HERBAL
MEDICINAL
PLANT
----------------------------------------------------------
CELANDINE
Chelidonium majus L. (Papaveraceae) +
BY
RETTODWIKART THENU
CELANDINE
(seh’luhn-deen)
Chelidonium majus L. (Papaveraceae) +
SUMMARY AND PHARMACEUTICAL COMMENT
The chemistry of C. majus aerial parts and root is well documented. The yellow-orange
alkaloid-containing latex occurs throughout the entire plant, and it is the
alkaloids which are considered to be the active principles. Precisely which of
the alkaloid constituents are responsible for the documented pharmacological
activities has not been determined. There is also evidence that, at least for
certain activities, all components of the total extract (i.e. alkaloids plus
other constituents, such as caffeic acid esters) are necessary, rather than a
single constituent, or group of constituents.
Several pharmacological properties, including antispasmodic,
choleretic, anti-inflammatory, cytotoxic and antimicrobial activities, have
been described for preparations of C. majus following preclinical studies, providing some supporting
evidence for the traditional uses. However, welldesigned clinical trials of C. majus preparations are lacking and
further studies are required to determine clinical efficacy and safety. To
date, clinical investigations are limited to a small number of trials which has
assessed the effects of proprietary products containing C. majus, often in combination
with other herbal ingredients, in patients with functional epigastric
disorders. These trials have involved relatively small numbers of participants
(less than 80 per trial) and been of short duration (up to six weeks).
Information on the safety and toxicity of C. Majus preparations is limited
and, in view of this, excessive use (higher than recommended dosages and/or for
long periods of time) of C. majus should be avoided.
Numerous reports have described hepatotoxic effects, including severe hepatitis, severe cholestasis and fibrosis, associated with the use of preparations of C. majus. The majority of these reports has involved different German manufacturers’ preparations of
C. majus,
several of which formulations include only C. majus extract as the active component; such preparations are usually standardised for content of chelidonine. A mechanism for
C. majus induced
hepatotoxicity has not been established, although because of the apparent lack
of a dosedependent effect and variable latent period in the reported cases, an
idiosyncratic reaction may be the most plausible explanation.
On the basis of the available evidence, and in view of the intended
uses for greater celandine, C.
majus preparations appear to have a negative benefit–harm profile. In
May 2003, the Complementary Medicines Evaluation Committee, which advises the
Australian Government’s Therapeutic Goods Administration, recommended that
preparations of C. Majus for
oral administration should include on their label statements advising consumers to use such products only under the supervision of a healthcare professional, to seek advice from a healthcare professional before using the product if the potential user has a history of liver disease,
and to stop using C. majus preparations if symptoms
associated with liver disease
occur.
Pharmacists and other healthcare professionals should be aware
that herbal products containing C. majus are readily available over the internet and from retail outlets;
such products are promoted as being beneficial in indigestion, dyspepsia,
nervousness, restlessness, sleeplessness and for nervous headaches and
menstrual complaints. There are no licensed C. majus products available in the UK, so the quality of commercially
available products is not assured.
TRADE NAMES
Celandine poppy, common
celandine, felonwort, garden celandine, greater celandine, rock poppy, swallow
wort, tetter wort, wart wort
DESCRIPTION
MEDICINAL PARTS: The medicinal
pans are the aerial parts that have been collected during the flowering season
and dried. The root, which has been collected in late autumn and dried, and the
fresh rhizome are also used medicinally.
FLOWER AND FRUIT: The
plant has yellow flowers arranged in umbels. There are 2 sepals, 4 petals,
numerous yellow stamens and l ovary. The fruit is pod-like and many-seeded. The
seeds are black-brown and glossy.
LEAVES, STEM AND ROOT: Celandine is a
30 to 120 cm high plant with an erect stem. The stem has irregularly
bifurcated, thickened nodes. The leaves are alternate and indent-pinnatifid. The
upper leaves are pinnatisect, dull green above, seagreen beneath. The plant
contains a dark-yellow latex.
CHARACTERISTICS: Celandine has a hot
and bitter taste. The latex has a narcotic fragrance.
HABITAT: Celandine is found
throughout Europe and the temperate and subarctic regions of Asia.
PRODUCTION: Celandine herb
consists of the dried, above ground parts of Chelidonium majus gathered during
flowering season. The herb is collected in the wild during the flowering season
and dried at high temperatures. Greater Celandine root is the root, harvested
between August and October, of Chelidonium majus. The herb is gathered in uncultivated
regions and harvested commercially.
OTHER NAMES: Tetterwort
SPECIES (FAMILY)
Chelidonium
majus L. (Papaveraceae)
SYNONYM(S)
Common celandine, garden celandine, swallow wort. Greater celandine
should not be confused with Lesser celandine (Ranunculus ficaria L.,
Ranunculaceae) which is unrelated.
ORIGIN
Celandine is a member of the
poppy family found in Asia, North America, and Europe.
PHARMACOPODIAL AND OTHER MONOGRAPHS
BHMA 2003(G66)
BP 2007 (herb) (G84)
Complete German Commission E (G3)
ESCOP 2003 (G76)
Martindale 35th edition (G85)
Ph Eur 2007 (aerial parts) (G81)
LEGAL CATEGORY (LICENSED PRODUCTS)
Greater
celandine is not on the GSL. Chelidonium majus is listed in Parts 2 and 3 to
the Medicines (Retail Sale or Supply of Herbal Remedies) Order 1977 (Statutory
Instrument 1977/2130) which restricts its sale or supply to that by a
registered pharmacist from a registered pharmacy, or that by a herbal
practitioner in response to a one-to-one consultation, provided maximum daily
dosage is not exceeded.(1)
CONSTITUENTS
The
plant is particularly well known for the presence of alkaloids which are
located in laticiferous vessels. The latex is yelloworange due to the presence
of benzophenanthridine and protoberberine alkaloids.
AERIAL PARTS
Acids Chelidonic,
malic, citric;(G75) caffeic (0.4%), ferulic (0.02%), p-coumaric (0.06%),
gentisic and p-hydroxybenzoic (traces, < 0.01%).(2)
Hydroxycinnamic acid derivatives (-)-2-(E)-caffeoyl-D-glyceric acid, (-)-4-(E)-caffeoyl-L-threonic
acid, (-)-2-(E)-caffeoyl threonic acid lactone, (þ)-(E)-caffeoyl-L-malic acid).(2)
Alkaloids Benzylisoquinoline
type, 0.1–1%.(G75) More than 20 have been identified including
benzophenanthridines (e.g. chelerythrine, chelidonine, sanguinarine, isochelidonine),
protoberberines (e.g. berberine, coptisine, sylopine), protopines (e.g. protopine).(3,
G75)
Others A
saponin, carotenoids,(G75) a phytocytostatin (chelidocystatin),(4) flavonoids.(2,
G75)
ROOT
Alkaloids Benzylisoquinoline
type, up to 3%,(G75) including benzophenanthridines (e.g. chelerythrine,
sanguinarine, chelidonine (0.2–0.4%)), protoberberines (e.g. coptisine),(5) protopines
(e.g. protopine, cryptopine,(6) a-allocryptopine =b-homochelidonine (0.01–0.06%)).
Others Choline,
histamine, tyramine, saponins, flavonol, chelidoniol, vitamin C, carotene.(6)
Sap (from leaves/roots)
Glycoproteins,
including a lectin.(7–9) In addition to the above, the alkaloids
(-)-turkiyenine(10) and (þ)-norchelidonine(11) have been isolated from material
comprising the whole plant.
Quality of Plant Material and Commercial
Products
The European Pharmacopoeia defines greater celandine as consisting
of the dried aerial parts collected during flowering and containing not less
than 0.6% of total alkaloids, expressed as chelidonine and calculated with
reference to the dried drug.(G81)
The alkaloids are found in both the aerial parts and the roots, although
there are differences in the total alkaloid content and the relative
proportions of the individual alkaloid constituents.(12) The concentrations of
the alkaloids chelerythrine, chelidonine, coptisine and sanguinarine in the latex
undergo daily variations, reaching a maximum in the summer in the evening and
in the middle of the day in the winter.(13) The increases in concentration during
the day are probably due to light and temperature, and decreases in
concentration during the night are probably due to catabolism rather than
translocation.(13) In contrast, the concentration of berberine appears to be
relatively stable.
