HERBAL
MEDICINAL
PLANT
----------------------------------------------------------
ST. JOHN’S WORT
Hypericum perforatum L. ++
(Raised from CRC)
BY
RETTODWIKART THENU
--------------------------------------
ST.
JOHN’S WORT
(saynt
jahnz wawrt)
Hypericum perforatum L. ++
(Raised from CRC)
SUMMARY AND PHARMACEUTICAL COMMENT
The chemical composition of St John’s wort has been well studied.
Documented pharmacological activities provide supporting evidence for several
of the traditional uses stated for St John’s wort. Many pharmacological
activities appear to be attributable to hypericin, hyperforin and/or the
flavonoidconstituents; hypericin is also reported to responsible for the photosensitive reactions
that have been documented for St John’s wort. With regard to the antidepressant
effects of St John’s wort, hyperforin rather than hypericin, as originally thought,
has emerged as one of the major constituents responsible for antidepressant
activity. However, further research is required in order to determine which
other constituents contribute to the antidepressant effect.
There are now over forty clinical trials of H. Perforatum preparations involving
patients with different types of depression, although a rigorous systematic review and
metaanalysis found that overall
the evidence is inconsistent and complex. H. perforatum preparations
and standard antidepressant
agents appear to show similar effects, whereas H. perforatum preparations have only small benefits
over placebo in patients
with major depression; in older studies in patients with mild-to-moderate depression, H. Perforatum preparations appear to be
of more benefit than placebo. A previous
systematic review/meta-analysis, for which inclusion criteria for trials were slightly less strict, found evidence
from randomised,
controlled trials that St John’s wort preparations were more efficacious than placebo in the treatment of
mildto-moderately severe depression.
An important point is that there is heterogeneity not only among
the trials and their results, but also among the different manufacturers’
products tested. Products are not necessarily equally effective, and the
results of the analyses above should not be extrapolated to other H. perforatum preparations, which may
differ considerably in their pharmaceutical quality. These comments also imply
that the need for dose adjustment should be considered for patients changing
from one St John’s wort product to another.
Clinical safety data from randomised controlled trials, systematic
reviews and meta-analyses of trials, and postmarketing surveillance and other
observational studies, indicate that certain St John’s wort extracts are
well-tolerated when taken at recommended doses for shorter periods of time (around
eight weeks). Certain St John’s wort preparations do appear to have a more
favourable safety profile, at least with short-term use, than standard
antidepressants, particularly older antidepressant agents, a factor that may be
important in patients continuing to take medication. Data from the small number
of longer-term (one year) studies support the tolerability of certain St John’s
wort extracts, although further investigation of long-term use is warranted.
Adverse events/effects reported are generally mild and most commonly gastrointestinal
symptoms. These observations, however, are based on data collected in the
settings of formal randomised or observational studies, and usually where H. Perforatum has been prescribed under
the supervision of a physician. The safety of St John’s wort products taken as
self-treatment without supervision by a healthcare professional requires further
study.
The risk of photosensitive reactions following oral ingestion of
St John’s wort preparations appears to be low, since serum and skin
concentrations of hypericin (the photosensitising constituent) after oral
administration of recommended doses are below 100 ng/mL, although caution is
advised as it is possible that there may be unusual absorption of hypericin in some
individuals and in fair-skinned individuals and after extended periods of solar
irradiation, there may be increased susceptibility to the photosensitising
properties of hypericin. Likewise, the phototoxic potential of topical
application of H. perforatum preparations appears to be
low, although caution is necessary, particularly as hypericin may penetrate
more highly through broken or lesional skin, and there may be increased susceptibility
to the photosensitising properties of hypericin in fair-skinned individuals and
after extended periods of solar irradiation.
There are important pharmacokinetic interactions between St
John’s wort preparations and certain other medicines, leading to a loss of or
reduction in the therapeutic effect of those medicines, and potential for
important pharmacodynamic interactions, which could lead to enhancement or
antagonism of pharmacological effects, depending on the activities of the
co-administered medicines.
Drugs that may be affected by pharmacokinetic interactions include
certain anticonvulsants, ciclosporin, digoxin, indinavir (and other HIV
protease inhibitors), oral contraceptives, theophylline and warfarin, and by
pharmacodynamic interactions, triptans and selective serotonin reuptake inhibitors.
Advice is that patients taking these medicines should stop taking St John’s
wort preparations, generally after seeking professional advice, as dose
adjustment may be necessary.
There is evidence that pharmacokinetic interactions arise through
induction, by constituents of St John’s wort preparations, of the cytochrome
P450 (CYP) drugmetabolising enzyme CYP3A4 (and possibly certain other CYP enzymes),
and through effects on P-glycoprotein (a transport protein). As CYP3A4 is
involved in the metabolism of many drugs, and as P-glycoprotein is involved
widely in drug transport, it is possible that St John’s wort preparations
interact with other medicines in addition to those already identified. In view
of the lack of toxicity data, St John’s wort preparations should not be used
during pregnancy and lactation. Pharmacists and other healthcare professionals
should be mindful that patients at all levels of health care may self-treat with
herbal and other non-prescription medicines, and that use is not necessarily
disclosed to healthcare professionals. St John’s wort products may be used in
addition to, or instead of, standard antidepressants and other conventional
medicines.
The prevalence of concurrent use of St John’s wort products and
antidepressant medicines may be particularly high among certain subgroups of
patients with depression: a crosssectional survey involving members of a
depression self-help group reported that over 50% were using St John’s wort and
that, among these individuals, the concurrent use of St John’s wort and
conventional antidepressants was 29% (see Sideeffects, Toxicity, Clinical data).
DESCRIPTION
TRADE NAMES
St. John's Wort
(available from numerous manufacturers and as combination product), St. John's
Wort Extract, Alterra, Advanced St. John's Wort, St. John's Wort Herb, St.
John's Wort High Potency, St. John's Wort Preferred, St. John's Wort
Standardized Extract, St. John's Power Time Release, Mood Support, KIRA,
Centrum St. John's Wort, Hypericalm, St. John's Powder 0.3%, Tension Tamer,
Hypercalm, St. John's Powder, St. John's Extra Strength
MEDICINAL PARTS: The medicinal
parts include the fresh buds and flowers separated from the inflorescences, the
aerial parts collected during the flowering season and dried, and the entire
fresh flowering plant.
FLOWER AND FRUIT: The
golden yellow flowers are in sparsely blossomed terminal cymes. The 5 sepals
are ovate-lanceolate to lanceolate and very pointed. The sepals are also
smooth, serrate at the tip, and marked by many light and dark glands. The 5
petals and numerous stamens are fused into 3 bundles. The ovary has a broad or
narrow oval shape. The fruit is a 3- valvular capsule, which is triangular and
oval. The seeds are cylindrical and shortly pointed at both ends. The seeds are
1 to 3 mm long, either black or dark brown, and covered in small warts.
LEAVES, STEM AND ROOT: The perennial
plant is 30 to 60 cm and contains a long-living branched root and rhizome,
which tapers toward each end. The reddish stem is erect, includes 2 raised
edges and can reach 100 cm in height. The oval-shaped, translucent, punctate
leaves are attached directly at the base and often covered in black glands.
CHARACTERISTICS: The flowers
release an odorless red juice when squeezed, which tastes weakly bitter and
irritating.
HABITAT: The plant is
indigenous to all of Europe, western Asia and northern Africa. It has been
introduced to eastern Asia, Australia and New Zealand, and it is cultivated in Poland
and Siberia.
PRODUCTION: St. John's Wort
consists of the dried aboveground parts of Hypericum perforatum gathered during
flowering season. The herb is cut at the start of the flowering season and
dried quickly in bunches in order'to preserve the oil and secreted contents.
NOT TO BE CONFUSED WITH: The plant may be
mistaken for other Hypericum species, such as Hypericum barbatum, Hypericum hirsutum, Hypericum maculatum, Hypericum montanum
and Hypericum tetrapterum.
OTHER NAMES: Hardhay, Amber,
Goatweed, Klamath Weed, Tipton Weed, Saint John's Word, St. Johnswort, Mellipertuis, Rosin Rose, Witches’ Herb
COMMON NAMES
Balsana
Arabic Countries
Balsana
India
Bassant
India
Blutkraut
Germany
Corazancillo
Spain
Corazonci
llo Argentina
Dendhu
India
Devil's
scorge Europe
Eisenblut
Europe
Flor
De Sao Joao Madeira
Fuga
daemonum Europe
Hartheu Europe
Heofariqon
Arabic Countries
Herba
de Millepertuis France
Herba
de Saint Jean France
Herrgottsbl
ut Germany
Hexenkraut Europe
Hierba
De San Juan Spain
Hipericao
Madeira
Hiperico
Argentina
Hipericon
Argentina
Hi
peri con Spain
Lperico Italy
Johan
is kraut Germany
Johannesort
Sweden
Johanniskraut
Europe
Liebeskraut
Europe
Pelatro
Italy
Pelicao
Madeira
Perforata
Italy
Pinillo
de Oro Spain
Qian
Ceng lou China
Saint
John's wort Greece
Sanjuanera
Spain
Sint-Janskruid
Netherlands
St.
John's Worth Canada
St.
John's Worth Estonia
St.
John ' s Worth Germany
St.
John's Wort USA
St.
John's Wort USSR
Tenturotou
Turkey
Teufelsflucht
Europe
Toutsaine
France
Witcher's
herb Europe
Zwieroboij
USSR
SPECIES (FAMILY)
Hypericum
perforatum L. (Guttiferae/Clusiaceae)
SYNONYM(S)
Hypericum, Hypericum
veronense Schrank, H. noeanum
Boiss., Millepertuis
ORIGIN
H. perforatum
is native to Europe, Western Asia, North Africa, Madeira and the Azores.
It
now grows in parts of North America and Australia.
PHARMACOPODIAL AND OTHER MONOGRAPHS
American Herbal Pharmacopoeia(G1)
BHMA 2003(G66)
BHP 1996(G9)
BP 2007(G84)
Complete German Commission E(G3)
ESCOP 2003 (G76)
Martindale 35th edition(G85)
Ph Eur 2007(G81)
USP29/NF24(G86)
WHO volume 2 (2002)(G70)
LEGAL CATEGORY (LICENSED PRODUCTS)
GSL (for external use only)(G37)
CONSTITUENTS
See
also References 1 and 2 and General References G1 and G2.
Anthraquinone derivatives (naphthodianthrones) Hypericin,
pseudohypericin and isohypericin; protohypericin and protopseudohypericin (biosynthetic
precursors of hypericin and pseudohypericin, respectively) are present in fresh
material.
Cyclopseudohypericin is also stated to
be present. The hypericin content (approximately 0.1–0.15%) includes both
hypericin and pseudohypericin(3) and is sometimes referred to as 'total hypericins'.
Flavonoids
Flavonols (e.g. kaempferol, quercetin), flavones (e.g. luteolin) and glycosides
(e.g. hyperoside, isoquercitrin, quercitrin, rutin), biflavonoids including
biapigenin (a flavone) and amentoflavone (a biapigenin derivative)(4, 5) and
catechins (flavonoids often associated with condensed tannins).(6, 7) The
concentrations of rutin, hyperoside and isoquercitrin have been reported as
1.6, 0.9 and 0.3%, respectively.(8)
Prenylated phloroglucinols
Hyperforin (2.0–4.5%) and adhyperforin (0.2–1.9%).(6, 9, 10,G1)
Tannins 8–9%.
Type not specified. Proanthocyanidins (condensed type) have been reported.(G2)
Other phenols
Caffeic, chlorogenic, p-coumaric, ferulic, phydroxybenzoic and vanillic acids.
Volatile oils 0.05–0.9%.
