Alkaloiden allgemein Enthalten immer N.
[Yasgur]
An alkaloid is any of various physiologically active nitrogen-containing
organic bases derived from plants.
Generally bitter in taste and alkaline in reaction and unite with acids to
form salts. Their common names usually end in –in.
Alkaloids = Nitrogen-containing natural products, mostly found in
actively growing young tissues [van Wyk and Wink,
2004]
[Bronwyn Claire Harris]
Alkaloid: A nitrogen containing substance which tends to have strong
actions and can effect a wide range of functions in the body (Balkarn, 1995:32).
‡ Gleichgewicht:
macht Wahrnehmung bewusst. Bewegen sich zwischen Bewusstsein + Organen/Auf- und
Abbau,
Ungleichgewicht
= ANGST. Stoffen, die Schritten der Pflanzen ins Tierische angeben
Pflanzengiften sind Stoffwechselausscheidungen. Werden in Mineral-salzige
ausgeschieden. Haben Astralwirkung in physischem Leib.
Alkaloiden
= N-haltige Substanzen ‡
Alkaloide (muskelerschlaffend/sekretionfördernd/lähmend/narkotisch/mindern Herzfrequenz)/Flavonoide (Antioxidanzien/wirken fördernd auf das Langzeit-Gedächtnis)
Piper belle hat Alkaloidenähnliche Basen aus Aminosäuren entstanden
Theophylline, caffeine and theobromine
closely related alkaloids known as xanthines.
[Ashley
Hilton/Adrian Ross]
Alkaloiden
in Strychnos henningsii:
Diaboline: a convulsant
and therefore causes seizures (Wikipedia, The Free Encyclopedia,
2009).
Holstiine: has antiplasmodial
activity, and can therefore be effectively used as an anti-malarial (Ayuko, Njau, Cornelius, Leah, Ndiege, 2008).
Strychnochromine and Guianensine:
These alkaloids are effective against Plasmodium
falciparum (Frederich,
Hayette, Tits, De
Mol, Angenot, 1999:2329).
[Rall (1980:592-593)]
Theophylline, caffeine and theobromine
are closely related known as xanthines.
According to him, they share
common pharmacological actions incl. diuresis,
central nervous system stimulation, cardiac stimulation and smooth
muscle relaxation; notably bronchial smooth muscle.
Vergleich. Enthalten in Acal. + Adianthum capillius + Aegle + Agn + Argyreia nervosa + Scop-ähnliche Wirkung)Aven + Banis-c + Bapt + Berb-a + Boldo +
Borra-o + Cact + Caul-robustum + Cean + Chel (24 Stück) + Chin + Chrysan-indicum + Clivia + Cocc-s. (sondert bei Gefahr eine gelbliche, übelriechende
Flüssigkeit ab, die giftige Alkaloide enthält, und stellt sich dabei tot) + Coptis chinensis + trifolia + Cory-gariana + Cub + Cur + Dulc + Echi + Equis + Esch +
Foenm-g + Fritillaria imperialis + Frittilaria thunbergii
+ Gent-macro-phillia + Hydr.
+ Hydrc. + Ip + Just + Narc-ps + Nux-v + Nymph. + Paeon + Pareir +
Pergala + Phellodendron
amurense + Pip-n (bis 90%)
+ Pulmo + Queb + Rham-f + Ribes-n + Sabad + Saussarea lappa + Stigm + Scroph + Spig + Spig-m +
Staph + Stach + Still + Symph
+ Syzyg + Swertia Chirata + Tax + Tuss-fa + Tust-eq + Typh-i + Uncaria rhynchophylla + Xan (stimulans) + Yohimb + Vinc.
Betin-m (wird aus Alkaloide gewonnen/als Mur-ac-ersatz verwendet).
Siehe: Giftgruppe + ‡ Mondzeitaltergruppe ‡ + Anhang (Pflanzen mit hohem Alkaloiden- und Tannin-Gehalt)
Allerlei: Binden Aminosäuren/Trennung durch Verdauung ruft Reaktion im Nervensystem hervor
Sind als Nitrogeniumverbindungen in Pflanzen/Tierorganismen vorhanden
Plants containing pyrrolizidine alkaloids:
Asteraceae
Boraginaceae
Symphytum officinale
Symphytum x uplandicum
Borago officinalis
Alkanna tinctoria
Anchusa officinalis
Cynoglossum officinale
Heliotropium arborescens
Lithospermum officinale
Myosotis scorpioides
Symphytum asperum
Symphytum tuberosum
Pyrrolizidines
Senecio aureus
Tussilago farfara
Adenostyles alliariae
Emilia sonchifolia
Eupatorium cannabinum
Petasites hybridus
Petasites spurius
Senecio cineraria
Senecio doronicum
Senecio jacobaea
Senecio nemorensis
Senecio vulgaris
4.1. Medicinal plants of the
family Boraginaceae containing pyrrolizidine alkaloids.
4.1.1. Alkanna tinctoria
(L.) Tausch
Alcannet (ger. Alkanna, fr. Orcanette
tinctoriale, it. Ancusa),
grows in South Europe, Turkey and Egypt and is still today cultivated in these
countries. From time immemorial the root of this herb is applied internally as antidiarrheal agent and externally in cases of skin
diseases. Due to its intensively purple-colored
dyestuffs, called alkannins, the bark of the root is
also used for staining cosmetics and foods. Three open-chain alkaloids,
7-angeloylretronecine, triangularine and dihydroxytriangularine, were isolated from the bark of the
root in a total concentration of 0.25 to 0.3% . The drug should however no
longer be administered internally. Prior to staining of foods, e.g. of
lemonades, alkaloids should previously be eliminated.