ACTIONS AND
PHARMACOLOGY
COMPOUNDS:
CELANDINE HERB
Isoquinoline
alkaloids of the protoberberine type: including coptisine (main alkaloid),
berberine
Isoquinoline
alkaloids of the benzophenanthridine type: including chelidonine,
sanguinarine, chelerythrine
Isoquinoline
alkaloids of the protopine type: including protopin, cryptopine
Caffeic acid
derivatives: including
2-(-)-coffeoyl-D-glyceric acid, coffeoyl-L-malic acid
USES
USES
Flowers and leaves of celandine are used to treat
spastic conditions of the gastrointestinal tract. Celandine is also used as a
liver and gallbladder tonic, to stimulate digestion, and to decrease infl
ammation. Roots of celandine are used to treat irregular menses and to decrease
pain of toothache, tooth extraction.
INVESTIGATIONAL
USES
Researchers are experimenting with the use of celandine
to strengthen the immune system and to treat cancer and AIDS.
FOOD USE
Greater celandine
is not used in foods.
HERBAL USE
Greater
celandine is stated to have antispasmodic, laxative, diuretic and alterative
properties.(G34, G49) It has been used traditionally in Western countries in
eczema and scurvy, as a cholagogue, in jaundice, gall bladder and biliary
diseases, and in preparations intended to remove obstructions of the liver and
gall bladder.(G34) The German Commission E approved greater celandine herb for
use in spastic discomfort of the bile ducts and gastrointestinal tract.(G3) Topical
preparations of the roots and aerial parts have been used in the treatment of
piles.(G34) The fresh latex has been used externally for the treatment of warts
and other skin conditions, such as corns, Tinea infections, eczema, and tumours
of the skin.(G66)
Figure 1. Greater
celandine (Chelidonium majus).
Figure 2. Greater
celandine – dried drug substance (herb).
Figure 3 Greater
celandine – dried drug substance (root).
ACTIONS
Antispasmodic
Action
In studies using frogs and mice, a celandine extract reduced
gastralgia and pain from gastric ulcers. Chelidonium has been shown to stimulate
bile fl ow when tested in guinea pigs (Rentz, 1948). It also has been shown to
relieve histamine-induced spasms in guinea pigs (Kustrak et al, 1982).
Nonspecifi c
Immune Stimulation
Celandine may act as a chemoprotective agent for
stomach cancer in humans. One study using 6-week-old rats showed that celandine
inhibited glandular stomach carcinogenesis (Kim et al, 1997). One celandine product
that is used in Europe but is not approved in the United States is Ukrain, which
is reported to be an antitumor product that acts by inhibiting RNA and DNA
replication (Ukranian Anticancer Institute, 1997; Habermehl et al, 2006).
Antimicrobial
Action
Several research articles have discussed the powerful
antimicrobial effects of celandine. Its effectiveness has been demonstrated
against Candida
pseudotropicalis, Microsporum
gypseum, Microsporum canis, Trichophyton mentagrophytes, Epidermophyton fl occosum, and Streptococcus mutans (Cheng et al, 2006) using herbs gathered during the fall
harvest (Vukusic et al, 1991). The strength of the herb varies depending on the
season of harvest.
PHARMACOLOGICAL ACTIONS
Several
pharmacological properties, including antispasmodic, choleretic,
anti-inflammatory, cytotoxic and antimicrobial activities, have been described
for preparations of C. majus following preclinical studies, providing some
supporting evidence for the traditional uses. However, there has been little rigorous
clinical investigation of C. majus and further studies are required to determine
its clinical efficacy and safety.
IN-VITRO AND ANIMAL STUDIES
Pharmacokinetics
No information on the pharmacokinetics of constituents following ingestion of
C. majus preparations was found. However, there is a limited amount of data on
the pharmacokinetics of individual constituents found in C. majus. In a
randomised controlled experiment involving swine fed sanguinarine and
chelerythrine (isolated from Macleya cordata (Wild.), Papaveraceae) in their
feed (mean daily intake 0.1 or 5 mg/kg body weight), or a standard diet, for 90
days, plasma concentrations of the alkaloids remained constant during the study
when assessed at days 30, 60 and 90,(15) although data to support this were not
provided in a report of the study. At the 90-day time point for both groups of
animals fed the alkaloids (i.e. 0.1 or 5 mg/kg body weight daily), sanguinarine
was detected in plasma, faeces and all tissues tested (liver, gingival, tongue,
stomach, intestine) with the exception of muscle tissue. Mean (standard deviation,
SD) concentrations (ng/g) in plasma were 4 (1) and 108 (4) and in faeces 1180
(72) and 16 110 (2604) for the low and high intakes of alkaloids, respectively.
Chelerythrine was detected in plasma (high alkaloid intake only), faeces,
liver, gingival and intestinal tissues. Mean (standard deviation, SD)
concentrations (ng/g) in plasma were 24
(4) (not detected in low alkaloid intake group) and in faeces 834 (120) and
8412 (1705) for the low and high intakes of alkaloids, respectively. These
results indicate that, in swine, sanguinarine and chelerythrine are mostly
excreted in the faeces and that a small proportion is absorbed and retained to
different extents by different tissues.(15)
Antispasmodic activity Antispasmodic
activity has been documented for an aqueous-methanolic extract of the flowering
aerial parts of C. majus and for the isolated constituents coptisine and
(þ)-caffeoylmalic acid following in vitro experiments involving isolated rat
ileum.(16) The extract (containing 0.81% alkaloids, 2.00% flavonoids, 1.20% hydroxycinnamic
acid derivatives and 0.06% (þ)-caffeoylmalic acid) displayed a mean (standard
error of mean; SEM) antispasmodic activity of 12.7% (4.0) relative to that of
control (acetylcholine), whereas values for coptisine at a concentration of 1.0
_ 10–5 g/mL organ bath and (þ)-caffeoylmalic acid 2.5 _ 10–5 g/mL organ bath
were 16.5 (3.0) and 6.9 (standard error = 2.6), respectively, indicating that
these two constituents contribute to the total antispasmodic activity of the
extract. A lower concentration of coptisine (0.5 _ 10–-5 g/mL organ bath) did
not exhibit any statistically significant antispasmodic activity,(16) although
no p values for this, or any of the other results, were given.