Major component (not less than 30%) is methyl-2-octane (saturated hydrocarbon);
others include n-nonane and traces of methyl-2-decane and n-undecane (saturated
hydrocarbons),(11) a- and b-pinene, a-terpineol, geraniol, and traces of
myrcene and limonene (monoterpenes), caryophyllene and humulene
(sesquiterpenes).(12, 13)
Other constituents
Acids (isovalerianic, nicotinic, myristic, palmitic, stearic), carotenoids,
choline, nicotinamide, pectin, bsitosterol, straight-chain saturated
hydrocarbons (C16, C30)(11, 14) and alcohols (C24, C26, C28).(11, 14)
Figure 1. St. John's Wort (Flower and Dried Herb)
CHEMICAL
CONSTITUENTS
(ppm
unless otherwise indicated)
Adhyperfolin:
Fl, Fr HPOB&
Alkanes
(C28,C30): Aer HPom
Alkanols
(C24,C26,C28): Aer HPom
Amentoflavone:
Aer 0.0267% HP0195
Amyrin,beta,
Aer HP0222
Apigenin:
Aer HP0152
Apigenin,
1 (3)-11 (8)-BI: FI HP0179
Apigenin,BI:
Aer HP0152
Apigenin,
1 (3)-11(8)-BI: Aer 72.5 HP02oo
Ascorbic
acid: Lf HPOll &
Biapigenin,
1-3 11-8: Aer 0.01 % HP0195
Cadiforin,hydroperoxy:
Aer 5.6 HP0137
Caffeic
acid: PI HP0214, Aer 0.1 % HP0234
Carotene,beta:
Aer 12.1 mgi% HP0122
Caryophyllene:
EQ HPom
Catechin,(+):
p1 HP0221 ,HP02o&
Catechin,epi(-):
PI HP0199
Chlorogenic
acid: PI HP 0199
Choline:
Aer 0.1 % HP0107
Cuprenene,alpha:
Lf EQHPOBB
Cyclopseudohypericin:
P1 HP0213, HP01BO
Cysteine:
PI HP0218
Decanal,n:
E QHPOB 3
Decane,2-methyl:
Aer HP013 4
Essential
oil: Aer 0.07-0.08% HP010B
Flavone:
Aer HP 0165
Gallic
acid: PI HP 0214
Glutamine:
PIHP 0218
Heptane,2-4-dione,5-methyl:
Lf EQHPOBB
Heptane,2-4-dione,6-methyl:
Lf EQHP0138
Hexacosan-1-ol:
Lf HP0220
Humulene:
EQ HPD133
Hypercinin,cyclo-pseudo:
Aer HPOl63
Hyperfolin:
Lf, St HP0139
Hyperfori
n: Aer HP0113, HP0162
Hypericin:
Fl 0.036-0.22% HP0185, Lf
0.195%,
EO 0.22% HPOll 2
Hypericin,proto-pseudo:
PI HPOlao, Fl
0.51% HP0168
Hypericin,proto:
PI HP0180 , Fl 0.182% HP0168
Hypericin,psuedo:
P1 HP0180 , Fl 0.10-
0_58% HPoJas,HP0168
Hyperoside:
P1 HP0130 , Aer 0.5-
4.0% HP0110,HP0242
lmanin:
Aer HPOBl
lshwarane:
Lf EQHPOBS
Kaempferol:
P1 HP0206
Kielcorin:
Rt HP0198
Leucine:
PI HP0218
Limonene:
Aer EQHPOB4
Linoleic
acid: Flowering tops 13% HP0173
Lutein:
FI HPom
Luteoxanthin:
FI HPom
Lysine:
P1 HP0218
Mangiferin:
Aer HP0163
Melatonin:
Fl4.4, Lf 17.5 HP0172
Myrcene:
Aer HP0134
Myricetin:
P1 HP0206
Myristic
acid: FI HPom
Neoxanthin:
FI HPom
Nicotinic
acid: Lf 7.2 HP0103
Nonane,n:
Aer EQ HPOB 4
Novoimanin:
Aer 3-4% HP0121
Octacosan-1-ol:
Lf HPono
Octanal,n:
EQ HPOB3
Octane,2-methyl:
Aer EQ HP0134
Ornithine:
P1 HP 0218
Palmitic
acid: Flowering tops 30.7% HP01 73
Perf
I avit: Aer HPOllS
Phenol:
Aer HP 0201
Phloroglucinol:
Aer HP 0201
Pinene,alpha:
Aer EQ HPOB 4
Pinene,beta:
Aer EQ HPOB 4
Proline:
P1 HP0218
Pyrano(4-3-B)-pyran-5-one,2
(H)-5-(H) 7-
iso-butyl-2-2-dimethyl:
Lf EQ HPona
Pyrano(4-3-B)-pyran-5-one,2(H)-5-(H)
7-
sec-butyl-2-2-dimethyl:
Lf EQ HPona
Pyrocatechol:
Aer HP0201
Pyrogallol:
Aer HP0201
Quercetin:
PI HP0114, HP0211
Quercetin-3
-0-gl ucu ron ide: Aer HP0181
Quercetin-3-0-xyloside:
AerHP0181
Quercetrin:
P1 HP 0169
Quercitin,iso:
PI HP0206
Quercitrin:
P1 HP 0126
Quercitrin,iso:
Aer HP0162
Resorcinol:
AerHP0201
Rutin:
PI HP0126, Aer 2.3 2% HP01ss
Scopoletin:
PI HP 0218
Sitosterol,beta:
Aer HPom
Stearic
acid: Flowering tops HP0173
Tannin:
Lf 12.4%, Fl 16.2%, St 3.8% HP0125
Taraxasterol:
Aer HP0222
Tetracosan-1-ol:
Lf HPono
Threonine:
pJ HP0218
Triacontan-1-ol:
Lf HP0220
Trollichrome:
FJ HPom
Trollixanthin:
FJ HPom
Trollixanthin,cis:
FJ HPom
Umbelliferone:
pJ HP0218
Undecan,n:
Aer EQ HP0134
Violaxanthin:
FJ HPom
Xanthone,
1-3-6-7 -tetra hydroxy: Lf HPD183
Xanthone,
1-3-6-trihydroxy: Aer HPOl63
USES
QUALITY OF PLANT MATERIAL AND
COMMERCIAL PRODUCTS
According to the British and European Pharmacopoeias, St John's wort
herb consists of the whole or cut dried flowering tops of H. perforatum,
harvested during flowering time, and contains not less than 0.08% of total
hypericins, expressed as hypericin, calculated with reference to the dried
drug.(G81, G84) Detailed descriptions of H. perforatum herb for use in
botanical, microscopic and macroscopic identification have been published,
along with qualitative and quantitative methods for the assessment of H. perforatum
herb raw material.(G1)
As with other herbal medicinal products, there is variation in the
qualitative and quantitative composition of commercial St John's wort
preparations. In the USA, analysis of 21 St John's wort products (18 of which
claimed to contain only standardised extracts and three of which were
combinations of extracts and crude plant material) found that seven products
did not meet at least one of the quality criteria assessed: four products had a
hypericin content ranging from 77% to 85% of that stated on their labels or, if
not stated on the label, of the minimum acceptable concentration permitted in
the analysis; one of the two products claiming to contain hyperforin contained
only 21.7% of the stated amount; five products contained cadmium exceeding acceptable
concentrations in the analysis, and two of these
products
contained more than twice the permitted concentration of cadmium.(15) Overall,
five of the 18 products labelled with hypericin and/or hyperforin concentrations,
and five of the seven products labelled as being produced from 'aerial parts',
failed the analysis. Another analytical study which investigated eight St John's
wort products marketed in the USA found that their hyperforin content varied
from 0.01–1.89%, and that only two products contained more than one percent
hyperforin, the minimum concentration suggested to be required for antidepressant
effects.(16) Similarly, hypericin content varied from 0.03–0.29% and, for
several products, the actual content ranged from 57–130% of that stated on the
label.
Analysis (using a liquid chromatographic method with fluorescent
detection) of 54 commercially available St John's wort products purchased in
the USA and Canada found that only two of the products had a total naphthodianthrone
concentration (hypericin and pseudohypericin) within 10% of that stated on the label.(17)
Overall, total naphthodianthrone content for tablets and capsules,
respectively, ranged from 0–108.6% and from 31.3– 80.2% of the amount stated on
the label. The naphthodianthrone content of products formulated as tinctures
ranged from 0– 118.6 mg/mL. Isolated hyperforin is susceptible to oxidation,
although the hyperforin content of dried herb and preparations containing extracts
of H. perforatum appears to be more stable.(18) Degradation products for
hyperforin include deoxyfurohyperforin A,(19) furohyperforin, furoadhyperforin
and furohyperforin A and other oxygenated hyperforin analogues.(20, 21)
A fast high-performance liquid chromatographic (HPLC) method
with photodiode array detection has been developed for the determination of six
of the naphthodianthrone (including hypericin) and phloroglucinol (including
hyperforin) compounds in H. perforatum extracts.(22) The method allows
quantitative determination of concentrations as low as 2 mg/mL and 0.5 mg/mL for
hyperforin and hypericin, respectively, while detection limits for these
compounds were 0.1 and 0.02 mg/mL, respectively.
Variation in St John's wort products is not limited to product composition,
but as with other herbal medicinal products also applies to the dissolution
profiles of products which might be considered to be pharmaceutically
equivalent. In vitro dissolution tests using biorelevant conditions (i.e.
simulated gastric fluid and similar substances as the dissolution media) were
used to determine the dissolution profiles of five St John's wort products purchased
in Germany. All products were ethanol or methanol extracts of St John's wort,
formulated as tablets or capsules and contained 300–612 mg extract per unit
dosage form.(23) In simulated gastric fluid without pepsin, and under conditions
simulating the fasted state in the proximal small intestine, dissolution of
hyperforin was 'not detected' and 'poor', respectively.
Dissolution of hyperforin improved under conditions simulating
postprandial conditions in the proximal small intestine for some products (e.g.
90% release within two hours), but was relatively poor for other products (e.g.
<50% release within two hours). Dissolution of hypericins into simulated
gastric fluid was also not detected; results for dissolution of hypericins into
other media were either not available or were deemed to be unreliable. Dissolution
of the flavonoid compounds tested (rutin, hyperoside, isoquercitrin and
quercitrin) was good into all media tested, although there were variations between
products in the release of rutin.(23) These results indicate that these St
John's wort products cannot be considered interchangeable; the implication
being that the need for dose adjustment should be considered for patients changing
from one St John's wort product to another.
USES
St. John’s wort is used to treat mild to moderate
depression and anxiety. It may be used topically as an antiinfl ammatory to
relieve hemorrhoids, as well as to treat vitiligo and burns.
INVESTIGATIONAL
USES
St. John’s wort is used experimentally to treat warts,
Kaposi’s sarcoma, cutaneous T-cell lymphoma, and other viruses such as infl
uenzae. It is also used experimentally as an antiretroviral in the treatment of
HIV, as an antiinfective against methicillinresistant strains of Staphylococcus
aureus, and for phytotherapy in the
treatment of psoriasis. Studies are underway to confi rm St. John’s wort’s use
in menopausal symptoms and seasonal affective disorder. It may be effective for
nicotine withdrawl symptoms.
FOOD USE
St
John's wort is listed by the Council of Europe as a natural source of food
flavouring (herb: category 5).(G17)
HERBAL USE
St
John's wort is stated to possess sedative and astringent properties. It has
been used for excitability, neuralgia, fibrositis, sciatica, wounds, menopausal
neurosis, anxiety and depression and as a nerve tonic.(G3, G7,G32) St John's
wort also has a long history of traditional use in topical preparations for
wound healing.(G1, G7) St John's wort is used extensively in homeopathic preparations
as well as in herbal products. Modern interest is focused on its use as an
antidepressant.
TRADITIONAL MEDICINAL USES
Arabic
countries. The
dried entire plant is used in the form of a vaginal pessary, in Unani medicine,
as an emmenagogue Hro219 •
Argentina. Olive oil
extract of the leaf is taken orally for menstrual cramps Hrom.
England. Hot water
extract of the dried leaf is used topically to promote hair growth, and for wounds
and bruises. The extract is taken orally for venomous bites and intestinal worms Hrozis.
Europe. Hot water
extract of the aerial part is taken orally as an emmenagogue, and as a
diuretic. Externally, the aerial part is used for wound healing Hro118. Hot water extract of the entire plant
is taken orally for menstrual complaints
Hro238 • Hot water extract of the leaf is taken orally to produce
abortion Hrozio.
Germany. The fresh leaf
and stem is eaten for nervous disorders and sleeplessnessHro139• Water extract
of the leaf is taken orally as an antidepressant Hro183.
Greece. Olive oil extract
of the flowers is used to treat skin wounds and herpes zoster. The flower in
olive oil is exposed to sun for a week. When the solution takes on an orange
color, it is applied to the infected area
Hr0186 . The aerial part is applied externally to aid wound healing Hr0109.