4.1.2. Anchusa
officinalis L.
Common bugloss
(ger. Ochsenzunge, fr. Buglosse officinale), is widely distributed in Europe. The aerial
parts of the plant are occasionally applied externally with contused injuries, ulcus cruris, sciatica, as
compresses with diseases of a joint and of the adjacent bones, internally as a
mild expectorant. The total alkaloid content of the dried drug is ca. 0. 12%. Besides
the nontoxic alkaloids laburnine and acetyl-laburnine it contains the toxic alkaloids intermedine, lycopsamine and
7-acetyllycopsamine . Common bugloss should no longer be used as medicinal
plant.
4.1.3. Borago officinalis L.
Borage (ger. Boretsch,
fr. Bourache, it. Boragine) is a native plant. It is distributed all over
Europe from Denmark to Spain and North Africa. It is cultivated in North
America.
Borage herb and flowers are not only used as salade
and spice but also in folk medicine as depuratives, prophylactics against
inflammation of the chest and peritoneum, in cases of rheumarthritis,
cough and throat diseases as well as phlebitis.
Besides the toxic alkaloids intermedine, lycopsamine and their 7-acetyl derivatives these materials
contain in very small amounts the slightly toxic amabiline,
supinine and
the nontoxic thesinin. The total alkaloid
amount is less than 0.001% relative to the dry weight. The German Federal
Health Administration (BGA) does not regard a use of the
claimed fields of applications as justified. On the other hand, there
are no objections against an occasional consumption as a spice.
4.1.4. Cynoglossum officinale
L.
Common bugloss, common hounds tongue, Beggar's-lice, (ger. Hundszunge, fr. Cynoglosse officinale, it. Cinoglosa) is
widely distributed in Europe. In folk medicine the flowering herb and the roots
are applied externally in cases of injuries and sprainings,
internally as antidiarrheal and a mucolytic
agent. Common bugloss contains the alkaloids heliosupine,
the N-oxide of the latter, 12-acetylheliosupine, echinatine
and 7-angeloylheliotridine. The alkaloids found by Mankov
et al. and Sykulska et al. by paper chromatography (cynoglossophine, viridiflorine, lasiocarpine, heliotrine and platyphylline) could not be confirmed. Since the total
content of alkaloids varying from 0.7 to 1.5% is very high neither the drug nor
preparations there of should be administered. The BGA considers a therapeutic
application no longer justified.
4.1.5. Heliotropium
arborescens L, (syn. H. corymbosum)
Ruiz. et Pav.
Garden heliotrope, (ger. Vanille-Heliotrop, Vanille-Sonnenwendkraut, fr. Fleur des Dames, it. Eliotropio) grows in Peru and Ecuador. In Europa it is cultivated as fragrant ornamental
plant. In medicine it is also applied in homeopathy in cases of
laryngitis and displacement of the uterus. In an older study it was claimed on
the basis of a TLC comparison that the drug
contained the alkaloid lasiocarpine.
A more recent investigation revealed, however, that the plant does not
contain lasiocarpine but indicine
and 12-acetylindicine, respectively the N-oxides of the two compounds in a
total
concentration of 0.007% in leaves and of 0.01% in roots. Since
PA-containing homeopathic preparations may be used for human purposes
externally from D4 on and internally from
D6 on there are no objections concerning applications of the indicated
limiting doses in human medicine.
4.1.6. Lithospermum officinale
L.
Gromwell, Stone-seed (ger. Steinsame,
fr. Grémil officinal, it. Miglio des Sole) is widely distributed in Europe. In folk
medicine it is used as antipyretic and gout remedy as well as in
cases of urolithic and intestinal complaints.
Fresh plant extracts are supposed to display an anticonceptive
effect. From the seeds of the gromwell the alkaloids lithosenine
and
12-acetyllithosenine could be
isolated in a total concentration of 0.003%. The plant or the seed thereof
should, if possible, no longer be used.
4.1.7. Myosotis scorpioides
L. (syn. M. palustris (L.) Hill)
True forget-me-not, (ger. Vergissmeinnicht,
fr. Myosotis des Marais)
widespread plant in Europe. In folk medicine it is used internally as a
sedative and tonic, externally in eye baths.
In the dried plant the alkaloids myoscorpine, scorpioidine, 7-acetylscorpioidine and symphytine
were detected in a total content of 0.08% [88, 89]. The application of
forget-me-not
is considered obsolete.
4.1.8. Symphytum asperum
Lepech
Prickly comfrey, Consound. (ger. Rauher Beinwell,
fr. Consoud èpineux), growing in Caucasia is cultivated and used as
medicinal and useful plant in the southern parts of Russia
and in Central Europe like S. officinale and
S. x uplandicum. In the dried leaves the total
alkaloid content amounts up to 0.13%, in the dried roots up to 0.14 to 0.37%.