In isolated
guinea-pig ileum, two hydroalcoholic (ethanol 70% w/w) extracts of C. majus
herb (at a concentration of 5 _ 10–4 g/ mL organ bath for both) relaxed
barium-chloride (10–6 g/mL)-induced contractions: mean (SEM) per cent
relaxation values were 53.5 (4.1) and 49.0 (3.7), for extracts one and two,
respectively.(17) The alkaloid content, determined by high-pressure liquid chromatography,
for extract one was chelidonine 0.38%, protopine 0.41% and coptisine 0.32% and
for extract two, 0.59%, 0.48% and 0.26%, respectively. Mean (SEM) per cent
relaxation values for the individual constituents chelidonine (both at a concentration
of 1 _ 10_5 g/mL organ bath) and protopine were 68.8 (11.2) and 54.8 (5.8),
respectively, whereas coptisine (up to 3 _ 10_5 g/mL) was ineffective. Values
for papaverine hydrochloride (1 _ 10_5 g/mL) under the same conditions were
87.2 (7.4). Further experiments using the two extracts and the individual alkaloids
produced concentration-dependent reductions in carbachol- and
electric-field-induced contractions. Together, these results indicate that the
antispasmodic effects of C. majus herb preparations comprise both musculotropic
and neurotropic mechanisms.(17)
In vitro studies
have demonstrated effects of an extract of C. majus herb and certain
constituent alkaloids at GABAA receptors. In radioreceptor assays, high concentrations
(more than 160 mg/ assay) of a dry ethanolic extract of C. majus herb inhibited
50% of specific [3H]-muscimol binding, whereas at lower concentrations (around
90 mg/assay), specific binding of 115% was observed, indicating induction of
positive co-operation.(18) The alkaloid content (mg/100 mg dry extract) of the
extract was determined as: allocryptopine 0.076, chelerythrine 0.009, protopine
0.465, sanguinarine 0.003 and stylopine 0.154. Further binding studies
indicated that the alkaloids allocryptopine, stylopine and protopine are
responsible for the positive cooperative effect and that, of these, the effect
is mainly due to protopine; the content of chelerythrine and sanguinarine was
considered to be too low to account for the effect.(18) The individual
protopine-type alkaloids protopine, cryptopine and allocryptopine (plant or
synthetic source not stated) enhance [3H]-GABA binding to rat brain synaptic
membrane receptors.(19)
Analgesic activity Several in vitro experiments
have proposed mechanisms for analgesic activity for C. majus, although
analgesic effects for C. majus preparations have yet to be demonstrated in preclinical
(animal) studies. Furthermore, to date, studies have not explored which constituents
of C. majus are involved in these mechanisms. The effects of C. majus on GABA
receptors have also been investigated with respect to determining analgesic
activity. In patch-clamp experiments using fresh periaqueductal grey (PAG) neurons
isolated from rats, an aqueous extract of Chelidonii herba (C. majus, and other
details of authentication and preparation, not specified) applied every two
minutes at concentrations of over 0.3–10 mg/mL elicited chloride ion current in
a concentration-dependent manner.(20) This effect was inhibited in a reversible
manner by the GABAA receptor antagonist bicuculline. Low concentrations of
Chelidonii herba (0.03 and 0.1 mg/mL) inhibited GABA-activated chloride
current; this effect was abolished by the application of the opioid antagonist naltrexone
in a proportion of PAGs and potentiated by naltrexone in other PAGs. As
inhibition of the inhibitory influence of GABA on neurons involved with
descending antinociceptive pathways is a mechanism of action of opioid
analgesics, the inhibitory action of Chelidonii herba on GABA may provide a
mechanism for analgesic activity.(20)
Further
experiments using similar methods have demonstrated that low concentrations (0.03
and 0.1 mg/mL) of an aqueous extract of Chelidonii herba (C. majus, and other
details of authentication and preparation, not specified) suppress
glycineactivated and increase glutamate-activated ion current in PAG neurons.(21)
(Glycine is an inhibitory neurotransmitter and glutamate an excitatory
neurotransmitter, so these effects are suggestive of increased PAG neuronal
excitability and activation of antinociceptive pathways.) In these studies, the
inhibitory effect of Chelidonii herba on glycine-activated ion current was
partially abolished by naltrexone, and the effect on glutamate-activated ion current
was not affected by naltrexone.
Choleretic activity A dry total extract
(extraction solvent 70% ethanol) of the aerial parts of C. majus harvested
during flowering (total alkaloid content 1.6%; caffeic acid esters 1.9%; after hydrolysis:
caffeic acid 1.1%, p-coumaric acid 0.11%, ferulic acid 0.02%) administered at a
concentration of 10 mg/mL/minute for 30 minutes led to a statistically significant
increase in bile flow in isolated perfused rat liver, compared with control (p
< 0.025).(22)
There were no
statistically significant increases in bile flow following administration of a
phenolic fraction (1 mg/mL/minute) and an alkaloid fraction (0.4 mg/mL/minute),
separately and in combination. This suggests that all components of the total extract
are necessary for activity, rather than a single constituent, or group of
constituents.
Anticancer activity There are some
preliminary data suggesting that C. majus herb extract may have preventive
effects against certain cancers, although this requires further research; there
are conflicting results regarding cytotoxic properties and antitumour activity
of C. majus preparations. In an in vivo study, rats were given the carcinogenic
agent Nmethyl- N0-nitro-N-nitrosoguanidine (MNNG; 200 mg/kg body weight by
gavage) and saturated sodium chloride solution (to mimic a high-salt diet), or
0.9% saline, over three weeks, followed by treatment with a water–methanol
extract of C. majus herb (0.1 or 0.2% in the diet for 16 weeks), or no further
treatment; animals were killed at 20 weeks.(23) At the end of the study,
preneoplastic pepsinogen-1-altered glands (PPAGs) in the pyloric mucosa of the
stomach occurred in all groups of rats, but the mean number of
PPAGs was
significantly lower in animals treated with 0.1% C. majus herb extract,
compared with animals treated with MNNG and saturated sodium chloride alone (p
< 0.02). However, there was no statistically significant difference in the
mean number of PPAGs in animals treated with 0.2% C. majus herb extract, compared
with this control group. There were also no statistically significant
differences between any groups in the numbers of animals with papilloma and squamous
cell carcinoma lesions of the forestomach.(23)
An ethanol–water
(1 : 1) dry extract of C. majus roots and rhizomes was inactive in animal
models of leukaemia (L-1210, mice) and carcinosarcoma (Walker 256, rats).(24)
However, the extract did exhibit cytotoxic activity in an assay utilising
Eagle's 9KB carcinoma of the nasopharynx (ED50 < 15 mg/mL). Coptisine chloride
and a second, unnamed, alkaloid were also shown to have cytotoxic activity.(24)
A polysaccharide fraction (CM-Ala) from a water extract of C. majus 'herbs'
inhibited the proliferation of several tumour cell lines in vitro. At a
concentration of 100 mg/mL, CM-Ala showed over 50% cytotoxicity for the P815
and B16F10 cell lines.(25)
Sanguinarine
intercalates with DNA,(26) and structure–activity relationship studies with
alkaloids of the protoberberine and benzophenanthridine types have shown that
intercalation is influenced by substitutions on rings C and D of the alkaloid molecules.(27)
The antiproliferative effects of C. majus have been explored in vitro in
studies using a rapidly multiplying human keratinocyte cell line (HaCaT cells).
C. majus herb dry extract (containing 0.68% alkaloids, calculated as
chelidonine) inhibited HaCaT cell growth, determined by direct counting of
cells, with an IC50 value of 1.9 mmol/L. The alkaloids sanguinarine, chelerythrine
and chelidonine gave IC50 values in the micromolar range (0.2, 3.2 and 3.3
mmol/L, respectively). The potency of sanguinarine was similar to that of the
antipsoriatic agent anthralin (IC50 = 0.7 mmol/L), whereas berberine showed a
low potency (IC50 = 30mmol/L).(28) Further work (measurement of lactate
dehydrogenase release into the culture medium as an indicator of plasma membrane
damage) indicated that the mechanism of action of C. majus extract was due to
cytostatic, rather than cytotoxic, activity. A substantial amount of preclinical
research has explored the effects of a preparation (Ukrain) comprising a
semi-synthetic thiophosphoric (triaziridide) derivative of the purified
alkaloid chelidonine isolated from C. majus. The molecule is reported to be a
trimer of chelidonine, with the alkaloid linked to thiophosphoric acid; the
chemical name of this preparation has been stated to be Tris{2{(5bS-(5ba,6b,12ba))-5b,6,7,12b,13,14-hexahydro-
13-methyl(1,3)-benzo-dioxolo(5,6-c)-1,3-dioxolo(4,5-i)phenanthridinium-6-ol}ethane-aminyl}phosphine
sulphide. 6hydrochloride.(29) However, chemical analyses of Ukrain using a
range of techniques were unable to confirm the existence of the proposed
trimeric molecule and indicated that the preparations tested simply contained a
mixture of C. majus alkaloids, including chelidonine.(30)
It has been
reported that Ukrain has antitumour activity in vitro against various cancer cell
lines and in vivo in several experimental models of cancer, as well as immunomodulatory
properties.(31) It has also been reported to induce cell cycle arrest and
apoptosis in human epidermoid cancer cell lines, but not in normal human
keratinocytes,(32) and to protect normal human fibroblasts, but not various
types of human tumour cells, against ionising radiation in in vitro experiments;(33)
radioprotective effects have also been reported following in vivo (preclinical)
studies.(34) Other properties reported include effects on bone tissue in vivo
(rats).(35)
Subsequent
research in some of these areas has, however, failed to replicate the findings.
