Theophyllin Chemische Eigenschaften,Einsatz,Produktion Methoden
ERSCHEINUNGSBILD
WEISSES KRISTALLINES PULVER
CHEMISCHE GEFAHREN
Die Substanz zersetzt sich beim Erhitzen unter Bildung von giftigen Rauchen mit Stickoxiden.
ARBEITSPLATZGRENZWERTE
TLV nicht festgelegt.
MAK nicht festgelegt.
AUFNAHMEWEGE
Aufnahme in den K?rper in gef?hrlichen Mengen durch Verschlucken.
INHALATIONSGEFAHREN
Eine bel?stigende Partikelkonzentration in der Luft kann schnell erreicht werden durch Dispergieren.
WIRKUNGEN BEI KURZZEITEXPOSITION
WIRKUNGEN BEI KURZZEITEXPOSITION: M?glich sind Auswirkungen auf das Herz und das Zentralnervensystem mit Herzrhythmusst?rungen und Kr?mpfen. Die Auswirkungen treten u.U. verz?gert ein.
LECKAGE
Pers?nliche Schutzausrüstung: Atemschutzger?t mit Partikelfilter entsprechend der Arbeitsplatzkonzentration des Stoffes. Verschüttetes Material in abdichtbaren Beh?ltern sammeln; falls erforderlich durch Anfeuchten Staubentwicklung verhindern. An sicheren Ort bringen.
R-S?tze Betriebsanweisung:
R22:Gesundheitssch?dlich beim Verschlucken.
R39/23/24/25:Giftig: ernste Gefahr irreversiblen Schadens durch Einatmen, Berührung mit der Haut und durch Verschlucken.
R23/24/25:Giftig beim Einatmen, Verschlucken und Berührung mit der Haut.
R11:Leichtentzündlich.
R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.
S-S?tze Betriebsanweisung:
S7:Beh?lter dicht geschlossen halten.
S16:Von Zündquellen fernhalten - Nicht rauchen.
S36/37:Bei der Arbeit geeignete Schutzhandschuhe und Schutzkleidung tragen.
S45:Bei Unfall oder Unwohlsein sofort Arzt zuziehen (wenn m?glich, dieses Etikett vorzeigen).
S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.
S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
Beschreibung
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).
Chemische Eigenschaften
white to light yellow crystal powder
Physikalische Eigenschaften
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).
Verwenden
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.
Definition
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.
Indications
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.
Allgemeine Beschreibung
Odorless white crystalline powder. Odorless. Bitter taste.
Air & Water Reaktionen
Slightly soluble in water.
Reaktivit?t anzeigen
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.
Hazard
Questionable carcinogen.
Brandgefahr
Flash point data for Theophylline are not available, however Theophylline is probably combustible.
Biologische Aktivit?t
Bronchodilator, anti-inflammatory and immunomodulator. Antagonizes adenosine receptors and is a weak non-selective inhibitor of phosphodiesterases (PDEs).
Mechanism of action
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.
Pharmakologie
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.
Clinical Use
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.
Nebenwirkungen
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.
Sicherheitsprofil
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.
Environmental Fate
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.
Stoffwechsel
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.
l?uterung methode
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.]
Vorsichtsma?nahmen
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.
Einzelnachweise
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)
Theophyllin Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Uracil
Ethylcyanacetat
3,7-Dihydro-1,3-dimethyl-1H-purin-2,6-dion, Kaliumsalz
Coffein
7,9-Dihydro-1,3,7-trimethyl-1H-purin-2,6,8(3H)-trion
3,7-Dihydro-1,7-dimethyl-1H-purin-2,6-dion
Theobromin
Downstream Produkte
8-Bromtheophyllin
7,9-Dihydro-1,3-dimethyl-1H-purin-2,6,8(3H)-trion
1,3-Dimethyl-8-nitro-1H-purine-2,6(3H,9H)-dione ,97%
Cholintheophyllinat
Aminophyllin
Doxofyllin
3,9-Dihydro-1,3,9-trimethyl-1H-purin-2,6-dion
teomorfolin
1,3-Dimethyl-8-nitro-3,7-dihydro-1H-purine-2,6-dione