India. Hot water
extract of the aerial part is taken orally as an anthelmintic and emmenagogue HP0244. Hot water extract of the dried aerial
part is taken orally as an emmenagogue, anthelmintic and diuretic Hro216 • Hot water extract of the dried
entire plant is taken orally as an anthelmintic and emmenagogue HP0240. Hot water extract of the entire plant
is taken orally as an emmenagogue Hr0106.
Italy. Acetic acid (2%)
extract of the dried flower is taken orally as an antihematoma. The infusion is
taken orally to treat articular aches Hro231
• Olive oil extract of the flowering tops is used externally for Herpes simplex
lesions, especially on the lips Hro229. Hot water extract of the dried
flowering tops is used topically for inflammations Hrozm.
Madeira. Infusion of the
entire plant is taken orally as a diuretic for gout, lithemia and kidney
diseases HP0192.
Soviet Union. Hot water
extract of the aerial part is taken orally for treating goiter Hro104. Hot water extract of the leaf is
taken orally for bacillary dysentery Hrom.
Spain. Hot water
extract of the dried aerial part is used externally for wound healing, and
orally as a spasmolytic and for colds
HP0230. Water extract of the flower and leaf is taken orally 2 to 3
times a day for scanty and difficult menstruation Hr0123 .
Turkey. Decoction of the
aerial part is taken orally for stomachache
Hr0190. Infusion of the dried aerial part is taken orally to treat stomachache.
One glass of the infusion with other herbs and flower is taken twice a day Hr0184. Hot water extract of the dried aerial
part is taken orally for neurological disorders, convulsions, tetanus,
ulcers Hro 191 ,common cold,
gastrointestinal disorders, jaundice, hepatic disorders, biliary disorders, and
the healing of woundsHrozos. Pounded fresh flower is applied directly on open wounds
to promote healing Hr0184.
USA. Fluid extract of
the inflorescence is taken orally for menorrhagia, hysteria, nervous affections, jaundice, worms, as a sedative, and
diuretic. Externally, the fluid extract is used to treat hard tumors Hro124. Hot water extract of the aerial part
is taken orally to promote menstruation and for painful menstruation Hro197. When administered to cows in the ration, the aerial part produced
eruptions on the udder Hrotzo. Hot water
extract of the dried flowering tops is taken orally as an astringent and has a
peculiar soothing effect. The extract is used as an ointment for skin
irritation and insect bites HP0241 •
Yugoslavia. Hot water
extract of the dried aerial part is taken orally for diabetes. Hot water extract
of the dried flower is taken orally for diabetes Hrom.
ACTIONS
PHARMACOLOGICAL ACTIONS
The
major active constituents are considered to be hyperforin (a prenylated
phloroglucinol) and hypericin (a naphthodianthrone), although other
biologically active constituents, e.g. flavonoids and tannins, are also
present.(25) Several pharmacological activities, including antidepressant,
anticancer, antiviral and antibacterial effects, have been documented for extracts
of St John's wort and/ or its constituents following preclinical studies.
Clinical studies mainly have described antidepressant effects for St John's
wort preparations.
IN VITRO AND ANIMAL STUDIES
Pharmacokinetics In vivo (rats), the bioavailability of
hypericin following oral administration was increased by co-administration of
procyanidin B2, isolated from H. perforatum, or hyperoside.(26) Antidepressant
activity The precise mechanism of action for the antidepressant effect of St
John's wort is unclear. Initially, attention was focused on hypericin as the
constituent of St John's wort believed to be responsible for the herb's
antidepressant effects. Inhibition of monoamine oxidase (MAO) type A and B in Figure
1 Selected constituents of St John’s wort. St John’s Wort rat brain
mitochondria in vitro was described for hypericin.(27)
However, other studies have demonstrated only weak or no MAO inhibition.(28–30)
In vitro receptor binding and enzyme inhibition assays carried out using
hypericum extract demonstrated significant receptor affinity for adenosine,
GABAA, GABAB, benzodiazepine and MAO types A and B, although, with the
exception of GABAA and GABAB, the concentrations of hypericum required were
unlikely to be attained after oral administration in humans.(31) Other biochemical
studies have reported that the hypericum extract LI 160 is only a weak
inhibitor of MAO-A and MAO-B activity, but that it inhibits the synaptosomal
uptake of serotonin (5- hydroxytryptamine or 5-HT), dopamine and noradrenaline (norepinephrine)
with approximately equal affinity and also leads to a downregulation of
b-receptors and an upregulation of 5-HT2 receptors in the rat frontal cortex.(32)
The effects of fluoxetine and hypericin- and flavonoid-standardised hypericum
extracts (LI 160, 0.3% hypericin and 6% flavonoids and Ph-50, 0.3% hypericin
and 50% flavonoids) on the concentrations of neurotransmitters in brain regions
were studied in rats.(33) All three preparations induced a significant increase
in 5-HT concentrations in the rat cortex, both LI 160 and Ph-50 caused
increases in noradrenaline (norepinephrine) and dopamine in the rat
diencephalon and Ph-50 also induced an increase in the noradrenaline
(norepinephrine) content in the brainstem, areas that are implicated in
depression.(33)
Other in vitro experiments using peripheral blood mononuclear cells
have shown that an alcoholic extract of H. Perforatum containing 0.25 mg/mL
hypericin downregulated mitogenmediated tryptophan degradation in a
concentration dependent manner.(34) Tryptophan is a precursor for biosynthesis
of 5-HT. Hyperforin has now emerged as being one of the major active constituents
of importance in antidepressant activity.(35) Hyperforin has been shown to be
an uptake inhibitor of 5-HT, dopamine, noradrenaline (norepinephrine), GABA and
L-glutamate in synaptosomal preparations(36) and to inhibit 5-HT uptake in rat
peritoneal cells in a dose-dependent manner.(37) Studies have also described
discrepancies between observed and theoretical IC50 values, indicating that
hyperforin is not the only component of hypericum extract that is responsible
for the observed effects.(37, 38) Adhyperforin, another phloroglucinol constituent
of H. perforatum, also inhibits the uptake of dopamine, serotonin and
norepinephrine in vitro, and its possible involvement in the antidepressant
activity of St John's wort requires further investigation.(39)
In
vitro screening of the activities of hypericin, pseudohypericin, hyperforin and
several flavonoid constituents of H. perforatum using 42 biogenic amine
receptors and transporters (available as part of the National Institute of
Mental Health Psychoactive Drug Screening Program of the USA) showed that compounds
significantly inhibited ligand binding at the following receptors in
particular: amentoflavone – serotonin (5-HT1D, 5- HT2C), dopamine-D3, opiate
(delta), benzodiazepine; hypericin and pseudohypericin – dopamine-D3,
dopamine-D4, b-adrenergic; hyperforin – dopamine-D1, dopamine-D5.(40) Hyperforin
was less active than the other constituents tested on all receptors screened. Screening
revealed some interactions at G-protein coupled receptors that were previously
unreported (e.g. hypericin and badrenergic activity).
The effects of hyperforin on interleukin-6 (IL-6) release in different
experimental models have been explored as a possible alternative mechanism for
antidepressant effects, since St John's wort has been shown to inhibit
substance-P mediated effects (substance P has been implicated in the aetiology
of depression).(41) Hyperforin inhibited both substance-P- and
lipopolysaccharide-induced IL-6 release in human astrocytoma cells (IC50 = 1.6
and 1.9 mmol/L, respectively), although concentrations required to achieve this
were around one order of magnitude higher than those found in the plasma of
patients treated with H. perforatum extracts.(42)
Other
findings indicate that flavonoids, as well as hyperforin and hypericin, are at
least some of the constituents of H. perforatum responsible for its
antidepressant activity.(43, 44) In vivo (mice and rats) experiments which
assessed the effects of a hydroalcoholic extract of H. perforatum (containing
hypericin 0.15% and hyperforin 3.2%) and the same extract with hypericin and
hyperforin removed in turn, showed that all extracts, including the extract
devoid of both hypericin and hyperforin (but containing 12% flavonoids),
retained activity in behavioural models.(43)
It
has been reported that the mode of action of hyperforin in serotonin uptake
inhibition seems to be associated with the elevation of free intracellular
sodium ion concentrations(45) and that this may be secondary to activation of
the Naþ/Hþ exchange as a result of a decrease in intracellular pH.(46) Further
in vitro experiments using two cell systems (human platelets and rat phaeochromocytoma
cells) have shown that hyperforin increases both intracellular sodium ion and calcium
ion concentrations, and that this is mediated through activation by hyperforin
of nonselective cation channels.(47)
Figure
1. St John’s wort (Hypericum perforatum).
Figure
2. St John’s wort – dried drug substance (herb).
S
Hyperforin was shown to inhibit 5-HT reuptake in washed platelets
but not in fresh platelet-rich plasma, suggesting that plasma-protein binding
could be a limiting factor for 5-HT uptake inhibition in vivo.(48)
A commercial extract of St John's wort has exhibited psychotropic
and antidepressant activities in mice.(49) Pure hyperforin and hypericum
extracts also demonstrated antidepressant activity in a despair behaviour test
in rats.(37) In other experimental models of depression, including acute and
chronic forms of escape deficit induced by stressors, hypericum extract was
shown to protect rats from the consequences of unavoidable stress.(50) In
studies using the rat forced swimming test, an experimental model of
depression, hypericum extracts induced a significant reduction in
immobility.(51) Flavonoid fractions and flavonoids isolated from these
fractions have also been reported to have antidepressant activity in the forced
swimming test in rats.(52)
Cytotoxic and anticancer activities The findings of a substantial
body of preclinical research have documented anticancer activites for H. perforatum
preparations and their constituents. A methanolic extract of H. perforatum (containing
hypericin 0.3% and hyperforin 3.8%) administered intraperitoneally (15 mg/kg
body weight) ten days before implantation of PC-3 human Caucasian prostate adenocarcinoma
cells in nude mice significantly reduced tumour growth and the number of
regional lymph node metastases (p < 0.01 for both).(53) The same extract at
a concentration of 1.41 mg/mL also significantly inhibited the proliferation of
PC-3 cells in vitro (IC50 = 0.42 mg/mL). Ethanolic extracts of H. Perforatum from
fresh and dried plant material (drug to extract ratio 1.3-1.5 : 1) inhibited
the proliferation of human malignant cells (e.g. leukamia cell lines K562 and
U937) in a concentration-dependent manner.(54) The extracts also induced apoptosis
of glioblastoma LN229 cells. The observed effects were potentiated by light
activation. In a similar series of experiments using extracts of H. perforatum containing
0.3% hypericins but differing concentrations of hyperforin (0.21%, 2.21% or
3.25% w/w) and flavonoids (5.3% or 10% w/w), antiproliferative activity of the
different extracts varied (GI50 values: 248.3 to 621.3 mg/mL and 378.2 to 911.7
mg/mL for K562 and U937 cell lines, respectively), indicating that the
flavonoid constituents, as well as hypericin and hyperforin, contribute to the
observed effects.(55) The possibility that constituents other than hypericin
have cytotoxic and/or antiproliferative activity is supported by further in
vitro work which showed that a methanolic extract of H. Perforatum flowering
parts inhibited growth of K562 cells and induced apoptosis to a greater extent
than did hypericin alone.(56) In mice injected with murine and human cancer
cell lines, seven days' pretreatment with hyperforin (as the stable
dicyclohexylammonium salt) intraperitoneally reduced several markers of cancer infiltration
and metastasis.(57) In rats given subcutaneous injections of MT-450 rat mammary
carcinoma cells, treatment with hyperforin (100 mL of 2 mmol/L solution
subcutaneously at the tumour site once daily) for two weeks starting 15 days
after tumour injection inhibited tumour growth to a similar extent as did
paclitaxel given according to the same dosage regimen.(58)
There is evidence that the mechanism by which hyperforin induces
apoptosis involves the activation of caspases (inactive proenzymes).(58, 59) Numerous
preclinical studies have established that hypericin is a photocytotoxic agent.