In vitro studies using normal, transformed and malignant cell lines have shown
that there was no difference in the effects of Ukrain on cell growth, cell
cycle progression and morphology for the different cell lines, indicating that
there is no selective toxicity towards malignant cells.(36) Other in vitro
research by the same authors has also raised doubts about claims of a lack of
adverse effects with Ukrain.(37)
Immunomodulatory
activity Incubation of spleen cells with protein-bound polysaccharide fractions
from a water extract of C. majus 'herbs' for 5 days increased the lytic
activity of spleen lymphocytes to Yac-1 tumour cells from 0.9% to 30.0% and 34.2%
for the fractions CM-Al and CM-Ala, respectively (p values not given).(25) The
optimal concentration for generation of activated killer cells was 5 mg/mL for
both fractions. Similarly, mouse peritoneal macrophages cultured with CM-Ala
(10–100 mg/ mL) show increased cytotoxicity, compared with control, as determined
by the degree of inhibition of radiolabelled thymidine uptake by tumour cells.
CM-Ala contains around 30% protein and 70% carbohydrate.(25)
Further work
suggested that CM-A1a may have a radioprotective effect in vivo. In experiments
involving mice given CMA1a 50 mg/kg intraperitoneally 24 hours before sublethal
doses of irradiation, platelet numbers were significantly increased in CMA1a treated
mice, compared with control, five days postirradiation, and white blood cell count
was significantly increased in CM-A1a treated mice, compared with control, nine
days postirradiation (p < 0.001 and < 0.01, respectively), indicating haematopoietic
recovery.(38) In other experiments involving mice given lethal doses of
irradiation (9 Gy), the survival rate for mice treated with CM-Ala 50 or 100
mg/kg intraperitoneally before irradiation was 80% at 30 days post-irradiation,
whereas all mice in the control group were dead by day 15 post-irradiation.
Anti-inflammatory activity Various effects
related to antiinflammatory activity have been documented for C. majus extract and
for certain alkaloids isolated from the plant. In in vitro experiments using
mouse peritoneal macrophages, nitric oxide production was significantly
increased when cells were treated with a water extract of C. majus dried
'herbs' (plant part not stated precisely) at concentrations of 0.01, 0.1 and 1
mg/mL together with murine recombinant interferon-gamma (rIFN-g), compared with
treatment with rIFN-g alone (p < 0.05), indicating a cooperative induction
of NO production.(39) NO production in mouse peritoneal macrophages induced by
C. majus extract plus rIFN-g was progressively inhibited by incubation with
increasing amounts (p < 0.05 for 0.01 and 0.1mM, compared with control)
of
NG-monomethyl-L-arginine (NGMMA) and by addition of the antioxidant compound
pyrrolidine dithiocarbamate (PDTC) at a concentration of 100 mM. Furthermore,
incubation of mouse peritoneal macrophages with C. majus extract (1 mg/mL) plus
rIFN-g increased tumour-necrosis-factor-alpha (TNF-a) production in a
concentration-dependent manner; adding the nuclear factor kappa B (NF-kB)
inhibitor PDTC significantly decreased the production of TNF-a, indicating that
C. majus extract increases TNF-a production via NF-kB activation.(39)
Anti-inflammatory
activity has also been described for the alkaloids sanguinarine and chelerythrine
isolated from C. Majus root following studies involving the carrageenan-induced
rat paw oedema test. Greatest inhibition of oedema was observed with subcutaneous
(rather than oral) administration of sanguinarine (rather than chelerythrine) 5
and 10 mg/kg body weight, compared with control (no p values stated).(40)
An extract of C.
majus herb and the alkaloids sanguinarine and chelerythrine (isolated from C.
majus root in this study) inhibited 5-lipoxygenase (5-LO) in isolated bovine
polymorphonuclear leukocytes (PMNL) with IC50 values of 1.9, 0.4 and 0.8
mmol/L, respectively.(41) Sanguinarine and chelerythrine also inhibited 12- lipoxygenase
(12-LO) obtained from mouse epidermis (IC50 = 13 and 33 mmol/L, respectively),
whereas C. majus herb extract (170 mg extract/mL test solution) was inactive.
Chelidonine was inactive against both lipoxygenase enzymes (IC50 = >100
mmol/L for each). The enzymes 5-LO and 12-LO are involved with leukotriene B4
and 12-hydroxyeicosatetraenoic acid synthesis.
Antimicrobial activity A glycoprotein
isolated from the juice of C. majus leaves and roots is active against
drug-resistant staphylococci and enterococci in vitro.(7) Minimum bactericidal concentration
(MBC) values against several strains (including clinical isolates) of
methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant S. aureus
(MRSA), mupirocinresistant MRSA, aminoglycoside-resistant Enterococcus faecalis
and aminoglycoside-resistant E. faecium were 31–125, 31–250, 31–125, 125–500
and 250–500 mg/L, respectively.
Chelerythrine
and the quaternary benzophenanthridine alkaloid fraction (containing chelerythrine
and sanguinarine 7 : 3 with traces of chelirubine) isolated from C. majus root
were ineffective in vitro against several Gram-negative bacterial strains,
including Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae.(40)
In contrast, substantial activity was observed in vitro for the alkaloid
fraction against Gram-positive bacteria, including Staphylococcus aureus,
beta-haemolytic streptococci and alphahaemolytic streptococci, and against
Candida albicans (minimum inhibitory concentration (MIC) values: 5, 10, 20 and
5 mg/mL, respectively). MBC values for the alkaloid fraction against these species
were 40, 10, 40 and >160 mg/mL, respectively. These findings are supported to
some extent by those of other studies. In tests using the liquid dilution
method, crude ethanolic extracts of the aerial parts of C. majus were inactive
against E. coli, P. aeruginosa, Bacillus cereus, Salmonella enteritidis and Candida
albicans.(42) In contrast, an ethanolic extract of C. Majus roots had MIC
values of 15.63, 62.50 and 62.50 mg dry plant material/mL for B. cereus, S.
enteritidis and C. albicans, but was inactive against E. coli and P.
aeruginosa. Berberine chloride and chelerythrine chloride, isolated from another
plant species (Fagara zanthoxyloides, Rutaceae), have activity against S.
aureus, Bacillus subtilis, Streptococcus pneumoniae, E. coli, Klebsiella
pneumoniae, P. aeruginosa, Proteus sp. and C. albicans.(43)
Antifungal
activity in vitro has also been documented for C. majus extracts against
Fusarium strains. In liquid medium assays, a methanolic extract of the whole plant
harvested at the flowering stage appeared to display the greatest antifungal
activity: five days after inoculation, growth of two Fusarium strains tested
was reduced to less than 40% of that seen with control, whereas this was
achieved for only one strain with an ethanolic extract and not at all with an
aqueous extract.(44) F. oxysporum f. sp. cubense was the strain most sensitive
to the methanolic extract, and F. Solani was the most sensitive strain to all three
extracts. In contrast, F. culmorum was insensitive to all three extracts.
Methanolic extracts of C. majus roots achieved greater inhibition of fungal growth
than did methanolic extracts of C. majus shoots: growth of F. oxysporum f. sp.
cubense, F. oxysporum f. sp. melonis and F. solani was reduced to less than 30%
of that seen with control, although growth of F. culmorum was unaffected.
Further
experiments used alkaloids isolated from C. Majus roots and shoots:
chelerythrine and sanguinarine were reported to be active against both F.
solani and F. culmorum, berberine was active against F. solani, and chelidonine
was inactive against both strains.(44) However, data supporting these
statements were not provided in the published report.
