レセルピン 化学特性,用途語,生産方法
外観
白色～うすい黄褐色, 粉末
溶解性
酢酸及びクロロホルムに易溶。エタノールに極めて難溶, 水及びアセトンにほとんど不溶。氷酢酸,クロロホルムに易溶、メタノール,エタノールに難溶、水,エーテルに不溶。
解説
レセルピン，白色または淡黄色の結晶．分解点265 ℃．氷酢酸，クロロホルムに易溶，メタノール，エタノールに難溶，水，エーテルに不溶．λmax 216，267，295 nm(log ε 4.79，4.23，4.01)．
森北出版「化学辞典（第2版）
用途
薬理研究用。
効能
血圧降下薬, 統合失調症治療薬, 小胞モノアミン輸送体阻害薬
作用
レセルピン，鎮静作用，血圧降下作用があり，精神安定剤として用いられる．温和に加水分解すると，メチルレセルパートと3,4,5-トリメトキシ安息香酸とに分解する．3位の異性体(イソレセルピン)は薬理作用が弱い．
商品名
アポプロン (第一三共); アポプロン (第一三共)
使用上の注意
光によって徐々に変化する。アルゴン封入
説明
Reserpine causes release of norepinephrine, dopamine, and serotonin at neuronal termini.
It weakens the intracellular uptake of biogenic amines and decreases the ability to store
them in vesicles.
化学的特性
Reserpine is a white to pale buff to slightly
yellow crystalline substance that darkens on exposure to
light.
物理的性質
Appearance: crystalline powder, colorless to yellowish brown, darker in case of
light. Solubility: soluble in chloroform, slightly soluble in acetone, and almost
insoluble in water, methanol, ethanol, or ether. Melting point: 264–265 °C.
Specific optical rotation: ?117.7°.
来歴
In 1931, Indian scholar Sen discovered Indian Rauvolfia have the antihypertensive
and antipsychotic effects. The following studies in medicinal chemistry and pharmacology
found that the main active ingredient is reserpine and clarified th mechanism of lowering blood pressure. In 1952, reserpine was first isolated and won
an important status in treating hypertension and neurological and psychiatric disorders
because of its remarkable physiological attributes. The structure analysis of
reserpine peaked in 1955.The total synthesis of reserpine is completed in 1956.
There are no effective antihypertensive drugs in clinic at the initial stage in our
country, and the reserpine imported from India was scarce and expensive, which
could not meet the urgent needs of patients. In
1958, the Bureau of Drug Administration of Ministry of Health presided over the
work of identifying the total alkaloids in Rauvolfia and approved the first Chinese
antihypertensive drug commercially named “Verticil”. Large scales of studies about
Chinese Rauvolfia as well as the numerous participants promote the rapid progress
of natural medicine. It can be taken as the earliest study in plant medicine since the
founding of China, providing valuable experience to our later studies.
使用
An indole alkaloid found in Rauwolfia serpentina. Inhibits vesicular uptake of catecholamines and serotonin. Reserpine is reasonably anticipated to be a human carcinogen. Antihypertensive.
定義
ChEBI: An alkaloid found in the roots of Rauwolfia serpentina and R. vomitoria.
生物学の機能
Reserpine (Serpasil) is the prototypical drug interfering
with norepinephrine storage. Reserpine lowers blood
pressure by reducing norepinephrine concentrations in
the noradrenergic nerves in such a way that less norepinephrine
is released during neuron activation.
Reserpine does not interfere with the release process
per se as does guanethidine.
Reserpine also interferes with the neuronal storage
of a variety of central transmitter amines such that significant
depletion of norepinephrine, dopamine, and 5-
hydroxytryptamine (serotonin) occurs. This central
transmitter depletion is responsible for the sedation and
other CNS side effects associated with reserpine therapy.
The depletion of brain amines also may contribute
to the antihypertensive effects of reserpine.