In these
the alkaloids resp. the N-oxides of intermedine
and lycopsamine, the 7-acetyl derivatives of the
latter two alkaloids (6, 7) symlandine, symviridine, myoscorpine. symphytine as
well as the major alkaloid echimidine typical
of S. asperum were detected [90, 91]. The presence of
the alkaloids asperumine, lasiocarpine,
echiumine, makrotomine, and
rousorine
found in the older studies of Manko et al. by
means of paper chromatography could not be confirmed [92-95]. Prickly comfrey
should no longer be used for medicinal purposes.
4.1.9. Symphytum caucasicum
Bieb.
Caucasian comfrey (ger. Kaukasischer
Beinwell, fr. Consoud de Caucase) grows in
Caucasia and is used there and in the European part of Russia as folk medicine.
In these areas it plays nearly the same important role as S. officinale in Central Europe. In the seventieth it was
repeatedly studied by Manko et al. who found a total
content of 0.48% of PAs.
Among these the following alkaloids were detected by means of paper and
thin-layer chromatography: the N-oxide of echimidine,
asperumine, echinatine, and
lasiocarpine. Since the latter three alkaloids have
not been found so far in other species of the genus Symphytum
further investigations of S. caucasicum are required.
Owing to its high alkaloid content an internal intake of this comfrey as a
medicinal plant is not recommendable.
4.1.10. Symphytum officinale
L. (syn. S. consolida (L.))
Comfrey, Common Comfrey (ger. Beinwell, Wallwurz, fr. Consoude officinale,
it. Consolida maggiore), is
widespread in Europe. The area of distribution extends from Denmark to Central
Russia. Both leaves and roots are used externally in cases of fractures,
contused injuries, sprainings, contusions strains, thrombophlebitis, mastitis, hematoma in the form of
extracts, ointments, compress pastes, etc., internally as infusions and
extracts in cases of gastro-intestinal diseases an respiratory tract diseases.
For vegetarians numerous recipe are offered for the preparation of comfrey salade, spinach soufflés, soupes,
bread, rolls, and root beverages.
In dried leaves 0.02 to 0.18 and in the roots 0.25 to 0.29% alkaloids
resp. their N-oxides were detected. The alkaloid include intermedine,
lycopsamine, their 7-acetyl derivatives, symlandine, symviridine, myoscorpine, and symphytine. The
presence of the alkaloids (echinatine, heliosupine N-oxide, heliotrine, lasiocarpine, and viridiflorine)
isolated and characterized by a Russian and Polish working group by means of
paper chromatography could not be confirmed.
A possible risk associated with the consumption of Symphytum
in humans was repeatedly reported and in medical literature several cases of
intoxication attributed to Symphytum and comfrey are
described. In animal tests acute toxic effects were detected in rats and goat.
Rats given for a longer period root drug or a mixture of the alkaloids intermedine and lycopsamine, that
are also contained in the comfrey, showed insuloma tumors of the pancreas, liver adenomas, hemangioendothelial
sarcomata, and tumors of the bladder.
In the long-term test with the root drug carcinogenicity could be
attributed to the main alkaloid symphytine. Moreover,
administration of the total alkaloid extract resulted in a mutagenic effect.
In view of the risks associated with the alkaloid content neither the
leaves nor the root should be used internally. However, under certain
conditions there are no objections to an external use provided the skin is
intact. In a study on the percutaneous absorption of
alkaloids from an alcoholic plant extract that had been applied to the skin of
rats 0.08 to 0.41% alkaloid N-oxides wen detected in
the urine even after two days. For therapeutic purposes the BGA permits
ointments and other preparation with 5 to 20% of dried drug to be applied
externally, the daily administered dose being not allowed to contain more than
10 mg of alkaloids including their N-oxides [134]. These requirements are met
by the application of species of very low alkaloid content.
4.1.11. Symphytum tuberosum
L.
Tuberous comfrey (ger. Knoten-Beinwell,
fr. Consoud tubereuse), grows in South-East Europe. Its allantoin content is very high; besides, it contains symlandine, echimidine and anadoline respectively the N-oxides of these alkaloids in a
total concentration of only 0.02%.
Tuberous comfrey is recommended for medicinal purposes as an alternative
to the other comfrey species.
4.1.12. Symphytum x uplandicum
Nyman (syn. S. peregrinum Ledeb.)
Russian comfrey (ger. Russischer
Beinwell, fr. Consoud de Russe), is a hybrid
generated from Symphytum officinale
L. and S. asperum Lepech.
It originates in Caucasia and has become widespread in Central Europe, England,
Canada, USA, Australia, New Zealand, Japan, Kenia and
South Africa. Under the designation of Russian comfrey it is not only
cultivated as medicinal plant but also on a large scale as vegetable,
fodder-and fertilizer plant. Roots and leaves contain intermedine,
lycopsamine, the 7-acetyl derivatives of these
alkaloids, uplandicine, symlandine,
symviridine, myoscorpine, symphytine, the major alkaloid echimidine,
and the N-oxides of these compounds in different concentrations. A total
alkaloid content of ca. 0.2% was found in the dried aerial parts. Russian
comfrey should no longer be used for medicinal purposes.
4.2. Medical plants of the family Asteraceae
containing pyrrolizidine alkaloids.