Hypericin photosensitisation has been documented for various cancer cell lines
in vitro(60–64) and in several in vivo experimental models of cancer.(61, 65) The
photocytotoxic effects of hypericin towards human leukaemic HL-60 cells can be
potientiated in vitro by co-incubation with acetazolamide(66) and quercetin.(67)
Phototoxicity and induction of apoptosis also occur with pseudohypericin in
vitro.(68) Hypericin photo-induced apoptosis may involve the tumour necrosis
factor (TNF)-related apoptosis-inducing ligand,(69) activation of caspases, such
as caspase-8,(69, 70) and inhibition of proteasome function (which is involved
in caspase activation).(71) Further in vitro studies have added a layer of
complexity to the above findings. Hypericin can induce apoptosis or necrosis, depending
on the intracellular hypericin concentration and/or the light-activating
dose.(72) Furthermore, exposure of U937 cells to hypericin and sub-lethal doses
of light irradiation induced subsequent photoresistance with light doses which
normally induced apoptosis.(73, 74)
In an in vitro system involving the human cytochrome P450 enzyme
CYP1A1, three commercially available H. Perforatum extracts as well as several
constituents of H. perforatum extracts (with the exception of rutin) inhibited
the CYP1A1-catalysed epoxidation of (_)-trans-7,8-dihydro-7,8-dihydroxy-benzo(a)pyrene,
the reaction which leads to formation of the carcinogenic product diolepoxide
2.(75) In vitro cytotoxicity against human colon carcinoma cells (CO 115) has
been described for hyperforin-related constituents isolated from Hypericum
calycinum and Hypericum revolutum.(76) Antimicrobial activity Extracts of H.
perforatum aerial parts have antibacterial activity against Gram-positive
bacteria, particularly Bacillus subtilis and B. cereus, but not Gram-negative bacteria
and yeasts, according to the findings of a series of in vitro assays.(77)
A leaf extract of H. perforatum has been documented as enhancing
the immunity of mice towards Staphylococcus aureus and Bordetella
pertussis.(78) Hyperforin has antibacterial activity against S. aureus,(9)
multi-drug resistant S. aureus and Grampositive bacteria, including
Streptococcus pyogenes and Corynebacterium diphtheriae.(79) However, the
antibacterial effects of hyperforin are only observed at high
concentrations.(80, 81) Other experiments have shown that S. aureus is able to
acquire resistance to hyperforin, but that this does not occur with hyperforin concentrations
similar to those found in patients treated with H. perforatum extracts for
depression.(82) Hyperforin did not exhibit any growth inhibitory effect against
Gram-negative bacteria, such as Enterococcus faecalis, Escherichia coli and Pseudomonas
aeruginosa or against Candida albicans.(79) Other antibacterial constituents
(imanine and novoimanine) have been isolated from St John's wort.(83, 84)
Several other species of Hypericum have been shown to have antimicrobial
activity.(85, 86) In disc-diffusion assays, 33 of 34 chloroform extracts of
Hypericum species (not including H. perforatum) showed substantial activity
against a clinical isolate of methicillin-resistant Staphylococcus aureus.(86)
Antiviral activity Flavonoid and catechin-containing fractions have
exhibited antiviral activity, inhibiting the influenza virus by 83–100%.(87)
Hypericin and pseudohypericin have been reported to inhibit several
encapsulated viruses in vitro, including herpes simplex types 1 and 2,(88, 89)
varicella-zoster virus(90) and human immunodeficiency virus type 1
(HIV-1).(91–94) Hypericin has also been reported to inactivate murine cytomegalovirus
(MCMV) and Sindbis virus.(94) The antiviral activity of hypericin appears to involve
a photoactivation process.(94, G1) An extract of a St John's wort product (5–50
mL/mL; no further details provided) and pure hypericin (5–20 mmol/L) inhibited
UV-induced HIV gene expression in HeLa cells in a concentration-dependent
manner, whereas hypericin without UV-induced HIV gene activation had no effect on
HIV gene expression.(95)
Other effects In vitro studies using a hamster vas deferens smooth
muscle cell line demonstrated that hyperforin induces the release of calcium
ions from mitochondrial or other sources followed by activation of cellular
metabolism.(96) It is not known whether this activity contributes to the
antidepressant effects of hyperforin.
Oral administration of a single dose of St John's wort (100,
200, 400, 600 or 800 mg/kg) to two strains of alcohol-preferring rats significantly
reduced alcohol intake in both strains.(97) In another study in experimental
alcoholism, acute intraperitoneal administration of St John's wort (10–40
mg/kg), fluoxetine (1–10 mg/kg) and imipramine (3–30 mg/kg) reduced alcohol
intake in a dosedependent manner in a 12-hour, limited access, two-bottle
choice (ethanol/water) procedure.(51) In alcohol-preferring mice, the dose (5 mg/kg
administered orally by gavage) of a hyperforin-rich carbon-dioxide extract of
H. perforatum required to reduce the intake of 10% ethanol to a statistically
significant extent was 125- fold lower than that required with a crude
methanolic extract (625 mg/kg) with negligible hyperforin content administered
by the same route.(98) In mice, oral administration of a Hypericum perforatum
extract (Ph-50) attenuated nicotine withdrawal symptoms.(99) Depression,
alcoholism and smoking are thought to have some neurochemical similarities,
such as low brain serotonin concentrations.(100, 101)
An extract of St John's wort was found to suppress inflammation
and leukocyte infiltration induced by carrageenan and prostaglandin E1 (PGE1)
in mice.(102) In vitro, hypericin has been shown to inhibit tumour necrosis
factor-induced activation of the transcription factor NF-kB,(103) specific
growth factorregulated protein kinases(104–106) and the release of arachidonic acid
and leukotriene B4.(107) In a rabbit model of proliferative vitreoretinopathy
(PVR), intravitreal injection of hypericin 0.1mL (10 or 100 mmol/L, but not 1
mmol/L) inhibited the progression of PVR when compared with severity in control
eyes five days after hypericin administration.(108) It was suggested that, as
protein kinase C is important in the cellular reactions occurring in PVR, modulation
of protein kinase C by hypericin may be a factor in this system. Hypericin and
pseudohypericin have been reported to inhibit 12-lipoxygenase activity; the products
of lipoxygenasecatalysed reactions, include leukotrienes.(109) Hyperforin has
also been shown to inhibit the activity of enzymes involved in inflammatory
pathways: in vitro, hyperforin inhibited 5-lipoxygenase and cyclooxygenase 1,
but not cyclooxygenase 2.(110)
Antioxidant properties have been reported for H. Perforatum following
in vitro experiments. St John's wort products (Nature's Plus and Movana,
respectively) obtained in the USA and labelled as being hypericin- (0.3–0.5%)
and hyperforin-standardised (minimum 3%) attenuated superoxide production in an
inverse concentration-dependent manner in a cell-free system and in an experimental
model using human vascular tissue.(111) Hyperforin isolated from H. perforatum
reduced radical formation by polymorphonuclear cells from healthy human donors
after stimulation with N-formyl-methionyl-leucyl-phenylalanine (IC50 = 1.8
mmol/L).(112) However, in other systems, hyperforin did not exhibit any
free-radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl and was
inactive in an enzymatic assay based on oxygen radical production by
horseradish peroxidase in the presence of hydrogen peroxide.
Imanine was reported to reduce blood pressure and increase the frequency
and depth of breathing following intravenous administration (50 mg/kg) to
rabbits.(83) A study of the vasoconstrictor action of water-soluble imanine and
imanine on the isolated rabbit ear indicated that their hypotensive action was
not due to a direct effect on the vasculature.(83) When perfused through the isolated
frog heart, both water-soluble imanine and imanine were found to cause cardiac
systolic arrest at a dilution of 1 _ 10_5.(83) Proanthocyanidin-containing fractions
isolated from St John's wort have been reported to inhibit contractions of the
isolated guinea-pig heart induced by histamine, PGF2a and potassium chloride.(113)
A tonus-raising effect on isolated guinea-pig and rabbit uteri has
been documented for a crude aqueous extract.(114) Of the group of plants
investigated, St John's wort was reported to exhibit the weakest uterotonic
activity. A dried methanol extract of St John's wort (no further details provided)
protected human neuroblastoma cells against hydrogen peroxide induced apoptosis
in vitro.(115) Analgesic activity in mice has been reported for a total flavonoid
fraction of H. perforatum;(116) the active principle was stated to be of the
quercetin type. Tannins isolated from St John's wort are stated to have mild astringent
activity.(117) The anthraquinone derivatives documented for St John's wort do
not possess any purgative action.(G62)
CLINICAL STUDIES
Clinical trials with extracts of St John's wort have focused
mainly on its effects in patients with depression, although there have been several
studies exploring its use in other conditions, including seasonal affective
disorder, chronic fatigue and premenstrual syndrome.(118)
Pharmacodynamics Initially, hypericin was thought to be responsible
for the antidepressant activity of St John's wort, although, more recently,
experimental(36, 37) and clinical evidence( 119) has emerged to indicate that
hyperforin is one of the major constituents required for antidepressant
activity. The precise mechanism of action of St John's wort's antidepressant
effect remains unclear (see Pharmacological Actions, In vitro and animal
studies). In a randomised, double-blind, placebo-controlled, crossover study
involving 16 healthy volunteers who received St John's wort extract
(Neuroplant) 300 mg three times daily for seven days, St John's wort extract did
not influence plasma norepinephrine (noradrenaline) concentrations, but
significantly increased plasma dihydroxyphenylacetic acid concentrations (the
main metabolite of dopamine), compared with placebo (p = 0.013).(120)
Studies in humans have reported conflicting results with respect
to the effects of St John's wort extracts on endocrinological parameters. A
double-blind, placebo-controlled, crossover study in 12 healthy male volunteers
investigated the effects of a single dose of St John's wort extract (LI 160)
(2700 mg, 9 _ 300-mg tablets standardised to 0.3% hypericin) on plasma
concentrations of growth hormone, prolactin and cortisol.(121) A significant increase
in plasma growth hormone concentration and a significant decrease in plasma
prolactin concentration were observed following St John's wort administration
relative to placebo administration. Plasma cortisol concentrations were unchanged.
These findings suggest that this dose of St John's wort extract may increase
aspects of brain dopamine function in humans, although further studies are
required to confirm this, assess dose–response relationships and determine
whether there is evidence for effects on dopaminergic systems in patients with depression
treated with St John's wort.(121) Another study, which used a randomised,
three-way, crossover design, investigated the effects of a single dose of St
John's wort extract (LI 160S) (600 or 300 mg) or placebo on hormone
concentrations in 12 healthy male volunteers.(122) Compared with placebo, St
John's wort extract (600 mg) increased cortisol secretion between 30 and 90
minutes after dosing, indicating an influence of St John's wort on certain CNS
neurotransmitters. There was no difference between the three groups with regard
to adrenocorticotrophic hormone (ACTH), growth hormone and prolactin
secretion.(122)
By contrast, in a randomised, single-blind, placebo-controlled, crossover
study involving 12 healthy male volunteers, mean serum ACTH concentrations, but
not cortisol, growth hormone and prolactin concentrations, were significantly
increased following oral administration of a St John's wort extract (WS-5570)
at doses of 600, 900 and 1200 mg/day on four different days (p < 0.05 versus
placebo). However, there were no significant differences in ACTH concentrations
between groups when a statistical adjustment (Bonferroni correction) was made
for post-hoc tests.(123) Differences in the findings of this study, compared
with previous work, may be due to differences between doses, products tested and
their bioavailabilities.(123)
Therapeutic effects Depression There
are now over forty clinical trials of H. perforatum preparations involving
patients with different types of depression, and many of these trials have been
included in systematic reviews.
A Cochrane systematic review included 37 randomised, double-blind,
controlled clinical trials of monopreparations of H. perforatum involving a
total of 4925 patients with depressive disorders.(24) Of these, 26 trials were
placebocontrolled, 14 compared H. perforatum preparations with standard
antidepressants (imipramine 50 to 150 mg daily, four trials; fluoxetine 20 to
40 mg daily, four trials; sertraline 75 to 150 mg daily, three trials;
amitriptyline 30 or 75 mg daily, two trials; maprotiline 75 mg daily, one
trial) and three of these studies(124–126) also included a placebo control
group. Trials involved a variety of H. perforatum preparations administered at
doses of 240 to 1800 mg extract daily. The treatment period was typically four
to six weeks (29 trials) although administration periods ranged from four to 12
weeks overall. The most frequently investigated product was LI-160 (Lichtwer
Pharma, Germany). Overall, 24 trials involved only patients with major depression.