一般的な説明
Reserpine (Serpasil, Reserpoid, Rau-Sed, Sandril) is a white to light yellow, crystalline alkaloid,practically insoluble in water, obtained from various speciesof Rauwolfia. In common with other compounds with anindole nucleus, it is susceptible to decomposition by lightand oxidation, especially when in solution. In the dry state,discoloration occurs rapidly when reserpine is exposed tolight, but the loss in potency is usually small. In solution,reserpine may break down with no appreciable color changewhen exposed to light, especially in clear glass containers;thus, color change cannot be used as an index of the amountof decomposition.
空気と水の反応
Insoluble in water. Reacts slowly with air and water. Darkens slowly on exposure to light.
反応プロフィール
Reserpine is a weak base and can form salts with strong acids. Incompatible with oxidizing agents and reducing agents.
危険性
Questionable carcinogen.
健康ハザード
Reserpine produces sedative, hypotensive,
LD50 value, intraperitoneal (mice): 5 mg/kg
LD50 value, oral (mice): 200 mg/kgand tranquilizing effects. This is due to itsactions of causing depletion of monoaminesfrom presynaptic nerve terminals in central and peripheral nervous systems. Theadverse side effects are drowsiness, nightmare, depression, excessive salivation, nausea, diarrhea, increased gastric secretion,abdominal cramps, and hypotension.
火災危険
Flash point data for Reserpine are not available; however, Reserpine is probably combustible.
生物活性
Binds the vesicular monoamine transporter (VMAT2) and inhibits transport of biogenic amines into adrenal chromaffin granules and synaptic vesicles. Causes depletion of biogenic amine stores. Antihypertensive and antipsychotic.
作用機序
Reserpine acts to replace and deplete the adrenergic neurons of their stores of norepinephrine by inhibiting the active
transport Mg-ATPase responsible for sequestering norepinephrine and dopamine within the storage vesicles. The
norepinephrine and dopamine that are not sequestered in vesicles are destroyed by MAO. As a result, the storage
vesicles contain little neurotransmitter, adrenergic transmission is dramatically inhibited, and sympathetic tone is
decreased, leading to vasodilation. Reserpine has the same effect on epinephrine storage in the adrenal medulla.
Reserpine readily enters the CNS, where it also depletes the stores of norepinephrine and serotonin. The CNS
neurotransmitter depletion led to the use of reserpine in treating certain mental illnesses.
薬物動態学
Limited information is available regarding the pharmacokinetics of reserpine. Peak blood concentrations for reserpine
occur within 2 hours following oral administration, and the full effects for reserpine usually are delayed for at least 2 to
3 weeks. Both CNS and cardiovascular effects may persist for several
days to several weeks after chronic oral therapy is discontinued. Reserpine appears to be widely distributed in body
tissues, especially adipose tissue; crosses the blood-brain barrier and the placenta; and is distributed into milk. The
elimination of reserpine appears to be biphasic, with a plasma half-life averaging 4.5 hours during the first phase and
approximately 11.3 days during the second phase. Reserpine is metabolized to unidentified inactive compounds.
Unchanged reserpine and its metabolites are excreted slowly in urine and feces, with an average of 60% reserpine
recovered in feces within 96 hours after oral administration of 0.25 mg of radiolabeled reserpine.
薬理学
Reserpine causes a breakdown of norepinephrine, dopamine, and serotonin in neuron endings. It weakens intracellular uptake of biogenic amines and reduces the ability if storing
them in vesicles. It is possible that reserpine acts on membrane vesicles, irreversibly
inhibiting ATP-Mg2 (adenosinetriphosphate) requiring process that is responsible for the
uptake of biogenic amines in interneuronal vesicles. Breakdown of catecholamines is
expressed by a decreased number of intraneuronal serotonin and dopamine.
臨床応用
Reserpine is effective orally and parenterally for thetreatment of hypertension. After a single intravenous dose,the onset of antihypertensive action usually begins in about1 hour. After intramuscular injection, the maximumeffect occurs within approximately 4 hours and lasts about10 hours. When it is given orally, the maximum effectoccurs within about 2 weeks and may persist up to 4 weeksafter the final dose. When used in conjunction with otherhypotensive drugs in the treatment of severe hypertension,the daily dose varies from 100 to 250μg.