4.2.1. Eupatorium cannabinum L.
Hemp agrimony, Thoroughwort (german Kunigundenkraut, Wasserdost, fr. Eupatoire chanvrine, it. Canape aquatica), is a widespread
plant in Europe which preferentially grows on humid soils and brook edges. The
aerial, flowering parts are used as immunostimulating
agent in cases of influenza infections, as a remedy against obstipation
and for decreasing the cholesterol level as well as a diuretic. In these parts
of the plant the unsaturated alkaloids intermedine, lycopsamine, amabiline, supinine, rinderine and echinatine were detected in different concentrations. A
continued use,
e.g. for the purpose of decreasing the cholesterol level, should be
renounced.
4.2.2. Adenostyles alliariae (Gouan) Kern
Grey adenostyl (ger. Grauer Alpendost, fr. Adénostyle alliaire),
is widespread in the countries of the Alps where it grows preferentially in the
region of the timber-line. Until the beginning of this century it was used by
the inhabitants of the Alps as a pectoral tea and as such relatively important.
It contains the alkaloids senecionine, seneciphylline and spartioidine,
the total alkaloid content being ca. 0.02% and thus relatively high. Recently,
a heavy liver disease (venoocclusive disease) in an
infant caused by erroneous ingestion of grey adenostyl
instead of coltsfoot was reported.
4.2.3. Emilia sonchifolia (L.) DC.
Emilia herb (ger. Emilienkraut),
is a medicinal plant widespread in the south of China. It is used there in folk
medicine as antipyretic, as a remedy against influenza and grippal
dysentery and analgetic. Following Tyrolian physician Leonhard Hohenegg,
this herb is praised as a particularly effective remedy against fever,
influenza, cough, and bronchitis in lay medicine. Emilia herb contains senkirkine and doronine in a
total concentration of up to 0.2%. Application of the amounts of this herb
recommended by Hohenegg would inevitably result in
intoxication.
4.2.4. Petasites hybridus
(L.) PH Gaertn., B. Mey
& Scherb. (syn. P. officinalis
Moench)
Pestilence-wort, Butter bur, Colts food (ger. Pestwurz, Grosser Huflattich, fr. Pétasite vulgaire, it. Cavo laccio, Petastite,
Tussilagine maggiore),
occurs in Central Europe. Its distribution extends from Denmark up to North and
West Asia. It preferentially grows on river banks and brooks. The leaves and
roots of this plant and preparations thereof are applied in cases of nervous
and painful spasmodic stages of different genesis in the gastro-intestinal
tract, liver, gallbladder and pancreas diseases, with headache, respiratory
tract disease, and for the promotion of sleep. Besides the alkaloids senecionine (40), integerrimine
(41), senkirkine (52), the dried root drug contains
trances of petasitenine (57), neopetasitenine
(58), the nontoxic alkaloids neoplatyphylline (49), isotussilagine (68), and tussilagine
(70) in a total amount of 1 to 100 mg per kilogram, the leaf drug contains less
than one tenth of this amount [154-156]. According to the BGA the root-stock
may be applied as therapeutic agent in the treatment of acute convulsive pain
in the region of the abdomen. The daily dose administered must not contain more
than 1 mg of the alkaloids or alkaloid N-oxides and the duration of application
is limited to four to six weeks per year [134].
4.2.5. Petasites spurius (Retz) RCHB
Spurious
pestilence-wort (ger. Filziger Pestwurz, fr. Pétasite bâtard,
Petit Taconnet), grows on the sandy river-banks of
the Elbe, Saale, Havel, Oder, and Spree. In Europe its distribution area
extends from Denmark, South Sweden, South Poland to Central Russia. In the
Baltic Sea countries mentioned the rhizome was or is still used internally as a
cough remedy. In addition to the toxic senkirkine
(52) with a concentration of ca. 0.007% also the nontoxic alkaloids farfugine (31), isotussilagine
(68), isotussilaginine (69), and tussilagine
(70) were detected in this plant [157]. An internal intake cannot be
recommended.
4.2.6. Senecio aureus
L.
Golden ragwort, Squaw weed, Life root, Stinking Willie (ger. Gold-Kreuzkraut, fr. Seneçon
d'or, it. Senecione aureono) is widely
distributed in North America and Canada where it grows on humid river-bank
meadows. Already the Red Indians cultivated this ragwort as medicinal plant in
many ways. Today it is still used by the aborigines as a remedy against
injuries, internally as diaphoretic, diuretic and emmenagogue.
The Red Indian wives today ingest high doses of this drug both for acceleration
of the the course of labor
and abortion. In Europe, especially in Germany, it is administered in
homeopathy as mother tincture and as dilutions down to D3 in the case of hemorrhage of various kinds of genesis in gynecology. The drug contains the alkaloids floridanine (53), otosenine (55)
and florosenine (56) in a total concentration of
0.02% [158, 159]. The presence of senecionine could
not be confirmed [160]. According to the regulations of the BGA golden ragwort
is allowed to be applied internally for therapeutic purposes in humans only in
concentrations from D6 on.
4.2.7. Senecio bicolor
(Wild.) Tod. ssp. cineraria (syn. S. cineraria DC., syn. Cineraria maritima L.)
Dusty miller,
cineraria ragwort, silver groundsel (ger. Cineraria-Kreuzkraut, Aschenkraut, fr. Seneçon cineraire)
grows in the Mediterranean areas and is cultivated in Europe as ornamental
plant. Extracts of the flowering herb are administered as eye drops in the
treatment of corneal clouding, cataracts and conjunctivitis especially in the
southern EU countries (Portugal). In the flowering plants senecionine
(40), retrorsine (42), seneciphylline
(45), otosenine (55), jaconine
(60), and jacobine (61) were detected in a total
concentration of 0.9% [161-167]. According to the regulations of the BGA in the
Federal Republic of Germany eye drops are allowed to be applied externally as a
homeopathic pharmaceutical with a degree of potency of D4 [22].