Antifungal activity against Cladosporium
herbarum has been described for the alkaloids chelidonine, dihydrochelerythrine
and dihydrosanguinarine isolated from a methanolic extract of C. majus fresh
root: minimum quantities of these compounds for inhibition of growth of C.
herbarum on thin-layer chromatography (TLC) plates were 10, 6 and 4 mg,
respectively.(45) Other work has shown little variation in the antimycotic activity
of C. majus plant material collected during different months. Ethanolic
extracts of C. majus plants collected in late July or early September were
active against Candida pseudotropicalis, M. gypseum, T. mentagrophytes, M.
canis and E. floccosum (zone of inhibition from 21 to 30 or more millimetres in
diameter). Ethanolic extracts of C. majus plants collected in early September
were also active against C. albicans.(46)
Antiviral activity In vitro activity against
adenoviruses and herpes simplex virus type I (HSV-1) has been documented for
the squeezed sap and a sodium chloride extract of the aerial parts of C.
majus.(47) Subsequent bioassay-guided fractionation of extracts of the aerial
parts and the root of the plant produced several fractions of which one in
particular at a concentration of 35 mg/ mL showed antiviral activity when
incubated with cells infected with adenovirus type 12. This fraction also
showed virucidal action against HSV-1, achieving 100% loss of virus infectivity after 90 minutes' incubation, although
adenoviruses types 5 and 12 were less sensitive, retaining 50% infectivity
after 120 minutes' incubation with the fraction. An extract obtained from the 'green'
parts of mature C. Majus plants was found to have inhibitory activity against cysteine,
but not serine, proteinases. The phytocystatin chelidocystatin, isolated from
the extract, inhibited the activity of the cysteine proteinases cathepsin L,
papain and cathepsin H (inhibition constant, Ki values: 5.6 _ 10–11 mol/L, 1.1
_ 10–10 mol/L and 7.5 _ 10–9 mol/L, respectively).(4)
The pure
compound chelidonine has weak inhibitory activity (IC50 around 200 mg/mL)
against human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT),
whereas berberine chloride has moderate inhibitory activity against this enzyme
(IC50 = 100 mg/mL).(48)
Other activities
A liquid alcoholic extract of C. majus herb, containing 0.64 mg/mL total
alkaloids, calculated as chelidonine, protected against indometacin-induced (10
mg/kg body weight) gastric damage in a dose-dependent manner (2.5–10 mL/kg)
when administered orally one hour before indometacin to rats.(49) Doses of C.
majus herb extract of 5 and 10 mL/kg body weight afforded over 50% protection
against the development of ulcers, compared with control.
Antioxidant
activity, determined using the FRAP (ferric reducing and antioxidant power)
method, has been reported for 20% and 40% alcohol–water (type not stated)
extracts of the fresh aerial parts of C. majus collected in Hungary.(50)
CLINICAL STUDIES
Pharmacokinetics
No information relating to the clinical pharmacokinetics of C. majus
preparations was found. Therapeutics Clinical investigation of C. majus
preparations is limited. The few clinical trials available have investigated
the effects of proprietary products containing C. majus, often in combination
with other herbal ingredients, in patients with functional epigastric
disorders. Further investigation of the efficacy and effectiveness of C. majus
preparations is required.
In
a randomised, double-blind, placebo-controlled trial, 60 patients with
functional epigastric complaints, including cramplike pains in the biliary and
gastrointestinal tracts, received tablets containing C. majus extract
(comprising 66.0 to 167.2 mg native dry extract, equivalent to 4mg total
alkaloids, calculated as chelidonine), or placebo, at a dosage of two tablets
three times daily for six weeks.(14) At the end of the study, the reduction in
symptom score (one of the primary outcome variables), assessed using the Zerssen
list, was significantly greater in the C. majus group, compared with the
placebo group (p = 0.003). Also, the physician's assessment of efficacy was
that 18/30 patients in the treatment group were improved or symptom-free,
compared with 8/30 in the placebo group (p =0.0038).(14)
The
effects of a combination preparation (Iberogast) containing extract of C. majus
herb (as well as extracts of bitter candy tuft, chamomile flower, peppermint leaves,
caraway fruit, liquorice root, lemon balm leaves, angelica root and milk
thistle fruit) were investigated in a randomised, double-blind,
placebo-controlled trial involving 60 patients with functional dyspepsia.(51)
Participants received Iberogast, a preparation similar to Iberogast but lacking
bitter candy tuft extract, or placebo, 20 drops three times daily for four
weeks. At the end of the study, participants who received one of the two
combination preparations, compared with those in the placebo group, had a
significant improvement in gastrointestinal symptom scores, one of the primary
outcome variables (p < 0.001). Another double-blind, placebo-controlled
trial assessed the effects of a combination preparation (Cholagogum F
Nattermann) containing dry extracts of C. majus and Curcuma longa in patients
with upper abdominal pain due to biliary system dysfunction.(52) Participants
received the herbal preparation (n =39), or placebo (n = 37), one capsule three
times daily for three weeks. Capsules of the herbal preparation were
standardised to contain 4mg total alkaloids calculated as chelidonine. During
the first week of treatment, reductions in the frequency of cramp-like pain
were reported for both the treatment and placebo groups, although the
difference between the groups was not statistically significant (p = 0.069).
There was, however, a statistically significant difference in the frequency of
episodes of dull/hollow pain between the treatment and placebo groups (p =
0.009).(52)
A
small number of other clinical investigations has explored the effects of a
preparation (Ukrain) comprising a semi-synthetic thiophosphoric (triaziridide)
derivative of the purified alkaloid chelidonine isolated from C. majus (see
Pharmacological Actions). Most of these investigations, typically case series
and small studies of varying methodological quality, have involved patients
with different types of cancer, including lung cancer,(53, 54) Kaposi's
sarcoma,(55) rectal or ovarian cancer,(56) breast cancer,(54) and children from
areas contaminated with radioactive material after the Chernobyl accident with
recurrent bronchopulmonary pathology.(57)
A
systematic review of seven randomised controlled trials of Ukrain in patients
with different types of cancer found that all included trials reported
beneficial effects for Ukrain, but that as most of the trials had methodological
limitations, their results were not definitive and further investigation in the
form of welldesigned randomised controlled trials is required.(58)
In
one study, a randomised, controlled trial involving 90 patients with pancreatic
cancer, participants received gemcitabine alone, Ukrain (NSC-631570) alone, or
gemcitabine followed by Ukrain.(59) Survival rates after six months were
reported to be 26, 65 and 74% for the gemcitabine, Ukrain, and gemcitabine plus
Ukrain groups, respectively (p < 0.01 for gemcitabine plus Ukrain versus
gemcitabine alone). A further study has assessed the effects of Ukrain in
patients with hepatitis C virus infection.(60)
ACTIVITIES
Abortifacient (f; MAD); Alterative (f; CRC; PNC);
Analgesic (1; CRC; PH2; PNC); Anthelminthic (f; MAD); Antiaggregant (1; MAB);
Antianaphylactic (1; PNC); Antibacterial (1; PNC); Anticancer (f; CRC);
Antiherpetic (1; MAB); Antiinflammatory (1; MAB; PNC); Antileukotriene (1;
MAB); Antimutagenic (1; MAB); Antisarcomic (1; MAB); Antiseptic (1; MAB; PH2);
Antispasmodic (1; KOM; MAB; SHT); Antithromboxane (1; MAB); Antitussive (1;
PNC); Antitumor (1; MAB); Antiviral (1; BRU; MAB); Aphrodisiac (f; CRC);
Candidicide (1; HH2; MAB); Cholagogue (1; BRU; PH2; SHT); Cholekinetic (1; MAB;
SHT); Choleretic (1; BRU; MAB; SHT); CNS-Depressant (1; HHB; PH2); Collyrium (f;
CRC); Cytotoxic (1; KOM; MAB; PH2); Deobstruent (f; CRC); Diaphoretic (f; CRC;
MAD); Diuretic (1; MAD; PNC); Expectorant (f; CRC); Fungicide (1; HH2; MAB);
Hepatoprotective (1; CRC; MAB); Hepatotoxic (1; BRU); Hypoglycemic (f; CRC);
Hypotensive (1; KOM; PH2; PNC); Immunostimulant (1; KOM; PH2); Keratopreventive
(1; MAB); Laxative (f; CRC); 5-Lipoxygenase-Inhibitor (1; MAB);
12-Lipoxygenase- Inhibitor (1; MAB); Myocontractant (f; PH2); Myorelaxant (1;
PNC); Protisticide (1; MAB); Sedative (f; CRC; HHB); Trichomonicide (1; MAB);
Uterocontractant (1; PH2); Vulnerary (1; MAB).