In most trials (n = 35), the Hamilton Rating Scale for Depression (HAMD) was
the instrument used to assess outcomes, and the methodological quality of the
majority of the included studies was considered to be 'reasonable to good'.(24)
Of the 26 trials (involving 3320 participants) comparing H. perforatum
preparations with placebo, 23 provided data which were eligible for
meta-analysis. For these studies, the results indicated that H. perforatum
preparations were more effective than placebo (response rate ratio (RRR), 95%
confidence interval (CI): 1.55, 1.42–1.70), although when the analysis was limited
to larger (i.e. more precise) trials in patients with major depression only,
the results showed a small benefit for H. perforatum over placebo (RRR, 95% CI:
1.15, 1.02–1.129).(24) Similarly, meta-analysis of data from the 23
placebo-controlled trials which used HAMD scores to assess outcomes indicated that
H. perforatum preparations were more effective than placebo (weighted mean
difference (WMD), 95% CI: _3.25, _3.74 to _2.77), but when the analysis was restricted
to the 12 such trials involving only patients with major depression, the effect
was less marked (WMD, 95% CI: _2.48, _3.06 to_1.89).
Meta-analysis of data from the 14 trials (involving 2283 participants)
comparing H. perforatum with standard antidepressant agents indicated that H.
perforatum preparations had similar effects to those of standard
antidepressants (RRR, 95% CI: 1.01, 0.93 to 1.10 and WMD, 95% CI: _0.06, _0.64 to
0.51 for trials providing response rate data (13 trials) and HAMD scores (11
trials), respectively).(24) Results were similar for sub-analysis of the trials
comparing H. Perforatum preparations with older antidepressants and comparisons
with newer antidepressants (selective serotonin reuptake inhibitors).
The conclusions drawn from this work were that the evidence is
inconsistent and complex. H. perforatum preparations and standard antidepressant agents appear to show similar
effects, whereas H. perforatum preparations have only small benefits over
placebo in patients with major depression; in older studies in patients with
mild-to-moderate depression, H. perforatum preparations appear to be of more
benefit than placebo.(24) An important point is that there is heterogeneity not
only among the trials and their results, but also among the different
manufacturers' products tested. Products are not necessarily equally effective,
and the results of the analyses above should not be extrapolated to other H. Perforatum
preparations, which may differ considerably in their pharmaceutical quality
(see Quality of plant material and commercial products). One of the trials
included in the systematic review was a randomised, double-blind, placebo-controlled,
multicentre study comparing an extract of H. perforatum (LI-160, standardised
for hypericin 0.12–0.28%) 900 mg daily with the SSRI sertraline (which is authorised
for the treatment of depression) at a dose of 50 mg daily in 340 patients with
major depressive disorder. The trial was funded by the National Center for
Complementary and Alternative Medicine and the National Institute of Mental Health,
USA, and was designed to assess whether or not H. perforatum extract was
superior to placebo after 8 weeks' treatment.(126)
However, at the end of the study, there were no statistically significant differences in the two primary outcome measures (changes in HAMD scores and response rate) not only between H. perforatum extract and placebo, but also between sertraline and placebo. Thus, this trial was criticised for lacking the sensitivity at least to detect the effectiveness of a treatment known to be effective (i.e. sertraline). A further issue which arose subsequently relates to adherence to treatment among participants randomised to the H. perforatum group. Analysis of blood samples available for 97 of the 113 H. perforatum recipients revealed that 80 (82%) had detectable concentrations of hyperforin in at least one sample, whereas 17 (17%) had no detectable hyperforin in any of their samples.(127) The sensitivity threshold of the assay was hyperforin 10 ng/mL. Furthermore, of 104 of the 116 participants randomised to placebo for whom blood samples were available, 18 (17%) had detectable concentrations of hyperforin in at least one sample. By contrast, sertraline and/or N-desmethylsertraline were detected in at least one sample for all sertraline recipients for whom blood samples were available (91 of 111). Reanalysis of the efficacy data using only data from participants with plasma hyperforin concentrations consistent swith their treatment allocation did not change the initial findings.(127)
However, at the end of the study, there were no statistically significant differences in the two primary outcome measures (changes in HAMD scores and response rate) not only between H. perforatum extract and placebo, but also between sertraline and placebo. Thus, this trial was criticised for lacking the sensitivity at least to detect the effectiveness of a treatment known to be effective (i.e. sertraline). A further issue which arose subsequently relates to adherence to treatment among participants randomised to the H. perforatum group. Analysis of blood samples available for 97 of the 113 H. perforatum recipients revealed that 80 (82%) had detectable concentrations of hyperforin in at least one sample, whereas 17 (17%) had no detectable hyperforin in any of their samples.(127) The sensitivity threshold of the assay was hyperforin 10 ng/mL. Furthermore, of 104 of the 116 participants randomised to placebo for whom blood samples were available, 18 (17%) had detectable concentrations of hyperforin in at least one sample. By contrast, sertraline and/or N-desmethylsertraline were detected in at least one sample for all sertraline recipients for whom blood samples were available (91 of 111). Reanalysis of the efficacy data using only data from participants with plasma hyperforin concentrations consistent swith their treatment allocation did not change the initial findings.(127)
A randomised, double-blind, multicentre trial comparing the effects
of a hydroalcoholic extract of H. perforatum herb (WS- 5570, drug to extract
ratio 3–7 : 1, standardised for hyperforin 3–6% and hypericin 0.12–0.28%;
Schwabe Pharmaceuticals) with those of paroxetine in the acute treatment of
moderate to severe depression has been published since the revised Cochrane
review was completed. In the study, after a placebo run-in phase, 251 participants
with acute major depression received H. perforatum extract 300 mg three times
daily (increased to 1800 mg daily in non-responders), or paroxetine 20 mg daily
(40 mg daily for non-responders), for six weeks.(128) At the end of the study,
the H. perforatum extract was reported to be at least as effective as
paroxetine in reducing symptoms of moderate to severe depression (mean
(standard deviation) reduction in HAMD scores from baseline values: 14.4 (8.8)
and 11.4 (8.6) for H. perforatum and paroxetine, respectively).
The review described above(24) was an update of a previous Cochrane
systematic review and meta-analysis of 27 randomised controlled trials of H.
perforatum preparations in depressive disorders.(129) The updated review had
stricter and tighter inclusion and exclusion criteria for trials – only trials which
explicitly stated that the method of treatment allocation was random and which used
a double-blind design were included, and trials investigating H. perforatum for
prevention of depression, those using combination preparations containing H.
perforatum, comparing H. perforatum with drugs not explicitly recommended as antidepressant
agents, measuring only physiological parameters and those with a treatment period
of less than four weeks were excluded.(24) Thus, the previous Cochrane review included
seven trials which were excluded from the updated review.
The results of the earlier meta-analysis showed that H. perforatum
preparations were significantly superior to placebo in the short-term treatment
of mild to moderately severe depressive disorders (rate ratio 2.47 and 95%
confidence interval (95% CI) 1.69–3.61). and as effective as conventional antidepressant
agents (single preparations, rate ratio 1.01 and 95% CI 0.87–1.16), although
for several reasons – for example, the use of low doses of conventional
antidepressants and the trials involving small numbers of patients – this
evidence was considered inadequate for establishing whether H. Perforatum preparations
were as effective as conventional antidepressant drugs.(129) Further studies
comparing St John's wort preparations with standard antidepressant agents in
well-defined patient groups and over longer periods were considered necessary.(129)
Another earlier meta-analysis employed tighter inclusion criteria
for trials in an effort to increase the validity of the analysis.(130) It
included only randomised, blinded, controlled trials of St John's wort as a single
preparation, which involved patients with depressive disorders as defined by
the standard criteria ICD-10 (International Statistical Classification of Diseases
and Related Health Problems), DSM-IIIR (Diagnostic and Statistical Manual) or
DSM-IV and which used the Hamilton Depression (HAMD) Scale for measuring
clinical outcomes. Six such trials involving 651 patients with mainly mild to
moderately severe depressive disorders were included; two trials were placebo
controlled and four compared St John's wort with standard antidepressants. The
studies lasted for 4–6 weeks and the doses of St John's wort extract ranged
from 200 to 900 mg daily; the range for total hypericin administered was 0.75–2.7
mg daily.
This meta-analysis showed that the response rate for St John's wort was significantly greater than
that for placebo (73.2% versus 37.9%, respectively, relative risk 1.48 and 95% CI
1.03–1.92) and similar to that observed with tricyclic antidepressants (64% versus
6.4% for St John's wort and tricyclic antidepressants, respectively, relative
risk 1.11 and 95% CI 0.92–1.29).(130) Despite the stringent inclusion criteria for
trials in this meta-analysis, it was concluded that further studies are
required in order to address methodological problems before it can be concluded
that St John's wort is an effective antidepressant.(130)
A systematic review of large-scale observational studies of H.
perforatum extracts in patients with depressive disorders is also available.
The review included 16 non-randomised studies (involving a total of 34 804
patients) each involving at least 100 participants with depressive disorders who
were treated with H. perforatum preparations for at least four weeks.(131) Fifteen
of the studies reported physician-assessed response rates, and these ranged
from 65% to 100% for short-term studies (four to around six weeks' treatment;
13 studies) and were 60% and 69% for the two long-term studies (52 weeks'
treatment). Patient-assessed response rates ranged from 63% to 98% (ten studies).
These results suggest that the H. perforatum extracts assessed are effective
for mild and moderately severe depressive disorders, although this conclusion
cannot be definitive since the studies did not include random allocation to
treatment and many had other methodological limitations.(131) Furthermore, the
studies included in the review assessed the effects of 12 different H.
perforatum products, with some differences in how they were standardised,
administered at doses ranging from 360 to 1200 mg extract daily. Thus, the
results cannot be extrapolated directly to other H. perforatum preparations
with a different phytochemical profile.
One of the studies included in the review assessed the effects of
an H. perforatum preparation in children aged under 12 years with symptoms of
depression and psychovegetative disturbances. This study reported the highest
physician- and patients-assessed response rates (100% and 98%, respectively).(132)
Other open, uncontrolled studies(133) have explored the effects of H.
perforatum preparations in children and adolescents, although the efficacy of
such preparations in these patient groups requires testing in randomised
controlled trials. In a dose-ranging trial involving 348 patients with mild to moderate
depression according to ICD-10 criteria, patients were randomised to receive St
John's wort extract three times daily equivalent to either 1mg (n = 119), 0.33
mg (n = 115) or 0.17 mg (n = 114) hypericin for six weeks.(134) At the end of
the treatment period, there was a significant reduction in HAMD scores compared
with baseline values. The response rates (according to recognised criteria) were
68%, 65% and 62% for 1, 0.33 and 0.17 mg hypericin, respectively; the
differences between groups were not statistically significant. Thus, the study
showed that there was no dose-dependent effect of hypericin in St John's wort
extracts.
Smoking
cessation A preliminary, uncontrolled study has assessed the effects of a
methanol (80%) extract of H. perforatum herb (LI-160, standardised for
hypericin 900 mg and a minimum of 2% hyperforin; drug to extract ratio 3–6 : 1)
as an aid to motivational/behavioural support in adult smokers who wish to stop
smoking. The rationale for investigating H. perforatum in this indication is
that there is an association between smoking and depression: nicotine may act
as an antidepressant in some smokers, and depression can be precipitated by
nicotine withdrawal, i.e. smoking cessation.(101) In the study, point
prevalence and continuous abstinence rates were both 18% at 3 months, and 0% at
12 months (intentionto- treat analysis); these rates compare poorly with
response rates in placebo groups in controlled clinical studies of other smoking
cessation interventions.(135)
Seasonal
affective disorder The effects of St John's wort extracts have been investigated in
studies involving subjects with seasonal affective disorder (SAD),(136, 137) although
as yet there have not been any trials that have included a placebo control group.
Twenty individuals with SAD were randomised to receive St John's wort (LI 160)
(300 mg) three times daily (equivalent to 0.9 mg hypericin) with or without bright
light therapy.(136) After four weeks, there were significant reductions in HAMD
scores in both groups compared with baseline values and there were no
statistically significant differences between groups. Another study evaluated
data from individuals with mild to moderate SAD who had used St John's wort
(300 mg) three times daily (equivalent to 0.9 mg hypericin) with (n = 133) or
without light therapy (n = 168) for eight weeks.(137) The study was not
randomised and involved data collection by postal questionnaires. Data from 301
returned questionnaires were suitable for analysis. Significant reductions in
the mean SAD scores were observed in both groups compared with baseline values;
the differences in the SAD scores between groups were statistically non-significant.