4.2.8. Senecio doronicum L.
Doronic ragwort (ger. Gamswurz-Kreuzkraut, fr. Seneçon Doronic,
it. Cardonella) grows on lime soils in the Alps.
Infusions of the flower-head were used by the inhabitants of the Alps as a
remedy against asthma. The flowering plants contain the alkaloids doronenine (66) and bulgarsenine
(67) [168, 169]. Administration of the doronic
ragwort as a remedy against asthma is regarded as obsolete.
4.2.9. Senecio jacobaea
L.
Tansy ragwort, European ragwort, (ger. Jakobs-Kreuzkraut,
fr. Seneçon Jacobèe, it. Jacobea) is widespread in Europe. Until the
beginning of this century it was used as antispasmodic, emmenagogue
and in gynecology in cases of functional amenorrhea.
Tansy ragwort contains a large number of PAs. The
total alkaloid content amounts to 0.2 to 0.3% of the dry weight of the
flowering plants. The following alkaloids were isolated from the plant: senecivernine (39), senecionine
(40), integerrimine (41), retrorsine
(42), usaramine (43), 21-hydroxyintegerrimine (44), seneciphylline (45), spartioidine
(46), riddelline (47), jacoline
(59), jaconine (60), jacobine
(61), jacozine (62), (Z)-erucifoline
(63), (E)-erucifoline (64), and acetylerucifoline
(65) [170-190]. In short- and long-term tests performed on mice and rats the
intake of both the powdered drug and extracts caused acute toxic and
carcinogenic effects [191-193]. In the Ames test ingestion of an alkaloid
extract gave rise to a mutagenic effect [194]. Of course, this medicinal plant
should not be used.
4.2.10. Senecio nemorensis
L. ssp. fuchsii C. Gmel.
(S. nemorensis L. ssp. fuchsii
Celak.), and S. nemorensis
ssp. nemorensis (S. nemorensis
ssp. jacquinianus (RCHB.) Celak.)
Both subspecies Fuchsii ragwort (ger. Fuchs-Kreuzkraut, fr. Seneçon de Fuchs), and Nemorensis ragwort, (ger. Hain-Kreuzkraut, fr. Seneçon de Jaquin), are closely
related to each other, thus allowing formation of hybrids. The distribution
area of fuchsii ragwort extends from Central Europe
via the northern parts of the Balkan to Caucasia. It frequently grows in
forests of the montaneous regions and moreover up to
an altitude of 2000 m. Nemorensis ragwort occurs
throughout the European-Siberian areas up to a maximum height of 1500 m. The
two herbs are applied as hemostyptic agents both in
dentistry and gynecology. Recently they have also
been recommended and applied as hypoglycemic agents
in cases of hypertension and diabetes. Fuchsii and nemorensis ragwort contain besides the open-chain PAs of the unsaturated retronecine
and saturated platynecine type such as 7- and
9-angeloylretronecine (32, 33), 7-senecioylretronecine (34), triangularine (35), fuchsisenecionine,
and sarracine also macrocyclic
12- and 13-membered, saturated and unsaturated alkaloids. These include platyphylline, nemorensine, bulgarsenine, senecionine, retroisosenine, doronenine, and
the N-oxides of these in very different concentrations. The medicinal effect is
ascribed to the nontoxic, saturated alkaloids fuchsisenecionine
and bulgarsenine which represent the largest
proportion of the alkaloids. In a toxicologic
long-term test on rats ingestion of a commercial dried drug containing besides
the nontoxic major alkaloid fuchsisenecionine in a
concentration of 0.37% the toxic senecionine in a
concentration of 0.007% caused a dose-dependent hepatotoxic
and carcinogenic effect. This effect is attributed to senecionine.
An alkaloid mixture of the same concentration displayed weak mutagenic effects.
As hemostyptic agent only extracts of Senecio nemorensis ssp. fuchsii should be administered because in these extracts
the portion of toxic alkaloids is much lower than that in S. nemorensis ssp. nemorensis. The
portion of toxic alkaloids of the retronecine type
such as senecionine, retroisosenine,
and doronenine should therefore be less than 1 mg.
Diabetics who frequently had taken ragwort tea for several years in order to
support their therapy should not use such extracts because of the health risks
associated with their ingestion. The BGA generally considers a medicinal
application of fuchsii ragwort and nemorensis ragwort no longer justified.
4.2.11. Senecio vulgaris L.
Common ragwort,
Common groundsel, Grindsel
(= Gewöhnliches Kreuzkraut, fr. Seneçon vulgaire, it. Cardoncello), is widespread in the plains and mountains of
Europe. In folk medicine it played
a certain role as emmenagogue and in cases of
functional amenorrhoea. Besides, it was applied similarly as Senecio jacobaea. Like the latter
it contains an unusually large number of alkaloids up to a total content of
0.16% dry weight of the aerial whole drug. These alkaloids include senecionine, integerrimine, retrosine, usamarine, seneciphylline, spartoidine, riddelline, and the corresponding N-oxides. But also in
this case preparations of this ragwort should neither be recommended nor
administered.