INDICATIONS
Adenopathy
(f; JLH); Amenorrhea (f; FAD; MAD); Anaphylaxis (1; PNC); Angina (f; HHB; PHR);
Anorexia (2; PHR); Arthrosis (f; MAD); Ascaris (f; CRC); Asthma (f; MAD; PHR;
PH2); Atherosclerosis (f; HH2; PHR; PH2); Bacteria (1; BRU; PNC); Biliary
Dyskinesia (2; KOM; SHT); Bleeding (f; MAD); Bronchosis (1; MAB; MAD; PNC); Bronchospasm
(1; PNC); Callus (f; CRC); Cancer (1; CRC; MAB; PHR); Cancer, breast (1; CRC;
JLH); Cancer, colon (1; CRC; FNF; JLH); Cancer, jaw (1; CRC; FNF; JLH); Cancer,
kidney (1; CRC; JLH); Cancer, lip (f; CRC; JLH); Cancer, liver (f; CRC; FNF;
JLH); Cancer, lung (1; MAB); Cancer, mouth (1; CRC; FNF; JLH); Cancer, neck (1;
CRC; FNF; JLH); Cancer, nose (1; CRC; FNF; JLH; PH2); Cancer, ovary (f; CRC;
FNF; JLH); Cancer, parotid (1; CRC; FNF; JLH); Cancer, penis (1; CRC; FNF;
JLH); Cancer, pharynx (1; FNF; PH2); Cancer, rectum (1; CRC; FNF; JLH); Cancer,
skin (f; CRC; FNF; JLH); Cancer, spleen (1; CRC; FNF; JLH); Cancer, stomach (1;
CRC; FNF; JLH; PH2); Cancer, testicle (1; CRC; FNF; JLH); Cancer, tongue (1;
CRC; FNF; JLH); Cancer, urethra (1; CRC; FNF; JLH); Cancer, uterus (1; CRC;
FNF; JLH); Candida (1; HH2; MAB); Catarrh (f; HHB; PHR); Cholangosis (2; MAB);
Cholecystosis (2; CRC; HHB; MAB; MAD; PHR; PH2); Cholelithiasis (2; MAB); Colitis
(1; MAB); Colonic Polyposis (2; MAB); Condylomata (1; CRC; HH2; MAB); Corneal Opacity
(f; MAB; MAD); Corn (f; CRC; PNC); Cramp (2; HHB; KOM; MAB; PH2; SHT); Dermatosis
(f; PH2); Dysmenorrhea (1; PHR); Dyspepsia (f; MAB); Eczema (f; CRC; FAD); Edema
(f; MAD; PHR; PH2); Egilops (f; CRC); Enterosis (2; HHB; KOM; MAB); Epithelioma
(f; MAD); Escherichia (1; HH2); Exanthema (f; MAD); Fever (f; CRC; MAD);
Fistula (f; MAD); Freckle (f; CRC; MAD); Frigidity (f; CRC); Fungus (1; HH2;
MAB); Gallstone (f; MAD); Gastrosis (2; BRU; HHB; KOM; MAB); Gastrospasm (2;
KOM); Gonorrhea (f; MAD); Gout (f; CRC; MAD; PHR; PH2); Headache (f; MAB); Hematuria
(f; MAD); Hemorrhoid (1; CRC; FAD); Hepatosis (2; CRC; MAB; MAD; PHR; PH2);
Herpes (1; MAB); High Blood Pressure (1; KOM; PHR; PH2; PNC); Hyperglycemia (f;
CRC); Hypertonia (f; KOM; PH2); Hypochondria (f; MAD); IBS (2; MAB);
Immunodepression (1; KOM; PH2); Induration (f; CRC); Infection (1; HH2; MAB);
Inflammation (1; FAD; MAB; PNC); Insomnia (f; CRC; HHB); Jaundice (f; CRC; HHB;
MAB; MAD; PHR; PH2); Lupus (f; MAD); Malaria (f; MAD); Mastosis (f; JLH; PH2);
Migraine (1; MAB); Myalgia (f; HHB); Mycosis (1; HH2; MAB); Nervousness (f;
CRC; HHB); Neuralgia (f; HHB); Ophthalmia (f; MAD); Pain (1; CRC; HHB; PH2;
PNC); Parotosis (f; JLH); Pertussis (2; MAB; MAD; PNC); Pharyngosis (f; PH2); Phimosis
(f; MAD); Phthisis (f; MAD); Pneumonia (f; HHB; MAD); Polyp (2; CRC; MAB; PHR;
PH2); Psoriasis (1; CRC; MAB; MAD); Rash (f; PH2); Respirosis (f; MAD);
Rheumatism (f; HHB); Rhinosis (f; JLH; PH2); Ringworm (f; CRC; FAD); Scabies
(f; MAD; PHR; PH2); Scurvy (f; CRC); Scrofula (f; CRC); Sore (f; MAD); Shigella
(1; HH2); Splenosis (f; MAD); Staphylococcus (1; HH2; MAD); Stomachache (f; HHB);
Stone (f; HHB; MAD; PHR); Tenesmus (f; MAD); Toothache (f; MAD; PHR); Tuberculosis
(f; MAD); Tumor (1; CRC; MAB); Ulcer (f; CRC); Vaginosis (1; MAB); Vertigo (f; MAD);
Virus (1; BRU; MAB); Wart (f; CRC; HHB; MAB; MAD; PHR); Water retention (1;
MAD; PNC); Wen (f; CRC); Wound (f; CRC; FAD); Yeast (1; HH2; MAB). “Spastic
discomfort of the bile ducts and gastrointestinal tract” (KOM).
INDICATIONS AND USAGE
CELANDINE HERB
Approved by Commission
E:
• Liver and
gallbladder complaints
Unproven Uses: Celandine is
used for spasmodic pain of the bile ducts and the gastrointestinal tract. In
folk medicine, it was used for skin conditions such as blister rashes, scabies and
warts. It is said to be effective in the treatment of cholecystitis,
chloelithiasis, catarrhal jaundice, gastroenteritis, and diffuse latent liver
and gall bladder complaints. It has also been used for intestinal polyps and
breast lumps. Other uses include angina pectoris, cramps, asthma,
arteriosclerosis, high blood pressure, stomach cancer, gout, edema and hepatitis.
Chinese Medicine: Celandine is used for inflammation of the rim
of the eyelid, febrile and ulcerating dermatitis, warts, edema, ascites,
jaundice and stomach carcinomas
CELANDINE ROOT
Unproven Uses: In folk medicine, the fresh roots are
chewed to alleviate toothache, and a powder derived from the roots is applied
to ease tooth extraction.
Chinese Medicine: Preparations are
used for irregular menstruation.
Homeopathic Uses: Chelidonium majus
is used for inflammation, stones and chronic disorders of the hepatobiliary system,
rheumatism and inflammation
of the lungs and pleura.
PRODUCT AVAILABILITY
Extract, tea, tincture
PLANT PARTS USED: Flowers, leaves, roots
DOSAGES
DOSAGES
·
Adult PO: 2-5 g herb (12-30 mg
total alkaloids as chelidonine) daily (Blumenthal, 1998; Jellin et al, 2008)
·
Adult PO tincture: 10-25 drops,
up to 1 ml (1:2 dilution) tid (Moore, 1996)
·
Adult PO fl uid extract: 1-2 ml
tid (Jellin et al, 2008)
·
Adult topical extract: apply to
warts and corns full strength
DOSAGES
Dosages
for oral administration (adults) recommended in older standard herbal reference
texts for the traditional uses are given below.
Spastic discomfort of the bile ducts
and gastrointestinal tract
Aerial parts Daily dosage 2–5 g, equivalent to
12–30 mg total alkaloids, calculated as chelidonine.(G3)
Gall stones, gall bladder and biliary
diseases
Aerial parts 1–2 g dried herb three times
daily.(G49) Modern standard herbal reference texts recommend the following
dosages for oral administration (adults).
Liver and gall bladder disorders,
cramp-like pain of the gall ducts and gastrointestinal tract
Liquid extract 1–2mL of a 1 : 2 preparation daily(G50) or 1–2mL
of a 1 : 1 preparation three times daily.(G76)
Tincture 2–4mL of a 1 : 5 preparation daily(G50) or 2–4mL
of a 1 : 10 preparation three times daily.(G76)
A
clinical trial of a monopreparation containing greater celandine (tablets
containing 66–167.2 mg dry extract (5.3–
7.5
: 1), equivalent to 4mg total alkaloids calculated as chelidonine) tested the
effects of two tablets taken three times daily (equivalent to 24 mg total
alkaloids, calculated as chelidonine) in patients with functional epigastric
complaints.(14)
DOSAGES
·
0.5 g herb single dose (HHB);
3–9 g herb/day (MAB); 2–5 g crude herb (or 12–30 mg total alkaloids) (KOM;
SHT);
·
0.5 g root (PHR); 2–4 ml liquid
extract (PNC); 1–2 ml/day fluid extract (1:2) (MAB); 2–4 ml/day tincture (1:5)
(MAB); 1.8–7.5 g juice (MAD).
