テオフィリン 化学特性,用途語,生産方法
外観
白色, 結晶性粉末～粉末
定義
本品は、次の化学式で表されるキサンチン誘導体である。
溶解性
水, エタノール, クロロホルムに難溶、エーテルにほとんど不溶、ジメチルホルムアミドに可溶。水酸化カリウム試液, アンモニア試液に可溶。水及びエタノールに溶けにくく、アセトンにほとんど溶けない。
解説
テオフィリン,無色の針状晶．融点270～274 ℃．pKa 8.77(25 ℃)．昇華性がある．酸やアルカリに可溶，アルコール類に微溶，エーテルに不溶．N-メチル化によりカフェインとなる．利尿薬として使われるが，その作用はテオブロミンやカフェインより強い．
森北出版「化学辞典（第2版）
用途
ホスホジエステラーゼ阻害作
用を示します。
用途
気管支拡張薬 強心薬 血管拡張薬 抗喘息薬 利尿薬
化粧品の成分用途
皮膚コンディショニング剤
効能
気管支拡張薬, ホスホジエステラーゼ阻害薬
製造
テオフィリン,キサンチン系アルカロイドの一種．テオブロミンの異性体．茶葉に含まれる．N,N-ジメチル尿素とシアノ酢酸エチルを縮合環化してピリミジン誘導体とし，トラウベのプリン合成法に従って誘導する．
商品名
スロービッド (サンド); スロービッド (サンド); テオドール (田辺三菱製薬); テオドール (田辺三菱製薬); テオドール (田辺三菱製薬); テオロング (エーザイ); ユニコン (日医工); ユニフィル (大塚製薬)
説明
Theophylline is a methylxanthine that acts as a weak bronchodilator. It is useful for chronic therapy and is not helpful in acute exacerbations.
Theophylline is a methylxanthine alkaloid that is a competitive inhibitor of phosphodiesterase (PDE; Ki = 100 μM). It is also a non-selective antagonist of adenosine A receptors (Ki = 14 μM for A1 and A2). Theophylline induces relaxation of feline bronchiole smooth muscle precontracted with acetylcholine (EC40 = 117 μM; EC80 = 208 μM). Formulations containing theophylline have been used in the treatment of asthma and chronic obstructive pulmonary disease (COPD).
化学的特性
white to light yellow crystal powder
物理的性質
Appearance: white, crystalline powder, odorless, with a bitter taste. Solubility:
freely soluble in solutions of alkali hydroxides and in ammonia; sparingly soluble
in alcohol, in chloroform, and in ether; slightly soluble in water. Water solubility,
7.36?g/L (20?°C); density, 1.62?g/cm3
; melting point, 270–274?°C; boiling point,
390.1?°C (760? mmHg); flash point, 189.7?°C; vapor pressure, 2.72E-06? mmHg
(25?°C).
使用
theophylline is tonic and skin conditioning. Its cosmetic activity is not clearly or definitively established. It is most often found in anti-cellulite products. Theophylline is in the same family of bio chemicals as caffeine. It is naturally occurring in tea.
定義
ChEBI: Theophylline is a dimethylxanthine having the two methyl groups located at positions 1 and 3. It is structurally similar to caffeine and is found in green and black tea. It has a role as a vasodilator agent, a bronchodilator agent, a muscle relaxant, an EC 3.1.4.* (phosphoric diester hydrolase) inhibitor, an anti-asthmatic drug, an anti-inflammatory agent, an immunomodulator, an adenosine receptor antagonist, a drug metabolite, a fungal metabolite and a human blood serum metabolite.
適応症
Twenty years ago theophylline (Theo-Dur, Slo-bid,
Uniphyl, Theo-24) and its more soluble ethylenediamine
salt, aminophylline, were the bronchodilators of
choice in the United States. Although the β2-adrenoceptor
agonists now fill this primary role, theophylline
continues to have an important place in the therapy of
asthma because it appears to have antiinflammatory as
well as bronchodilator activity.
一般的な説明
Odorless white crystalline powder. Odorless. Bitter taste.
空気と水の反応
Slightly soluble in water.
反応プロフィール
Theophylline neutralizes acids in exothermic reactions to form salts plus water. May be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen may be generated in combination with strong reducing agents, such as hydrides.
危険性
Questionable carcinogen.
火災危険
Flash point data for Theophylline are not available, however Theophylline is probably combustible.
生物活性
Bronchodilator, anti-inflammatory and immunomodulator. Antagonizes adenosine receptors and is a weak non-selective inhibitor of phosphodiesterases (PDEs).
作用機序
In spite of a great deal of investigation, just how theophylline causes bronchodilation is not clearly understood. Inhibition of the enzyme PDE, which is responsible for the hydrolysis of cAMP and cyclic guanosine monophosphate (cGMP), generally is put forth as the mechanism of action; however, theophylline also is an adenosine antagonist and has been implicated in stimulation of the release of catecholamines. It has been clearly shown that theophylline does inhibit PDEs in vitro, and x-ray crystallographic studies have identified the binding residues that interact with the methylxanthines. Theophylline binds to a subpocket of the active site and appears to be sandwiched between a phenylalanine and a valine via hydrophobic bonds. Its binding affinity is reinforced by hydrogenbonding between a tyrosine and N-7 and a glutamine and O-6 of the xanthine ring system. There are more than 11 families of PDEs, and studies have shown that theophylline binds in a similar manner to both the PDE4 and PDE5 family isoforms.