4.2.12. Tussilago farfara
L.
Coltsfoot, Horsefoot (ger.
Huflattich. fr. Pas d'âne, Tussilage, it. Farfaro) is an important medicinal plant not only in Europe
and Asia but also in the USA and Canada. It either grows in the latter two
countries or has been imported. For medicinal purposes flower buds, flowers,
leaves, and roots are used. From time immemorial coltsfoot has been employed in
cases of colds, asthma, influenza, gastro-enteritis, diarrhea,
for metabolic stimulation, blood purification and externally for the treatment
of wounds. Depending on its origin, the dry drug contains different amounts of senkirkine ranging from 0.1 to 150 ppm,
in some cases also 0.1 to 10 ppm of senecionine, besides the nontoxic alkaloids isotussilagine, isotussilaginine,
tussilagine and tussilaginine,
usually in a total amount of <2 ppm. Owing to the
known hepatotoxicity and hepatocarcinogenicity
of senkirkine and senecionine
a Japanese working group performed a feeding experiment on rats for nearly two
years. At nonphysiologic high dosage of dried flower
buds hemangiosarcomas, hepatocellular
adenomas and carcinomas could be detected.
In 1988, intoxication of an infant resulting in death was ascribed to
coltsfoot. However, from the description of the case and the analysis of the
tea mixture it was concluded that ingestion of coltsfoot was not the factor
causing death. The tea mixture contained in addition to coltsfoot leaves also
leaves and roots of pestilence-wort [230-232]. The
BGA permits only leaves and tea mixtures the toxic PA content of which does not
exceed 10 mg. With extracts and fresh plant-pressed juice the limiting value
may be 1 mg. The period of application is confined to maximally six weeks a
year.
4.3. Honey containing pyrrolizidine alkaloids
Depending on the origin of the nectar collected by the bees, honey also
contain PAs. In honey originating from Senecio jacobaea the alkaloids senecionine, seneciphylline, jacoline, jaconine, jacobine, and jacozine were
detected in a total concentration of 0.3 to 3.2 mg. From the honey of Senecio vernalis the alkaloids senecivernine, senecionine and senkirkine were isolated in a total concentration of ca.
0.5-1.0 mg. In honey from Echium plantagineum
besides echimidine as major component the alkaloids echiumine, uplandicine as well as
intermedine, lycopsamine,
and the acetyl derivative of the latter two compounds were found in a total
concentration of 0.27 to 0.95 mg. Macrocyclic PAs, mainly seneciphylline, could
be detected in the concentration range of 30-70 mg/kg in a honey sample from
the Alpine foothills region of Switzerland. Measurable concentrations of PAs must always be reckoned with in the case of large-area monocultures
of PA-containing plants. In England, Scotland and Ireland honey from is known
and notorious for its strong aroma and bitter taste. This honey obviously also
contains alkaloids. However, since honey is of minor importance as a staple
food an intoxication may hardly occur.
5. Toxicity of pyrrolizidine alkaloids.
Alkaloids derived from 1-hydroxymethyl-l,2-dehydropyrrolizidine and esterified with at least one branched C5 carboxylic acid
display a toxic, carcinogenic and mutagenic effect. Nearly 100 of the PAs known so far possess such a structure. Enhancement of
the effect occurs if a further hydroxy group is
introduced into the 7-position and also esterified,
especially if the necinediol is esterified
with a dicarboxylic acid to afford a macrocyclic compound. Alkaloid N-oxides, on principle,
display the same toxicity. Since they are, in contrast to the bases, extremely
water-soluble they are subject to different pharmacokinetics. After oral
administration the alkaloids or their N-oxides are resorbed
in the intestine, the N-oxides being previously reduced by the reductases of the bacterial flora.
Part of the alkaloids is cleaved into necines
and necic acids by the nonspecific esterases of the blood. Necines
are nontoxic and are excreted as conjugates via the kidneys and urine. The main
proportion of the alkaloids on the other hand is transported into the liver
where metabolic conversions induce reactions known as "intoxication
reactions" <poisonings>.
5.1. Acute and Chronic Toxicity
In liver cells PAs give rise to the following
changes:
10- to 30- fold enlargement of
the liver cells (megalocytosis)
enlargement of the liver
nuclei with increasing nuclear chromatin
disturbances of the liver cell
metabolism with considerable functional losses
occurrence of irregular mitoses with simultaneous inhibition of mitosis
due to DNA blocking
cytoclases
fatty degeneration.
These reactions are induced by a single intake of 10 to 20 mg of an
alkaloid or alkaloid mixture.
If cytoclasis comprises larger regions of
liver parenchyma death results.
Lower amounts of alkaloids (less than 10 µg) and longer disposition
periods give rise to further damages:
proliferation of biliary tract epithelials
inflammatory infiltrates
congestive and centrilobular necrosis of Venae hepaticae (VOD)
cirrhosis
generation of carcinomas.
This necrosis has been introduced in the medical literature as Venoocclusive Disease (VOD) and is regarded as specific PA
intoxication (seneciosis). It is practically identical
with the clinical picture of the Budd-Chiari
syndrome. The clinical symptoms usually occur suddenly and comprise:
colicky pains in epigastrium
vomiting and diarrhea
ascites
formation within several days
enlargement and induration of the liver within a few weeks.