DOSAGES
MODE OF ADMINISTRATION: Comminuted and
powdered drug for infusions and decoctions; dried extracts for liquid and solid
medicinal forms for internal use.
PREPARATIONS:
Fluid extract — 1:1 in 25% ethanol.
Tincture — 1:10 in 45% ethanol (BHP83).
Tea — allow 1V2 dessertspoonfuls to draw in
boiling water for 10 minutes.
Infusion — 15 gm dried herb to 1 liter of water,
leave to draw for 15 minutes.
DAILY DOSAGE: The average daily
dose is 2 to 4 gm of drug in liquid or solid extracts, equivalent to 12 to 30
mg total alkaloids calculated as chelidonine; fluid extract, 1 to 2 ml three
times daily; decoction, 3 cups daily; infusion, 3 cups between meals.
STORAGE: Celandine herb
should be protected carefully from light.
CELANDINE ROOT
MODE OF ADMINISTRATION:
Most
standardized and compound preparations contain the extract of Celandine herb;
various homeopathic preparations also contain dilutions of the fresh herb
Greater Celandine.
DAILY DOSAGE: The standard
dose is 0.5 gm of drug.
HOMEOPATHIC DOSAGE: 5 drops, 1
tablet, 10 globules every 30 to 60 minutes (acute) or 1 to 3 times daily
(chronic); parenterally: 1 to 2 ml sc acute: 3 times daily; chronic: once daily
(HAB1).
STORAGE: Preparations
must be stored carefully.
PRECAUTIONS AND ADVERSE REACTIONS
GENERAL: No health hazards
or side effects are known in conjunction with the proper administration of
designated therapeutic dosages. Older scientific literature credits the plant
with toxicity (burning in the mouth, nausea, vomiting,
bloody diarrhea,
hematuria, stupor), but recent studies offer no clear proof of this; animal experiments
yielded no results. No symptoms of inflammation were observed in the eyes of rabbits
following introduction of the chyle. Nevertheless, contact between it and the
eyes should be avoided.
PREGNANCY: Not to be used
during pregnancy.
CELANDINE ROOT
No health
hazards or side effects are known in conjunction with the proper administration
of designated therapeutic dosages. Older scientific literature credits the
plant with toxicity (burning in the mouth, nausea, vomiting, bloody diarrhea,
hematuria, stupor), but recent studies offer no clear proof of this. Animal
experiments yielded no examples of
toxicity.
CONTRAINDICATIONS, INTERACTIONS, AND SIDE
EFFECTS
Class
2b, 2d (AHP). None known (KOM). Not to be used by children (AHP). Canadian
regulations do not allow celandine in food. Australians counsel that it “may
affect glaucoma treatment.” Germans report that it takes more than 500 g
celandine to cause toxic effects in cattle and horses (AHP). Side effects include
dry mouth and dizziness (PNC). Overdoses can cause dizziness, hematuria,
intestinal colic, stomach pain, and urinary urgency (SHT). Consumption of fresh
herb may cause GI distress (AHP). Stem juice allergenic, irritant, and
paralytic (FAD). “Thought to be hepatotoxic”(BRU).
CONTRA-INDICATIONS, WARNINGS
Greater
celandine is contraindicated in patients with biliary obstructions, existing or
previous liver disease.(G76) In view of the evidence of hepatotoxicity, use of
C. majus extracts at dosages higher than those recommended (see Dosage) and/or
for longer periods should be avoided. Monitoring of liver enzyme activity is recommended
for patients using C. majus preparations for longer than four weeks.(G76)
Drug Interactions No interactions have been
documented for C. majus. However, in view of the documented pharmacological effects,
whether or not there is potential for clinically important interactions with
other medicines with similar or opposing effects and used concurrently should
be considered.
Pregnancy and Lactation The safety of C. majus has not been established. In view
of the lack of information on the use of C. majus during pregnancy and lactation,
its use should be avoided during these periods.
CONTRAINDICATIONS
CLASS
2B/2D HERB. Celandine should not be used
during pregnancy and breastfeeding. It should not be given to children.
Celandine should not be given to those with biliary obstruction, glaucoma, or
hepatic disease. If used alone, this herb is for short-term use only; if used
in a formula, it can be used long term (Moore, 1996).
SIDE
EFFECTS/ADVERSE REACTIONS
CNS: Dizziness, drowsiness, fatigue, lethargy, insomnia,
restlessness
CV: Hypotension
GI: Nausea, hepatotoxicity (mild to severe)
GU: Polyuria, polydipsia
INTEG: Stabbing or itching sensation at lesion
EFFECTS: CELANDINE HERB
Celandine has
mild analgesic, cholagogic, antimicrobial,, oncostatic and central-sedative
effects. It also acts as a spasmolytic on smooth muscles. In animal tests,
Celandine is a cytostatic. It also has a nonspecific immune-stimulating effect.
Note: The blood pressure-lowering effects
and the therapeutic efficacy for mild forms of hypertonia (borderline hypertonia)
need further investigation.
COMPOUNDS: CELANDINE ROOT
Isoquinoline
alkaloids of the protoberberine type: including coptisine (main alkaloid),
berberine
Isoquinoline
alkaloids of the benzophenanthridine type: including chelidonine.
sanguinarine, chelerythrin
Isoquinoline
alkaloids of the protopine-type: including protopin, cryptopine
Caffeic acid
derivatives: including
2-(-)-coffeoyl-D-glyceric acid, coffeoyl-L-malic acid
EFFECTS: CELANDINE ROOT
Only
clinical studies and experiments on the fresh plants are available. However,
previous studies have shown that the extract, with an alkaloid content of 80%,
should have similar effects to those of the fresh leaves. These effects include
immobilization in mice, when it was applied subcutaneously and orally. On
rabbit intestines it caused limpness; and in higher doses, tone reduction. When
applied to the rabbit uterus, it caused contraction of the smooth muscle.
Positive inotropic effects were observed in isolated cat and frog hearts; in a
canine heart-lung preparation it stimulated the heart, raised blood pressure
and widened the arteries.
Experimental
data are unavailable, therefore the results must be considered unofficial.
An
oncostatic effect was observed through the cytotoxic results of Eagle's 9 KB carcinoma
of the naso-pharynx in cell cultures.
SIDE-EFFECTS, TOXICITY
There
is a limited amount of information relating to the safety and toxicity of
preparations of C. majus.
CLINICAL DATA
Only limited data relating to safety aspects of C. majus are available
from clinical trials. Such studies in any case are not designed primarily to
assess safety, and generally have the statistical power only to detect common,
acute adverse events. A randomised, double-blind, placebo-controlled trial
involving 60 patients with functional epigastric complaints who received tablets
containing C. majus extract (comprising 66.0 to 167.2 mg native dry extract,
equivalent to 4mg total alkaloids, calculated as chelidonine), or placebo, at a
dosage of two tablets three times daily for six weeks reported a similar number
of adverse events for both groups (three and five for the C. majus preparation
and placebo, respectively).(14) In another double-blind, placebo-controlled trial,
no adverse events occurred in patients (n = 39) with upper abdominal pain due
to biliary system dysfunction who received a preparation (Cholagogum F
Nattermann) containing dry extracts of C. majus and Curcuma longa one capsule (standardised
to contain 4mg total alkaloids calculated as chelidonine) three times daily for
three weeks.(52)
Hepatobtoxicity Several case reports have described hepatotoxic effects,
including severe hepatitis, severe cholestasis and fibrosis, associated with
the use of preparations of C. majus.(61) One report describes ten cases of
acute hepatitis in women who had ingested preparations containing C. majus extract
for one to nine months before the onset of symptoms of hepatotoxicity.(62) In
all ten cases, other common causes for hepatitis were excluded, and liver function
test values before intake of C. majus were normal for the seven patients for
whom these data were available. The ten cases concerned use of five different
German manufacturers' preparations of C. majus, three of which formulations
include only C. majus extract as the active component; such preparations are usually
standardised for content of chelidonine. A mechanism for C. majus induced
hepatotoxicity has not been established, although because of the apparent lack
of a dose-dependent effect and variable latent period in the reported cases, an
idiosyncratic reaction may be the most plausible explanation.(62)
Two further cases describe a 39-year-old woman and a 69-yearold man
who both presented with symptoms of acute hepatitis, including dark brown urine
and jaundice; laboratory tests revealed that both patients had highly elevated
liver function test values.(63) The woman had been taking a preparation
containing C. Majus for four weeks before the onset of symptoms, and the man
had taken capsules containing C. majus (each capsule standardised for 4mg
chelidonine) and Curcuma longa for six weeks before symptom onset; other
possible causes of hepatotoxicity were excluded. Both patients recovered after
stopping treatment with C.majus.