Antiviral
activity Antiviral activity has been reported for hypericin against human
immunodeficiency virus (HIV).(138, 139) Several uncontrolled studies in
HIV-positive patients who received St John's wort extract have reported immunologic
and clinical benefits, including increases in CD4 cell counts in some patients.(140,
141) In a phase I, doseescalating study, 30 HIV-positive patients with CD4 cell
counts <350 cells/mm3 received intravenous synthetic hypericin twice weekly
(0.25 or 0.5 mg/kg body weight), three times weekly (0.25 mg/kg) or oral
hypericin daily (0.5 mg/kg).(142) Sixteen patients discontinued treatment early
because of toxic effects, and phototoxicity in several other patients prevented
completion of dose escalation. Antiretroviral activity as assessed by significant
changes in HIV p24 antigen level, HIV titre, HIV RNA copies and CD4 cell counts
was not observed. In contrast, in a phase-I dose-escalation study involving 19 patients
with hepatitis C virus (HCV) infection who received hypericin administered
orally at doses of 0.05 and 0.10 mg/kg daily for eight weeks, there was no
evidence of antiviral activity as determined by median changes in HCV RNA
concentrations in plasma.(143)
OTHER
STUDIES
The potential for the use of St John's wort in 20 individuals
presenting with fatigue(144) and in 19 women with self-reported premenstrual
syndrome(145) has also been explored in uncontrolled pilot studies. Significant
improvements in perceived fatigue and in symptoms of depression and anxiety
were seen after six weeks' treatment with St John's wort (equivalent to 0.9 mg
hypericin daily) compared with baseline values(144) and in overall premenstrual
syndrome scores after treatment with St John's wort (equivalent to 0.9 mg hypericin
daily) for two menstrual cycles.(145) Thus, there is scope for conducting
randomised controlled trials of St John's wort in these conditions.(144, 145)
A randomised, double-blind, placebo-controlled trial assessed
the effects of an 80% methanol extract of St John's wort (LI-160; containing
300 mg extract, drug to extract ratio 4–7 : 1) in 175 patients with somatoform
disorders (usually characterised by chronic multiple physical symptoms not explained
by underlying organic pathology). Participants received St John's wort extract
300 mg twice daily (n = 87), or placebo (n = 88), for six weeks. At the end of
the study, according to an intention-to-treat analysis, St John's wort recipients,
compared with placebo recipients, showed statistically significant improvements
on the six individual variables comprising the primary efficacy analysis and in
the combined score (p < 0.0001 for all comparisons).(146)
Another randomised, double-blind, parallel-group trial investigated
the effects of LI-160 300 mg extract twice daily (increased in increments to a
maximum of 1800 mg extract daily at the physician's discretion), or placebo,
for 12 weeks in 41 individuals with social phobia (social anxiety disorder). At
the end of the study, there was no statistically significant difference between
the two groups in Liebowitz Social Anxiety Scale scores, the primary outcome
measure (p = 0.79).(147) In a randomised, double-blind, placebo-controlled
trial, 179 women with menopause-related psychovegetative symptoms received a
combination preparation of St John's wort and black cohosh (Cimicifuga
racemosa) or placebo for six weeks.(148) The results indicated that the
combination product had a significantly greater effect on the symptoms than did
placebo. A randomised, double-blind, phase I study involving 55 healthy
volunteers who received St John's wort (900 mg) daily (containing 0.5%
hyperforin), St John's wort (900 mg) daily (containing 5.0% hyperforin) or
placebo for eight days investigated the effects on quantitative
electroencephalogram as an indicator of drug-induced pharmacological action.(149)
Reproducible central pharmacodynamic effects were apparent in both groups of St
John's wort recipients compared with placebo recipients. The effects were
greater in subjects who received extract containing 5.0% hyperforin than in
those who received extract containing 0.5% hyperforin.
Placebo-controlled, crossover studies investigating the effects of
St John's wort (0.9 and 1.8 mg) on the sleep polysomnogram of healthy subjects reported that both doses of
St John's wort significantly increased rapid eye movement (REM) sleep latency
compared with placebo, but had no effect on REM sleep duration or other
parameters of sleep architecture.(150) In a randomised, double-blind,
placebo-controlled trial involving 23 overweight but otherwise healthy adults,
subjects who received treatment with St John's wort (900 mg) daily, Citrus
aurantium extract (975 mg) daily and caffeine (528 mg) daily lost significantly
more body weight than did subjects in the placebo and no-treatment control
groups.(151)
A placebo-controlled, crossover study in 19 healthy volunteers who
received St John's wort for 15 days either alone or in combination with ethanol
(to achieve a blood alcohol concentration of 0.05%) reported that there were no
differences between the two groups in sense of well-being or adverse events.(152) A randomised,
double-blind, placebo-controlled, six-week trial involving 72 long-distance runners
and triathletes reported significant improvements in endurance capacity in
subjects who received vitamin E with St John's wort compared with subjects who
received vitamin E alone or placebo.(153)
In a randomised, double-blind trial involving 21 patients with
symmetrical mild to moderate atopic dermatitis, participants used a topical
preparation of H. Perforatum (cream containing 5% of a carbon-dioxide extract;
drug to extract ratio 20–25 : 1, containing total 9.9% hyperforins) with a
final hyperforin content of 1.5%, or placebo, twice daily for four weeks.(154) Treatment
was randomLy allocated to be applied to the left or right side of the body. At
the end of the study, the H. perforatum preparation was found to be superior to
placebo with respect to the primary outcome measure (clinical intensity of skin
lesions; p < 0.022 for H. Perforatum versus placebo).
In a randomised, double-blind, crossover trial involving 54 diabetic
and non-diabetic patients with polyneuropathy, the analgesic effects of an H.
perforatum preparation (Calmigen, Sanopharm; each tablet containing hypericin
900 mg, no further details of preparation provided) one tablet three times
daily were compared with those of placebo.(155) The rationale for investigating
the effects of H. perforatum on pain was centred around evidence that the
antidepressant effect of H. Perforatum preparations is due to effects on
monoaminergic systems, and that effects on such systems may be the mechanism of
action of agents such as tricyclic antidepressants currently used in painful
polyneuropathy. In the study, patients' daily ratings of pain using numeric
rating scales were used as the primary outcome measure. At the end of the
treatment period, there were no statistically significant differences in total
pain score between the H. perforatum and placebo groups (14 and 15, respectively;
p = 0.05), in individual pain rating scales (p = 0.09 to 0.33), or in
participants' evaluations of pain relief (p = 0.07).(155)
In a double-blind, controlled, crossover study, 12 healthy volunteers
aged 18 to 54 years received tablets containing an extract of H. perforatum
(Hyperiforte, each tablet contained 300 mg extract standardised for hyperforin
3–5% and hypericin 0.3%). Participants received placebo, and three and six
tablets of the extract as a single dose in a random order and undertook a battery
of memory tests before and after each administration. The results indicated
that the H. Perforatum extract did not have nootropic effects,(156) although as
a sample size calculation does not appear to have been carried out, it is possible
that the study did not have adequate statistical power to detect any
differences.
A preliminary study found that a mixture of oils extracted from
H. perforatum and Calendula arvensis reduced the surface area of wounds in
women who had undergone Caesarean section during childbirth, when compared with
control (wheatgerm oil).(157) However, the study did not involve random
allocation to treatment and was not blinded, so the findings cannot be
attributed definitively to the intervention. The use of intravesical instillation
of hypericin as a photosensitiser in human bladders together with blue light irradiation
and fluorescence detection has been described as a diagnostic tool for the detection
of bladder carcinoma. The technique had 98.5% specificity in detecting carcinoma
in situ and dysplasia, and had a sensitivity of 93%.(158, 159)
Pharmacokinetics Detailed pharmacokinetic studies have been carried
out with the hypericin-standardised St John's wort extract LI 160 and with
certain other H. perforatum extracts.(1, G1) Administration of single oral
doses of LI 160 (300, 900 and 1800 mg) to healthy male volunteers resulted in
peak plasma hypericin concentrations of 1.5, 7.5 and 14.2 ng/mL for the three doses,
respectively. Peak plasma concentrations were seen with hypericin after 2.0–2.6
hours and with pseudohypericin after 0.4– 0.6 hours. The elimination half-life
of hypericin was between 24.8 and 26.5 hours. Repeated doses of LI 160 (300 mg)
three times daily resulted in steady-state concentrations after four days.(160)
Oral administration of the St John's wort extract WS 5572 (300 mg, equivalent
to 14.8 mg hyperforin) resulted in peak plasma concentrations of 150 ng/mL
being reached 3.5 hours after administration.(161) The elimination half-life
was 9 hours. Following repeated doses of 300 mg three times daily, the estimated
steady-state plasma hyperforin concentrations were 100 ng/mL.
In open trials involving 18 healthy male volunteers, following oral
administration of a single tablet of a dry extract of H. perforatum (STW-3,
containing 612 mg extract equivalent to hypericin 600 mg, pseudohypericin 1200
mg, hyperforin 13.5 mg, flavonoids 73.2 mg; drug to extract ratio 5–8 : 1),
pharmacokinetic parameters for hypericin, pseudohypericin and hyperforin, respectively,
were: maximum plasma concentration, 3.14, 8.5 and 83.5 ng/mL; time to maximum concentration,
8.1, 3.0 and 4.4 hours; elimination half-life, 23.8, 25.4 and 19.6 hours.(162) The
flavonoid compounds quercetin and isorhamnetin showed two peaks of maximum
plasma concentration, separated by about four hours (quercetin: 47.7 ng/mL by
1.2 hours and 43.8 ng/mL by 5.5 hours; isorhamnetin: 7.6 ng/mL by 1.5 hours and
9.0 ng/mL by 6.4 hours). The elimination half-life for these constituents was
4.2 and 4.5 hours for quercetin and isorhamnetin, respectively. Pharmacokinetic
parameters following multiple dosing (STW-3 once daily for 14 days) were
similar.(162)
In an open, randomised, two-way, crossover study involving 12 healthy
volunteers, the bioavailability of hyperforin after a single oral
administration of a softgel capsule containing H. Perforatum dry extract 300 mg
(containing 0.3% hypericin and 5% hyperforin) was found to be superior to that
following a single oral administration of a hard gelatin capsule containing the
same extract.(163) The mean (standard deviation) peak plasma hyperforin concentrations
were 168.4 (57.8) and 84.3 (33.5) ng/mL following administration of the softgel
and hard gelatin capsules, respectively, although a p value was not reported.
Hypericin, however, was not detectable in almost half of the participants for each
dosage form. In nine male patients with superficial transition cell carcinoma
of the bladder, intravesical instillation to the bladder of 40 mL of a 8 mmol/L
hypericin solution for 2 to 3 hours followed by photodynamic diagnosis of
bladder tumours, plasma concentrations of hypericin in samples taken one hour
after the end of the instillation were below the detection limit (<6 nmol/ L).(164)
A method for the simultaneous determination of hypericin and hyperforin
in human plasma using liquid chromatography and tandem mass spectrometry
(LC–MS–MS) has been developed and validated.(165) Using the method, the limits
of quantification for hypericin and hyperforin were 0.05 ng/mL and 0.035 ng/mL,
respectively. These low limits may allow detection of ingestion of hypericin
and hyperforin for up to several days after discontinuation of treatment.
PHARMACOLOGY
Ø HERB: Saint John’s wort
(Hyperici herba). The herb consists of the fresh plant material or dried aerial
parts of Hypericum perforatum L., collected during the time of
flowering, and preparations of the same.
Ø IMPORTANT Constituents: Anthracene
derivatives, 0.1–0.15 % (hypericin, pseudohypericin), flavonoids, 2–4 % (hyperoside,
0.7 %, quercetin, rutin), acylphloroglucinols, 2–4 % (hyperforin), essential
oil (0.1–1 %), oligomeric procyanidins, and other catechinic tannins (6.5–15
%).
Ø NOTE: Plants with the
highest hypericin content generally have the highest content of all other
constituents.
Ø PHARMACOLOGICAL PROPERTIES
·
Oral hypericum preparations have mild sedative, antidepressant,
and anxiolytic effects (probably due to synergistic effects of the
constituents).