副作用
The most troublesome untoward effects of treatment
with reserpine involve the CNS. Sedation and depression
are the most common, although nightmares
and thoughts of suicide also occur. Reserpine treatment,
therefore, is contraindicated in patients with a history
of severe depression. The occasional report of reserpine-
induced extrapyramidal symptoms, which are
similar to those seen in patients with Parkinson’ s disease,
is believed to be a result of dopamine depletion
from neurons in the CNS.
Peripheral nervous system side effects are the result
of a reserpine-induced reduction of sympathetic function
and unopposed parasympathetic activity; symptoms
include nasal congestion, postural hypotension, diarrhea,
bradycardia, increased gastric secretion, and
occasionally impotence. Because of the increased gastric
secretion, reserpine is contraindicated for patients with peptic ulcer. In patients with little cardiac reserve,
reserpine must be administered with caution because of
its ability to interfere with sympathetic stimulation of
the heart.
安全性プロファイル
Confirmed human carcinogen producing tumors of the sh and brain. Poison by ingestion, intravenous, subcutaneous, and intraperitoneal routes. Mutation data reported. An experimental teratogen. Human and experimental reproductive effects by ingestion: sullbirth, reduced viability, and other neonatal measures or effects. In humans, 0.014 mg/kg causes psychotropic effects. A medicine with side effects. Used as an addltive permitted in the feed and drinking water of animals and/or for the treatment of food-producing animals. Also permitted in food for human consumption. A sedative. When heated to decomposition it emits toxic fumes of NOx.
職業ばく露
Reserpine, a pharmaceutical, is a natu-
rally occurring substance that is isolated from the roots of
the plant rauwolfia serpentina. Insoluble in water.
Reserpine is used as a hypertensive for humans and ani-
mals; tranquilizer, and sedative. Permitted for use as an
additive in food for human consumption, and the feed and
drinking water of food-producing animals.
発がん性
Reserpine is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.
環境運命予測
Reserpine is a naturally occurring alkaloid produced by several
members of genus Rauwolfia, indigenous to India, Burma,
Malaysia, Thailand, Nepal, and Indonesia. The release of
reserpine to the environment through several waste streams is
possible due to the manufacture of reserpine and/or excretion
following therapeutic use. It has a pKb of 6.6 and is expected to
be in a partially protonated state in the environment. Reserpine
released into air at ambient temperature and pressure exists
only in the particulate phase and is removed from the atmosphere
by wet and dry deposition. Reserpine released to soil is available in oral dosage forms in combinations with hydralazine
(a vasodilator) and/or hydrochlorothiazide (a thiazide
diuretic). Occupational exposure would be expected to occur
through inhalation or dermal contact.
輸送方法
UN1544 Alkaloids, solid, n.o.s. or Alkaloid salts,
solid, Hazard Class: 6.1; Labels: 6.1-Poisonous materials,
Technical Name Required. UN3077 Environmentally haz-
ardous substances, solid, n.o.s., Hazard class: 9; Labels: 9-
Miscellaneous hazardous material, Technical Name
Required.
純化方法
Crystallise reserpine from aqueous Me2CO or Et2O. [Woodward et al. Tertrahedron 2 155 1958, Beilstein 25 III/IV 1319.]
不和合性
A weak acid; keep away from bases.
Incompatible with 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, oxoa-
cids, epoxides, and strong reducing agents such as hydri-
deds and active metals. 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, dithio-
carbamates, 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 possi-
bly dangerous to the environment to dispose of expired or
waste drugs and pharmaceuticals by flushing them down
the toilet or discarding them to the trash. Household quanti-
ties 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. Consult with environmental regula-
tory agencies for guidance on acceptable disposal practices.
Generators of waste containing this contaminant (≥100 kg/
mo) must conform with EPA regulations governing storage,
transportation, treatment, and waste disposal.
参考文献
Muller, Schlittler, Bein., Experientia, 8,338 (1952)
Woodward et al., Tetrahedron, 2, 1 (1958)
Jilek e t aI., Collect. Czech. Chem. Commun., 26, 687 (1961)
Hakkesteegt., Pharm. Weekbl., 105,829 (1970)
レセルピン 上流と下流の製品情報
原材料
準備製品