In serious cases the following symptoms are additionally observed:
vasomotoric
states of collapse
hematemesis
bleeding diarrhea.
The seriousness of the intoxication is not only dependent on the dosis administered but also on endogenic
(age, sex) and exogenic (alcohol, drug, living
conditions) factors.
Children are more sensitive to PA intoxications. The Kwashiorkhor
disease frequently observed with children in Central Africa is also related to
a damage of liver cells by PAs, the liver having lost
its ability to synthesize endogenic proteins.
Besides these effects on the liver, severe toxic pulmonary damages with
pulmonary-arterial hypertension and subsequent right ventricular failure were
observed. When the metabolities can no longer be
trapped in the liver cells they are transported via the blood into the
pulmonary arterioles where they cause damage to the endothelial vessels. In the
capillaries the latter are stimulated to proliferation causing a mediahypertrophy in the arterioles and thus a pressure
increase in the pulmonary circulation and acute right ventricular failure
similar to the classical cor pulmonale
[282-286].
The toxicity of several PAs could be directly
corroborated by means of the "yeast test" performed with Saccaromyces cerevisiae [287,
288].
5.2. Carcinogenicity of pyrrolizidine
alkaloids
A subtoxic intake (less than 1 mg) of PAs over longer periods resulted in the following gradually
occurring changes of organs:
megalocytosis
VOD
fatty degeneration
proliferation of the biliary tract epithelials
liver cirrhosis
nodular hyperplasia
adenomas or carcinomas.
The frequent occurrence of primary liver tumors
in the natives of Central Africa and South Africa is ascribed to the
consumption of traditional medicinal plants of the genera Crotalaria, Cynoglossum, Heliotropium and Senecio. In numerous experiments on animals with plants,
with the extracts of the latter or with the alkaloids occurring in the
aforementioned plant genera or in their species the clinical picture could be
confirmed.
5.3. Mutagenicity and genotoxicity
of pyrrolizidine alkaloids
The mutagenicity of PAs
has already been extensively studied. In this review article only those studies
referring to the medical plants and the alkaloids contained in the latter are
described. The plant extracts or the alkaloid mixtures of Senecio
jacobaea, Senecio nemorensis ssp. fuchsii, Senecio fuchsii, and Symphytum officinale investigated
in different test systems all exhibited a mutagenic effect. The alkaloids
having a relation to the discussed medicinal plants also possess mutagenic
properties. These alkaloids belong to the plant genera Senecio
and Petasites (senecionine,
integerrimine, retrosine
and N-oxides, seneciphylline, jacobine,
senkirkine), Eupatorium (supinine)
and Symphytum (intermedine,
lycopsamine, the N-acetyl derivatives of these, symphytine, echimidine).
The following test systems were used: Escherichia coli, Salmonella typhimurium (Ames), Aspergillus nidulans, Vicia faba, Allium cepa,
Drosophila melanogaster, leucocytes from marsupials,
hepatic cells from rats and mice, liver cells from Chinese hamsters, mice and
cattle as well as human lymphocytes. However, the various test systems used
afforded different results. Although it was found that the studied alkaloids
exhibit mutagenic properties the potency of the mutagenicity
of the individual alkaloids could not be ascertained [315-339]. This was only
realized by an extensive investigation of Frei et al.
who made use of the wing spot test of Drosophila melanogaster
[340]. 16 alkaloids were tested under the same conditions, thus allowing
comparative studies and even a quantitative assessment of the genotoxicity to be made for the first time. The following
order of decreasing mutagenicity of the alkaloids was
established:
The series starts with the alkaloid with the highest mutagenicity,
the senkirkine. The activity decreases via three
powers of ten up to supinine that displays no
activity.
Hence, the macrocyclic alkaloids senkirkine and senecionine
possess the highest activity. Retrorsine which may be
regarded as 12-hydroxymethyl derivative of senecionine
exhibits a fivehold weaker mutagenicity.
Jacoline which may also be considered as a hydroxy derivative of senecionine
likewise exhibits a weak effect. Obviously, increasing hydroxylation of necic acids decreases the mutagenic effect. Among the
open-chain diesters 7-acetylintermedine and
7-acetyllycopsamine display a five to ten times weaker activity than the macrocyclic compounds, while the acetyl esters possess a
two to three times higher activity than e.g. the alkaloids symphytine
and symlandine. The antitumor therapeutic agent indicine N-oxide exhibits only a very weak mutagenic
effect. Obviously, also in this case the general principle applies that the
mutagenic activity decreases with increasing hydroxylation. By means of this
very extensive study the mutagenicity of other
alkaloids, which have not been investigated so far, may be assessed.
5.4. Teratogenicity of pyrrolizidine
alkaloids
The teratogenic effect of PAs
was demonstrated by a single intraperitoneal
injection of heliotrine into pregnant rats. At
concentrations of 50 to 200 mg alkaloid/kg body weight teratogenic
changes were observed. Doses above 200 mg/kg resulted in uterine death and
degradation of the fetuses. Similar results were
obtained with heliotrine and its metabolite dehydroheliotrine, the latter exhibiting however a teratogenicity which 2.5 times as high as that of the
initial alkaloid. The teratogenic properties of heliotrine were also demonstrated by experiments on larvae
of fruit flies, Drosophila melanogaster.