·
Oily topical hypericum preparations have mainly antiphlogistic
effects due to their high content of flavonoids; they also exhibit
antibacterial, antiviral, and immunomodulatory action.
ACTIVITIES
Analgesic (1; CAN; CRC; EFS); Anticancer (1; MAB); Antibacterial
(1; FAD; MAB; PH2; VVG); Antidepressant (2; APA; BGB; CRC; PH2; SHT; WAM);
Antidote (1; FNF; MAD); Antiedemic (1; CAN); Antiherpetic (1; MAB);
Antiinflammatory (1; APA; FAD; PIP; PH2); Antineuralgic (f; BGB);
Antiretroviral (1; APA; FAD); Antiseptic (1; HHB; PH2); Antispasmodic (f; HHB);
Antiulcerogenic (1; CAN); Antiviral (2; APA; PH2; SKY; VVG); Anxiolytic (2;
PH2; PNC); Aperitif (1; CAN); Astringent (f; CRC; EFS; PNC); COMT Inhibitor (f;
MAB); Cholagogue (f; CRC; EFS); Digestive (f; CRC; EFS); Diuretic (f; BGB; DEP;
EFS; VVG); Dopaminergic (1; MAB; PH2); Emmenagogue (f; DEM; MAD); Expectorant
(f; CRC; EFS); GABA-Reuptake Inhibitor (1; MAB); Hemostat (f; DEM; MAD);
Hypotensive (1; CAN); Immunostimulant (1; CAN); MAOI (1; KOM; PHR; PH2); Melatoninergic
(1; PH2); Nervine (1; EFS; MAB; WAM); Psychotropic (1; CAN); Resolvent (f;
CRC); Sedative (1; CAN; FAD; MAD; PH2); Serotoninergic (1; MAB; PH2); SSRI (1; MAB;
PHR; PH2); Stimulant (f; CRC); Tonic (1; CAN; CRC; WAM); Tranquilizer (1; CAN; CRC;
PNC); Uterotonic (f; EFS); Vasoconstrictor (1; CAN); Vermifuge (f; CEB; CRC;
DEP; EFS); Vulnerary (1; APA; MAB; WAM).
AIDS therapeutic
effect. Sixty
early ARC patients were administered St. Johns' Wort tablets (standardized at
0.14% hypericin) with or without AZT for 6 months. Twentyfive patients
completed the 6 months of therapy (most of the patients were lost to follow up).
No significant CD4+, CDS+ or P24 antigen levels were seen in any of the groups HPozzs.
Analgesic
activity. Ethanol/water
(1: 1) extract of the entire plant, administered intragastrically to mice, was
not effective vs hot plate and tail clip methods HPom. Ethanol/water ( 1:1)
extract of the dried aerial part, administered intraperitoneally to mice at a
dose of 250.0 mg/kg, was effective vs tail flick response to radiant heat HP0193
• Flavonoid fraction of the dried shoots, administered intraperitoneally to
mice, was effective HPom.
Anesthetic
activity. The
essential oil was effective in treating earaches when administered as an ear
drop HPons.
Antianginal
activity. The
leaf (20-60%), mixed with Filipendula ulmaria ( 40-80%) and 1.5% salicylic
acid, has been patented as a treatment for angina pectoris and cardiac diseases
HP0243 •
Antibacterial
activity. Chloroform
extract of the dried aerial part, at a concentration of 0.04 mL/disc, was
active on Staphylococcus aureus, Staphylococcus oxford, and Streptococcus
mutans, and inactive on Escherichia coli, Proteus vulgaris,
Pseudomonas aeruginosa, and Streptococcus sanguis. The water extract
was active on Staphylococcus oxford and inactive on Escherichia coli,
Proteus vulgaris, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus
mutans, and Streptococcus sanguis. The methanol extract was active
on Escherichia coli, Proteus vulgaris, Streptococcus mutans, Streptococcus
sanguis and, in broth culture,was active on Staphylococcus oxford, MIC
0.62 mg/mL, and on Staphylococcus aureus, MIC 1.25 mg/mL. The petroleum
ether extract, on agar plate at a concentration of 0.04 mL/disc, was
active on Pseudomonas aeruginosa and, in broth culture, was active on Staphylococcus
aureus, Staphylococcus oxford, Streptococcus mutans, Streptococcus
sanguis, Escherichia coli and Proteus vulgaris; MIC 0.31,
0.31, 0.31, 0.62, 1.25, and 1.25, respectivelyHrozos. The chloroform extract,
at a concentration of 1.0 gm/liter on agar plate, produced weak activity, and
the methanol extract was inactive on Klebsiella pneumonia. The chloroform
and methanol extracts were inactive on Escherichia coli, Staphylococcus aureus
and Pseudomonas aeruginosaHP0230 • Ethanol (95%) extract of the
dried entire plant, on agar plate at variable concentrations, was inactive on Aerobacter
aero genes, Bacillus globifer and erythromycin and tetracycline resistant
strains, Bacillus mycoides, Bacillus subtilis, Escherichia coli and
streptomycin resistant strain, Proteus morganii, Proteus vulgaris, Pseudomonas
aeruginosa, Serratia marcescens, and Streptococcus aureus Hrom.
Methanol extract of the dried aerial part, on agar plate at a concentration of
20.0 microliters/disc, was active on Escherichia coli; equivocal on Pseudomonas
aeruginosa and Staphylococcus aureus (methicillin-sensitive);
inactive on Enterobacter aero genes, Klebsiella pneu-monia,
Salmonella typhimurium TA98 and Serratia marcescens; and produced
weak activity on Bacillus subtilisHroz45 • Petroleum ether extract of
the dried aerial part, on agar plate, was active on Staphylococcus aureusHr0147
• The aerial part, on agar plate, was active on Escherichia coli, Proteus
vulgaris, Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus
mutansHro153 •
Antidepressant
activity. Ethanol/water
(1: 1) extract of the dried aerial part, administered intraperitoneally to mice
at a dose of 250.0 mg/kg, decreased swimming time, rota-rod walking time and
decreased exploratory activityHr0193 • Exudate from the aerial part used in a
clinical trial was superior to placebo in alleviating the symptoms of depression
as quantified by the Hamilton scaleHr0196 • Hydro-alcoholic extract of the dried
aerial part, taken orally by 105 patients with mild depression of short
duration at a dose of 900.0 mg/day, was active in a double-blind study with
either 300 mg of the extract or placebo 3 times a day for 4 weeks. The effectiveness
was judged according to the Hamilton depression scale after 2 and 4 weeks. The
values of the mean basic score in these periods fell from 15.8 to 9.6 and 7.2
in the active group, and in the placebo group from 15.8 to 12.3 and 11.3. The
differences between active and placebo groups were statistically significant at
p < 0.05 and p < 0.01 achieved after 2 and 4 weeks, respectively. In the active
group 28 of the 42 patients (67%), and in the placebo group, 13 of the 4 7
patients (28%) responded to treatment. Notable side effects were not
foundHr0161 • In a randomized, double-blind study, the effectiveness and
tolerance of a standardized preparation of Hypericum perforatum was
examined and compared to maprotiline in a group of 102 patients with
depression, in accordance with IC0-10, F 32.1. The study was conducted in the
offices of neurology and psychiatry specialists. The patients received, over a
period of 4 weeks, either 300 mg Hypericum perforatum extract or 25 mg maprotiline
pills 3 times daily. The effectiveness was determined using the Hamilton depression
scale (HAMO), the depression scale according to Von Zerssen (0-S), and the
clinical global impression scale (COl). The total score of the HAMO scale dropped
during the 4 weeks of therapy in both treatment groups by about 50%. The mean
values of the 0-S scale and the CGI scale showed similar results, and after 4 weeks
of therapy, no significant differences in either treatment group were
noticedHr0164 • A meta-analysis of 23 comparisons or placebo- controlled
randomized trials of 1757 patients with mild to moderate depressions demonstrated
that a dose of 900.0 mg/day of hydro-alcoholic extract of the dried aerial part,
when taken orally, was significantly superior to placebo (p = 0.05) and as
effective as standard antidepressant drugs. The side effects were lower in the
extract treated groupHr0164 • In a randomized double-blind, placebo-controlled
study of 50 patients with mild to moderate depression, treatment with 900 mg/day
of hydro-alcoholic extract of the dried aerial part for 4 weeks was
significantly more effective than placebo for reducing depressive symptoms.
Thirty-nine patients with depression with somatic symptoms were treated with
the extract for 4 weeks at a dose of 300 mg 3 times daily. The result showed a
significant improvement in the active treatment group at the 5% level as compared
to placebo. Seventy percent of the patients treated with the extract were free
of symptoms after 4 weeks. Typical symptoms of depression such as lack of
activity, tiredness, fatigue and disturbed sleep were especially responsive. In
no case were any undesirable side effects observedHPOIIY. The leaf, taken
orally by adults at a dose of 900.0 mg/person, was active in a double- blind, placebo-controlled
study of 105 patientsHro191 • The aerial part, taken orally by human adults of
both sexes at a dose of 1.8 gm/day, was active. In a multi-center study of the
extract in severely depressed patients (HAMD score >20), in a randomized, double-blind
study involving 20 psychiatric hospitals and day care centers in Germany, 209
patients received 6 weeks treatment of the extract, 600 mg 3 times daily or
imipramine, 50 mg 3 times daily. Results indicated that both preparations were
effective, although there was a trend in favor of imipramine. A randomized 6 week
trial comparing a dose of 900 mg daily of Hypericum perforatum extract
with 75 mg daily of amitriptyline in 165 patients with mild-to-moderate
depression showed that both the extract and amitryptyline reduced mean HAMD
scores when compared with baseline values. Amitriptyline appeared to have a
more beneficial effect than Hypericum perforatum, although the side
effects profile of Hypericum perforatum extract was more favorableHP0
141 • The aerial part, taken orally by human adults of both sexes at a dose of 900.0
mg/day, was active. The effectiveness and acceptance of a 4-week treatment with
Hypericum perforatum extract were investigated by 663 private
practitioners. The results of the 3250 patients (76% women and 24% men), were
recorded using data sheets. The age of the patients ranged from 20 to 90 years
of age (mean 51 years). Forty-nine percent of the patients were mildly
depressed, 46% intermediate and 3% severely depressed. In about 30% of the
patients, the situation normalized or improved during the therapy. Undesired
drug effects were reported in 79 (2.4%) patients and 48 (1.5%) discontinued the
therapy. The most frequently noted side effects were gastrointestinal
irritations (0.6%), allergic reactions (0.5%), tiredness (0.4%), and
restlessness (0.3%)HPots4• Ethanol (95%) extract of the aerial part, taken
orally by human adults of both sexes at a dose of 300.0 mg/day, was activeHPom.
Hydro-alcoholic extract of the aerial part, taken orally at a dose of 900.0
mg/day, was active. Seventy-two patients of 11 physi-cians' practices were
treated in a doubleblind study for a period of 6 weeks either with Hypericum
perforatum extract or with placebo. Inclusion criterion was a major depression
in accordance with DSM-III-R. The changes were controlled using 4 psychometric scales
(HAMD, D-S, BEB, GCI). The statistic evaluation revealed, after 4 weeks of
therapy, in all 4 psychometric tests, a significant improvement in the active group
as compared to the placebo group; after switching the placebo group to active treatment
(5th and 6th week of therapy), significant improvements were found in the original
placebo group. No serious side effects were observedHP0171 • Methanol extract of
the aerial part, taken orally by human adults in 16 clinical studies of St.
John's wort for the treatment of mild to moderate depression from 1991-1997,
was activeHPom. In a 6 week study comparing
Hypericum perforatum (300 mg 3 times daily) with imipramine (25 mg 3
times daily), the Hamilton depression scale scores decreased from 20.2 to 8.8
in the Hypericum perforatum group, and 19.4 to 10.7 in the imipramine
group. Fewer and milder side effects were noted in the Hypericum perforatum group.