The World Health Organization's Uppsala Monitoring Centre (WHO-UMC;
Collaborating Centre for International Drug Monitoring) receives summary reports
of suspected adverse drug reactions from national pharmacovigilance centres of
over 70 countries worldwide, including the UK. At the end of June 2005, the
WHO-UMC's Vigisearch database contained a total of 47 reports, describing a
total of 147 adverse reactions, for products containing C. majus only as the
active ingredient (see Table 1). All but one (Belgium) of these reports
originated from Germany.(64)
The specific products (manufacturer) associated with the reactions
were: Ardeycholan N (Ardeypharm), two reports; Chol 4000 (Lichtenstein), six
reports; Chol Sabona (Sabona), two reports; Cholarist (Steiner), ten reports;
Gallopas (Pascoe), four reports; Panchelidon (Kanoldt), eight reports;
Panchelidon N (Boots Pharmaceuticals), ten reports; Siosol Febna (one report); celandine/chelidonium
extract (specific product not stated), four reports. In seven cases, the patient
concerned was taking other medicines, although C. majus extract was the sole
suspected drug in five of these seven reports. Six of the total number of reports
provided information on dechallenge; in all six cases, the reaction(s) had
abated on stopping C. majus extract. The outcomes for the 47 reports were stated
as: died (one report); not recovered (six reports); recovered (ten reports);
unknown (30 reports). (These data were obtained from the Vigisearch database
held by the WHO Collaborating Centre for International Drug Monitoring,
Uppsala, Sweden. The information is not homogeneous at least with respect to
origin or likelihood that the pharmaceutical product caused the adverse reaction.
Any information included in this report does not represent the opinion of the
World Health Organization.)
In May 2003, the Complementary Medicines Evaluation Committee,
which advises the Australian Government's Therapeutic Goods Administration, recommended
that preparations of C. majus for oral administration should include on their
label statements advising consumers to use such products only under the
supervision of a healthcare professional, to seek advice from a healthcare
professional before using the product if the potential user has a history of
liver disease, and to stop using C. Majus preparations if symptoms associated
with liver disease occur.(65) Healthcare professionals who identify suspected
adverse drug reactions associated with C. majus preparations should report these
using the appropriate spontaneous reporting form.
Other reactions Contact dermatitis has been reported in a 64- year-old
woman who had used C. majus juice externally to treat warts.(66) Within a few
hours of applying the preparation, the woman experienced severe itching and
erythema, with papules, at the application site. Six weeks later, the woman
experienced the same symptoms after applying the juice to a facial wart. In
both instances, the reaction resolved within a few days without treatment.
Subsequently, the woman displayed positive reactions to patch testing with C.
majus juice and to extracts of C. Majus branch, stem and root at concentrations
of 0.1, 1 and 10 mg/ mL.(66) A case report describing this reaction does not
state the source of the plant material and authentication and phytochemical analysis
of the materials do not appear to have been undertaken.
PRECLINICAL DATA
In vitro inhibition of rat liver alanine aminotransferase (ALT)
has been described for the benzophenanthridine alkaloids sanguinarine and
chelerythrine. Sanguinarine was a more powerful inhibitor than was
chelerythrine (ID50 values: 3.4 _ 10–6mol/L and 4.0 _ 10–6mol/L,
respectively).(67) In other experiments, sanguinarine, chelerythrine, berberine
and coptisine inhibited oxygen uptake by mitochondria obtained from mouse
liver, whereas chelidonine had virtually no effect.(68)
In a randomised controlled experiment, swine were fed sanguinarine
and chelerythrine (isolated from Macleya cordata (Wild.), Papaveraceae) in
their feed (mean daily intake 0.1 or 5 mg/ kg body weight), or a standard diet,
for 90 days (n = 3 per group).(15) At the 30-, 60- and 90-day assessments,
there were no statistically significant differences between the alkaloid-fed groups
and the control group with respect to the following haematological and
biochemical parameters: haemoglobin, haematocrit, erythrocyte and leukocyte
counts, total protein, albumin, glucose, cholesterol, triacylglycerols,
creatinine, urea, total bilirubin and alkaline phosphatase (ALP). However, at
day 90, statistically significant differences were observed for ALT, aspartate
aminotransferase (AST) and gamma-glutamyl transferase (GGT) for the higher
alkaloid intake group, compared with control and, for GGT, for the lower
alkaloid intake group (p < 0.05 for all).(15)
There are conflicting results regarding possible cytotoxicity of
C. majus preparations (see Pharmacological Actions, In-vitro and animal
studies, Anticancer activity). Sanguinarine–intercalates with DNA.(26)
Table 1 Summary
of spontaneous reports (n =
47) of adverse drug reactions associated with single-ingredient Chelidonium majus preparations held in the
Vigisearch database of the World Health Organization’s Uppsala Monitoring
Centre for the period up to end of June 2005.(a, 64)
Key:
GT = glutamyl transferase; LDH = lactate dehydrogenase; SGOT = serum
glutamic-oxaloacetic transaminase (= aspartate transaminase/aspartate aminotransferase);
SGPT = serum glutamate pyruvate transaminase (= alanine transaminase/alanine
aminotransferase)
a Caveat
statement. These data were obtained from the Vigisearch database held by the
WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden.
The information is not homogeneous at least with respect to origin or
likelihood that the pharmaceutical
CLIENT CONSIDERATIONS
ASSESS
·
Assess the reason the client is
using celandine medicinally.
·
Assess for hepatotoxicity
(increased hepatic function test results, clay-colored stools, right
upper-quadrant pain, jaundice). If present, discontinue use of celandine.
ADMINISTER
·
Instruct the client to store
celandine in a cool, dry place, away from heat and moisture.
TEACH
CLIENT/FAMILY
·
Caution the client not to use
celandine in children or those who are pregnant or breastfeeding until more
research is available.
·
Teach the client to recognize
the symptoms of hepatotoxicity: clay-colored stools, jaundice, and right
upper-quadrant pain.
EXTRACTS
Extracts,
as well as chelidonine, chelerythrine, protopine, and sanguinarine have
antibacterial and antitussive activities (PNC). Chelidonine lowers arterial
blood pressure, relaxes smooth muscle spasms and bronchial spasm, increases
urine production, and delays or inhibits the development of anaphylactic shock in
vivo. Alpha-allocryptopine, chelidonine, and sanguinarine have in vivo analgesic
activities (PNC). LD50 (decoction) 9500 mg/kg ipr mouse (MAB); LD50 (alkaloids)
300 mg/kg scu mouse (MAB).
Barnes, J., Anderson, L. A., and Phillipson, J. D.
2007. Herbal Medicines Third Edition. Pharmaceutical
Press. Auckland and London.
Duke, J. A. with Mary Jo Bogenschutz-Godwin, Judi
duCellier, Peggy-Ann K. Duke. 2002. Handbook of Medicinal Herbs 2nd
Ed. CRC Press LLC. USA.
Gruenwald, J., Brendler, T., Jaenicke, Ch. 2000. PDR for
Herbal Medicines. Medical Economics Company, Inc. at Montvale,
NJ 07645-1742. USA
Linda S-Roth. 2010. Mosby’s Handbook Of
Herbs & Natural Supplements, Fourth Edition. Mosby Elsevier. USA
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