicalis are also
slightly susceptible.
併用する際の注意点
錠剤を服用する際、カルシウム、マグネシウム、アルミニウム、ランタン、鉄などの金属を含む食物との併用には注意が必要です。ミノサイクリンと上記の金属がキレートを形成し、ミノサイクリンの吸収が低下する恐れがあります。併用する場合は2〜4時間間隔をあけてください。
錠剤と注射剤共通して挙げられる併用注意薬は、ワルファリンカリウムなどの抗凝血剤、SU系血糖降下剤、メトトレキサート、ポリフィマーナトリウム、ジゴキシン、経口避妊剤、ビタミンA製剤 (経口剤) です。
使用用途
ミノサイクリンは、テトラサイクリン系抗生物質として幅広く医療の現場で使用されています。効果を示すのは、ブドウ球菌属、溶血性レンサ球菌、肺炎球菌などのグラム陽性細菌や、大腸菌、クレブシエラ属、エンテロバクター属などのグラム陰性細菌です。
また、作用する部位が細胞壁ではないため、細胞壁を持たないリケッチア、クラミジアに対しても、抗菌作用を期待できます。ミノサイクリンの適応症は多岐にわたりますが、代表的なものは前立腺炎、肺炎、膀胱炎、外耳・中耳炎、尋常性ざ瘡などです。
特に尋常性ざ瘡 (ニキビ) に関しては、日本皮膚科学会の「尋常性ざ瘡治療ガイドライン」にて推奨度Aの薬剤に分類されています。
応用例（製薬）
A semisynthetic tetracycline derivative supplied as the hydrochloride
for oral administration.
薬物動態学
Oral absorption： 95–100%
Cmax 150 mg oral： 4 mg/L after 2h
300 mg oral： 2 mg/L after 2 h
Plasma half-life： 12–24 h
Volume of distribution： 80–115 L
Plasma protein binding： 76%
Absorption
Food does not significantly affect absorption, which is depressed
by co-administration with milk. It is chelated by metals and
suffers the effects of antacids and ferrous sulfate common to
tetracyclines. On a regimen of 100 mg every 12 h, steady-state
concentrations ranged between 2.3 and 3.5 mg/L.
Distribution
The high lipophilicity of minocycline provides wide distribution
and tissue concentrations that often exceed those of
the plasma. The tissue:plasma ratio in maxillary sinus and
tonsillar tissue is 1.6： that in lung is 3–4. Sputum concentrations
may reach 37–60% of simultaneous plasma levels.
In bile, liver and gallbladder the ratios are 38, 12 and 6.5,
respectively.
Prostatic and seminal fluid concentrations range from 40%
to 100% of those of serum. CSF penetration is poor, especially
in the non-inflamed state. Concentrations in tears and
saliva are high, and may explain its beneficial effect in the
treatment of meningococcal carriage.
Metabolism
Biotransformation to three microbiologically inactive
metabolites occurs in the liver： the most abundant is
9-hydroxyminocycline.
Excretion
Only 4–9% of administered drug is excreted in the urine, and
in renal failure elimination is little affected. Neither hemodialysis
nor peritoneal dialysis affects drug elimination. Fecal excretion is relatively low and evidence for enterohepatic
recirculation remains uncertain. Despite high hepatic excretion,
dose accumulation does not occur in liver disease, such
as cirrhosis. Type IIa and type IV hyperlipidemic patients
show a decreased minocycline clearance of 50%, suggesting
that dose modification may be necessary.
臨床応用
There appear to be few situations in which it has a unique
therapeutic advantage over other tetracyclines. Its use has been
tempered by the high incidence of vestibular side effects.
Although used in the long-term management of acne, the
potential for skin pigmentation must be considered. Because
of its high tissue concentrations, it may occasionally provide a
useful alternative to other agents for the treatment of chronic
prostatitis. It has a role in the treatment of sexually transmitted
chlamydial infections.
副作用
Minocycline shares the untoward reactions common to the
group with gastrointestinal side effects being most common,
and more prevalent in women. Diarrhea is relatively
uncommon, presumably as a result of its lower fecal concentrations.
Hypersensitivity reactions, including rashes,
interstitial nephritis and pulmonary eosinophilia, are occasionally
seen.
Staining of the permanent dentition occurs with all tetracyclines;
a side effect that appears to be unique to minocycline
is that of tissue discoloration and skin pigmentation. Tissues
that may become pigmented include the skin, skull and other
bones and the thyroid gland, which at autopsy appears blackened.
The pigmentation tends to resolve slowly with discontinuation
of the drug and is related to the length of therapy.
Three types of pigmentation have been identified:
? A brown macular discoloration (‘muddy skin syndrome’),
which occurs in sun-exposed parts and is histologically
associated with melanin deposition.
? Blue–black macular pigmentation occurring within
inflamed areas and scars associated with hemosiderin
deposition.
? Circumscribed macular blue–gray pigmented areas
occurring in sun-exposed and unexposed skin, which
appears to be linked to a breakdown product of
minocycline.
CNS toxicity has been prominent, notably benign intracranial
hypertension, which resolves on discontinuation of the
drug, and, more commonly, dizziness, ataxia, vertigo, tinnitus,
nausea and vomiting, which appear to be more frequent
in women. These primarily vestibular side effects have ranged
in frequency from 4.5% to 86%. They partly coincide with
plasma concentration peaks, but their exact pathogenesis has
yet to be determined.
ミノサイクリン 上流と下流の製品情報
原材料
準備製品