5.5. Metabolism
5.5.1. Metabolism of 1,2-unsaturated pyrrolizidine
alkaloids
Metabolic reactions occur in the liver. A portion of the alkaloids,
which, as is well-known, are esters are hydrolyzed by nonspecific esterases. The produced necines
are supposed to be excreted renally. Alkaloids of
this kind are relatively nontoxic because the necines
do not produce toxic metabolites [344-346]. However, if the carboxylic acids
contain branched chains hydrolysis is strongly impaired by sterical
hindrance. If these difficultly hydrolyzable
alkaloids contain as a basic constituent a necine of
the supinidine, heliotridine,
retronecine, or crotanecine
type they are converted into the corresponding N-oxides by microsomal
oxygenases. These N-oxides undergo rearrangement and
elimination of water to afford the corresponding dehydropyrrolizidine
alkaloids. Moreover, hydroxylation of the carbon atoms adjacent to the nitrogen
atom (C-3 and C-8) is also supposed to occur, leading to the very unstable 3-
and 4-hydroxypyrrolizidine alkaloids. Elimination of water from these alkaloids
followed by rearrangement yields the corresponding dehydropyrrolizidine
alkaloids [347-3531. As shown in Fig. 9 these alkaloids possess an allyl structure causing an increase in reactivity.
Also alkaloids of the otonecine type differing
from the other PAs by a methyl group at the nitrogen
atom and a "quasi" ketonic function at C-8
were degraded similarly. After cationic elimination of the methyl group the
nor-N-otonecine alkaloids rearranges to the 8-hydroxy
derivative and the latter to the corresponding dehydropyrrolizidine
alkaloid.
Dehydropyrrolizidines representing (A)pyrrolidine
(B)pyrrole derivatives are highly reactive and are
the virtually active species of the PAs.
In the presence of nucleophilic systems (Nu-)
the diesters undergo either a simple or a double
bimolecular nucleophilic substitution (SN2 reaction).
In parallel occurring reactions a hydrolysis leading to the formation of dehydronecines (dehydroretronecine,
dehydroheliotridine) may also take place. These
compounds are similarly reactive, i.e. their toxicity and carcinogenicity
resemble those of dehydroalkaloids.
According to Mattocks et al. the reaction of the macrocyclic
alkaloids starts in the 7-position. MNDO (Modified Neglect of Differential
Overlaps) calculations, a standard method for determining charges and energy
contributions on van-der-Waals-surfaces, especially
in the case of heteroatom-containing organic molecules, reveal that locations
of scission contain higher partial charges than the other molecular regions. In
the case of dehydrosenecionine these locations are at
-0.341 for the 9-H2CO and at -0.328 for the 7-HCO group.
Hydroxy, mercapto
or amino groups of enzymes, globulins, hemoglobin but
also of purine and pyrimidine
bases or their nucleosides may function as nucleophiles.
Hence, DNS and/or RNS may also undergo alkylations.
Already simple alkylation affords an adduct that causes a lasting change of a
DNS and/or RNS strand. A double alkylation may give rise to irreversible cross
linking of both strands. If no repair process occurs a carcinogenic reaction
may be definitly predicted.
Recently, a further metabolic reaction has been assumed. According to Segall et al. the alkaloid, e.g. senecionine,
is supposed to be degraded to (E)-4-hydroxy-2-hexenal as demonstrated by the
reaction.
Aldehydes with a double bond in the
2,3-position display liver toxic properties.
5.5.2. Metabolism of 1,2-saturated pyrrolizidine
alkaloids
Saturated pyrrolizidines and their necines are nontoxic. According to Mattocks et al. the
alkaloids platyphylline and rosmarine
undergo enzymatic hydrolytic cleavage at C-7 with simultaneous formation of a pyrrole unit of ring B.
In contrast to dehydro(A)pyrroles
the nitrogen atom of which exists in a very unstable conjugated state and may
thus readily react with nucleophiles, 1,2-saturated pyrrolizidines are considerably more stable and not
susceptible to reactions with nucleophiles.
6. Outlook
After it had been demonstrated that test systems containing some
alkaloids or alkaloid N-oxides exhibited an antitumor effect several attempts
were made to use PAs in medicinal treatment of carcinosis. Since indicine itself
does not show mutagenic properties its N-oxide was successfully applied in
clinical studies on infantile leukemia.
Unfortunately, liver damages like liver necrosis and liver cirrhosis were
observed as side reactions so that a further therapeutic utilization was no
longer justified.
In the Pharmacopoea Sinica
of 1978 the alkaloid monocrotaline is described. It
was used for the treatment of dermatomas. On account
of its highly toxic and carcinogenic side effects it is not mentioned in the
new edition of 1985 and also no longer used.
The saturated alkaloid platyphylline displays spasmolytic and antiasthmatic
properties and was included in the Pharmacopoe of the
former UDSSR <Soviet Union> (1980). Compared to other spasmolytics
and antiasthmatics it exhibits no particular effect
so that it has gained no importance.
The use of medicinal plants represents a considerable risk of health.
Because of the liberalization of the international world trade an increasing
number of medicinal plants are offered as "miracle drugs" and
imported to Europe without control as the example of the Emilia herb
demonstrates.
Phytologie:
Verdauung(kühlend
Fieber/Gelbsucht/Leber/Verdauung
Entzündungshemmend/leicht
beruhigend/antibiotisch
Vorwort/Suchen Zeichen/Abkürzungen Impressum