薬理学
Smooth muscle relaxation, central nervous system
(CNS) excitation, and cardiac stimulation are the principal
pharmacological effects observed in patients
treated with theophylline.The action of theophylline on
the respiratory system is easily seen in the asthmatic by
the resolution of obstruction and improvement in pulmonary
function. Other mechanisms that may contribute
to the action of theophylline in asthma include
antagonism of adenosine, inhibition of mediator release,
increased sympathetic activity, alteration in immune
cell function, and reduction in respiratory muscle
fatigue. Theophylline also may exert an antiinflammatory
effect through its ability to modulate inflammatory
mediator release and immune cell function.
Inhibition of cyclic nucleotide phosphodiesterases is
widely accepted as the predominant mechanism by
which theophylline produces bronchodilation. Phosphodiesterases
are enzymes that inactivate cAMP and
cyclic guanosine monophosphate (GMP), second messengers
that mediate bronchial smooth muscle relaxation.
臨床応用
The principal use of theophylline is in the management
of asthma. It is also used to treat the reversible component
of airway obstruction associated with chronic obstructive
pulmonary disease and to relieve dyspnea associated
with pulmonary edema that develops from
congestive heart failure.
副作用
Theophylline has a narrow therapeutic index and produces
side effects that can be severe, even life threatening.
Importantly, the plasma concentration of theophylline
cannot be predicted reliably from the dose. In
one study, the oral dosage of theophylline required to
produce therapeutic plasma levels (i.e., between 10 and
20 μg/mL) varied between 400 and 3,200 mg/day.
Heterogeneity among individuals in the rate at which
they metabolize theophylline appears to be the principal
factor responsible for the variability in plasma levels.
Such conditions as heart failure, liver disease, and severe
respiratory obstruction will slow the metabolism of
theophylline.
安全性プロファイル
Human poison by
ingestion, parenteral, intravenous, and rectal
routes. Experimental poison by multiple
routes. An experimental teratogen. Human
systemic effects: coma, convulsions or effect
on seizure threshold, cyanosis, EKG
changes, fever and other metabolic effects,
heart arrhythmias, heart rate change,
hyperglycemia, metabolic acidosis, nausea or
vomiting, potassium-level changes,
respiratory stimulation, salivary gland
changes, somnolence, tremor. Experimental
reproductive effects. Human mutation data
reported. Used as a dturetic, cardtac
stimulant, smooth muscle relaxant, and to
treat asthma. When heated to
decomposition it emits toxic fumes of NOx.
環境運命予測
Theophylline is readily broken down in the environment.
It may undergo photolytic degradation in the air or when
exposed to light. In moist soil, or aqueous environments, it
undergoes rapid biodegradation.
代謝
Chemically, theophylline is 1,3-dimethylxanthine and contains both an acidic and a basic nitrogen
(N-7 and N-9, respectively). Physiologically, it behaves as an acid (pKa = 8.6), and its poor
aqueous solubility can be enhanced by salt formation with organic bases. Theophylline is
metabolized by a combination of C-8 oxidation and N-demethylation to yield methyluric acid
metabolites. The major urinary metabolite is 1,3-dimethyl uric acid, which is the
product of the action of xanthine oxidase. Because none of the metabolites is uric acid itself, theophylline can be safely given to patients who suffer from gout.
純化方法
It crystallises from H2O as the monohydrate which becomes anhydrous above 100o. It is freely soluble in hot H2O, but its solubility at 15o is 0.44%. It complexes with heavy metals. It is a diuretic, vasodilator and a cardiac stimulant. [Lister Purines Part II, Fused Pyrimidines Brown Ed, Wiley-Interscience pp253-254 1971, ISBN 0-471-38205-1, Beilstein 26 H 455, 26 I 134, 26 II 263, 26 III/IV 2331.]
予防処置
Theophylline should be used with caution in patientswith myocardial disease, liver disease, and acutemyocardial infarction. The half-life of theophylline isprolonged in patients with congestive heart failure.Because of its narrow margin of safety, extreme cautionis warranted when coadministering drugs, such as cimetidineor zileuton, that may interfere with the metabolismof theophylline. Indeed, coadministration of zileutonwith theophylline is contraindicated. It is alsoprudent to be careful when using theophylline in patientswith a history of seizures.
参考文献
Fischer., Ber., 30, 553 (1897)
Schwabe., Arch. Pharm., 245, 312 (1907)
Biltz, Strufe.,Annalen, 404, 137, 170(1914)
Yoshitomi., Chem. Abstr., 19,2303 (1925)
Mossini., Boll. chim. farm., 75, 557 (1936)
Deichmeister., Farm. Zhur., 13, 18 (1940)
Deichmeister., Chem. Zentr., 1, 1280 (1942)
Deniges., Bull. trav. soc. ph arm. Bordeaux, 79, 141 (1941)
Lesser., Drug & Cosmetic Ind., 66, 276,340 (1950)
テオフィリン 上流と下流の製品情報
原材料
準備製品
8-ブロモテオフィリン
8-ヒドロキシ-1,3-ジメチルキサンチン
1,3-Dimethyl-8-nitro-1H-purine-2,6(3H,9H)-dione ,97%
コリンテオフィリン
アミノフィリン
ドキソフィリン
3,9-ジヒドロ-1,3,9-トリメチル-1H-プリン-2,6-ジオン
teomorfolin
1,3-Dimethyl-8-nitro-3,7-dihydro-1H-purine-2,6-dione