In a 4 week double-blind trial of 105 out-patients with mild depression of
short duration, 67% of the patients taking Hypericum perforatum improved,
compared to 28% of the placebo group. No side effects were noted. Metaanalysis of
23 randomized trials of 1757 patients with mild or moderate depression indicated
that Hypericum perforatum was more effective than the placebo and as
effective as the standard antidepressant drugs. Fewer side effects were observed
in the Hypericum perforatum group (19 .8%) as compared to the
standard antidepressant (52.8%). In a 4 week study in which Hypericum
perforatum extract was compared with maprotline (25 mg/3 times a day) in
102 depressed patients, no significant differences were observed in either
groupHPo 142 • The dried aerial part, taken orally by adults, was activeHP0156
·Hro158 • Ethanol (95%) extract of the dried aerial part, administered
intragastrically to male gerbils at a dose of 2.0 mg/kg, was active vs clonidine-induced
depression. A dose of 5.0 mg/kg, administered intragastrically to mice, was
active; it enhanced the exploratory activity in a foreign environment and activity
in the water wheel testHP0160 • In a double-blind comparative study of 135 depressed
patients in 20 centers with typical depressions with single episode, several episodes,
depressive neurosis, and adjustment disorder with depressed mood in accordance
with DSM-III-R, 300 mg of hydro-alcoholic extract of the dried aerial part or
25 mg impramine were administered orally 3 times daily for 6 weeks. The main
assessment criteria were the Hamilton depression scale, the depression scale according
to Von Zerssen and the Clinical Global Impressions. In both groups, a parallel reduction
of the Hamilton score from 20.2 to 8.8 (extract, n = 67) or from 19.4 to 10.7
(imipramine, n = 68), and the transformed 0-S point values from 39.6 to 27.2 and
39.0 to 29.2 (imipramine) were found. In the group dosed with the extract,
fewer and milder side effects were found as compared to imipramine. Tincture of
the dried leaf was taken orally at a dose of 30 drops 3 times a day for 4-6
weeks by 6 women with depressive symptoms. In all of the patients there was an
increase in 3-methoxy-4-hydroxy- phenylglucol, which is an expression of antidepressive
reaction. The patients showed a quantitative improvement in anxiety, dysphoric
mood, loss of interest, hypersomnia, anorexia, morning depression, insomnia, obstipation,
psychomotor retardation and feelings of worthlessness. The leaf (20-60%), mixed
with Filipendula ulmaria ( 40-80%) and 1.5% salicylic acid, has been
patented as a treatment for angina pectoris and cardiac diseasesHrom.
Hydroalcoholic extract of the dried flower and leaf, taken orally by adults of
both sexes, was activeHP0246 •
Antifungal
activity. Ethanol
(95%) extract of the dried aerial part, on agar plate at a concentration of
6-10 mg/mL, was active on several fungiHro216 • Ethanol (95%) extract of the
dried entire plant, on agar plate at variable concentrations, was inactive on Fusarium
culmoun, Fusarium solani, Penicillum notatum and Scopulariopsis speciesHrom.
Methanol extract of the dried aerial part, on agar plate at a
concentration of 80.0 mg/disc, was inactive on Aspergillus flavus,
Aspergillus fumigatus, Fusarium tricintum, Trichoderma viride, and Trichophyton
mentagrophytes, and produced weak activity on Microsporum cookei and
Microsporum gypseumHP0189 • Ethanol/water ( 1:1) extract of the dried flowering
tops, at a concentration of 833.0 mg of the dried plant material/mL on agar plate,
was inactive on Aspergillus niger, Botrytis cinerea, Penicillum
digitata, Rhizopus nigricans, and Trichophyton
mentagrophytesHroz47 • The fresh entire plant, on agar plate at a concentration
of 1.0 gm/mL, was inactive on Cytospora species, Fames annosus, and
Pestaalotia funereaHroz48 •
Anti-inflammatory
activity. Ethanol
(80%) extract of the dried flowering tops, administered by gastric intubation
to male rats at dose of 100.0 mg/kg, produced 14% inhibition of edema vs carrageenin-induced
pedal edemaHrozoJ. The essential oil, used externally by adults of both sexes,
was active in alleviating bedsores in elderly patientsHP0249 •
Antimycobacterial
activity. Chloroform
and methanol extracts of the dried aerial part, on agar plate at a
concentration of > 1.0 gm/liter, were inactive on Mycobacterium phleiHPoZJO.
Ethanol (95%) extract of the fresh flowers ( 1 part of fresh plant material
to 3 parts of solvent), on agar plate, produced strong activity, and the water
extract produced weak activity on Mycobacterium tuberculosisHron6 • Ethanol
(95%) extract of the dried entire plant, on agar plate at vari able
concentrations, was inactive on Myco~ bacterium
phlei and Mycobacterium smegmatisHrom. Fresh leaf juice, on agar
plate, was active on Mycobacterium tuberculosis, MIC 1 :80Hrows. Methanol
extract of the dried aerial part, on agar plate at a concentration of 20.0
microliters/disc, was active on Mycobacterium phleiHro 182 •
Antipsoriatic
activity. The
leaf (20-60%), mixed with Filipendula ulmaria ( 40-80%) and 1.5% salicylic
acid, has been patented as a treatment for rheumatism, phlebitis and
psoriasisHro243 •
Antispasmodic
activity. Ethanol
(95%) extract of the dried aerial part, at a concentration of 200.0 mcg/mL, was
active on guinea pig ileum vs histamine-induced contractions, and strong
activity was produced vs barium-induced contractions. The water extract was
inactive vs histamine-induced contractions, and produced weak activity vs
barium-induced contractionsHrom.
Antitumor activity.
Water
and ethanol (95%) extracts of the entire plant, administered intraperitoneally
to mice, were inactive on Sarcoma 180 (solid) and CAEhrlich- ascitesHPoioi.
Antiviral
activity. Acetone,
hot water and ethyl acetate extracts of the aerial part, in cell culture, were
active on influenza virusHrom. Ethanol/water (1: 1) extract of the entire
plant, in cell culture at a concentration of 0.05 mg/mL, was inactive on
vaccinia virusHrozJz. The hydro-alcoholic extract and decoction of the dried
stem, at a concentration of 100.0 mcg/mL in cell culture on Vero cells, was
inactive on Herpes simplex 1 and 2 virus and HIV when assayed in JM cellsHro
194 • Water extract of the aerial part, in cell culture at a concentration of 10.0%,
was active on Herpes virus type 2, influenza virus A2 (Manheim 57) and vaccinia
virus, and inactive on poliovirus 11Hro226 • Hot water extract of the dried
flower and leaf, administered intraperitoneally to mice at a concentration of
5.0%, was active on encephalitis virus (unspecified)Hrozso.
Antiyeast
activity. Chloroform
and methanol extracts of the dried aerial part, on agar plate at a
concentration of > 1.0 gm/ liter, were inactive on Candida albicansHro210
• Methanol extract of the dried aerial part, on agar plate at a
concentration of 80.0 mg/ disc, was inactive on Candida albicans and Saccharomyces
cerevisiaeHP0189 • Ethanol/water (1: 1) extract of the dried entire plant,
on agar plate at variable concentrations, was inactive on Kloekera brevis and
Saccharomyces cerevisiaeHrom. Ethanol/water (1: 1) extract of the dried
flowering top, at a concentration of 833.0 mg of plant material/mL, was inactive
on Saccharomyces pastorianus and Candida albicansHroz47 •
Arachidonic acid
release stimulation. Methanol
extract of the aerial part was inactive vs cortical cellsHro150 •
Barbiturate
sleeping time decrease. Ethanol/ water (1: 1) extract of the dried aerial part,
administered intraperitoneally to mice at a dose of 500.0 mg/kg, was active vs CCl4-induced
hepatotoxicityHrozos.
Benzodiazepine receptor
binding. Methanol
extract of the dried flower and the dried leaf inhibited 3H-flumazenil binding to
benzodiazepine binding sites of the GABA receptors, lC50 6.83 and 200.0 mcg/mL,
respec ti vel yHro176 •
Bile secretion
increase. Ethanol/water
( 1:1) extract of the dried aerial part, administered intraperitoneally to mice
at a dose of 500.0 mg/kg, was activeHrozos.
Cardiotonic
activity. Hot
water extract of the stem, administered intravenously to frogs, produced weak
activityHr0100 •
Catechol-o-methyl
transferase inhibition. Methanol extract of the dried aerial part, at a concentration
of 1.0 mmol, was active. The petroleum ether extract was inactiveHr0170 •
Chromosome
aberrations. Ethanol
(95%) extract of the dried leaf, administered intra gastrically to hamsters at
a dose of 10.0 mL/ kg, was inactiveHrozo7.
CNS depressant
activity. Ethanol/water
( 1:1) extract of the dried aerial part, administered intragastrically to mice
at a concentration of 25.5 mg/kg, produced weak activity. The activity decreased
with increased dosage using the actimeter test, results significant at P
<0.005 levelHP0149.
Convulsant
activity. The
aerial part in both the fresh and dried form, in the ration of sheep, was active
when the photosensitized animals contacted waterHP0128.
Coronary blood
flow increase. Flavonoid
fraction of the dried aerial part, at a concentration of 1.0 mcg/mL, was active
on guinea pig heartHP0144.
Creatine
phosphokinase enhancement. The aerial part, administered intragastrically to
cattle of both sexes at a dose of 3.0 gm/kg, was activeHro143.
Cryoprotective
activity. Methanol
extract of the aerial part, in cell culture at a concentration of 40.0 mcg/mL,
was inactive vs cortical cell line. The extract was also inactive vs OP120-induced
cytotoxicity in cortical cells and NMDA-treated cortical cellsHPoiso.
Cutaneous
circulation effect. Hydro-alcoholic
extract of the aerial part, taken orally by human adults of both sexes at a
dose of 900.0 mg/day, was inactive in a clinical study of 25 individuals with
mild depression. The effect of Hypericum perforatum on cutaneous circulation
indicated no difference between the test group and the control groupHPOI74.
Cytotoxic
activity. Water
and ethanol (95%) extracts of the entire plant, in cell culture, were inactive
on CA-9KB, E050 100.0 meg/ mL and >0.1 mg/mL respectivelyHPoioi. Water extract
of the aerial part, in cell culture at a concentration of 10.0%, produced weak activity
on Hela cellsHro226 •
Diuretic
activity. Ethanol/water
( 1:1) extract of the entire plant, administered intragastrically to rats at a
dose of 7 50.0 mg/kg, was inactiveHrom. Flavonoid fraction of the dried aerial
part, at a dose of 4.0 gm/kg, produced weak activityHroz42 . Water extract of
the entire plant was active on dogsHPOIJO.
DNA repair induction.
Ethanol
(95%) extract of the dried leaves was active on rat liver cellsHrozo7.
Dopamine uptake
inhibition. Carbon
dioxide extract of the dried flower and leaf was active on synaptosomesHrozs1.
Emmolient
effect. Olive
oil extract of the flower was active as a burn treatment when applied
topicallyHro140.
GABA inhibition.
Carbon
dioxide extract of the dried flower and leaf was active on synaptosomesHrozs1.
GABA receptor
binding decrease. Hydroalcoholic
extract of the dried flower and leaf inhibited muscimol and COP binding to OABA
receptors, IC50 3.24 and 3.31 meg/ mL, respectivelyHrom.
Genotoxicity
activity. Ethanol
(95%) extract of the dried leaf was inactive in in vitro studies in systems
such as hypoxanthine guanidine phosphoribosyl transferase test, unscheduled DNA
synthesis test and Syrian hamster embryo cell transformation testHrozo1.
Glutamate
receptor binding decrease. Hydro-alcoholic extract of the dried flower and
leaf inhibited COP binding to the NMDA receptorsHrozsz.
Glutamate uptake
inhibition. Carbon
dioxide extract of the dried flower and leaf was active on synaptosomesHrozs1.
Glutamate-oxaloacetate
inhibition. Ethanol
(95%) extract of the dried leaf, administered intragastrically to mice at
variable dosage levels, was inactive vs fur spot testHrozo7.
Glycolysis
inhibition. Water
extract of the dried aerial part was active on the brainHPOI57 •
Hair stimulant
effect. Water
extract of the entire plant, applied topically together with a mixture of other
plants, was effective for alopeciaHrom.
Hemagglutinin
activity. Saline
extract of the dried seeds, at a concentration of 10%, was inactive on the
human RBCHPom.
Hepatotoxic
activity. Thirty-one
HIV positive patients were administered over-thecounter hypericin-containing
herbal extracts orally. No statistically significant changes in CD4+ levels
were seen in any patient group of the study. Five patients experienced elevated
live function testsHrozzs.
Hypertensive
activity. Hot
water extract of the stem, administered intravenously to dogs at a dose of 1.0 mL/animal,
was effecti veHPOIOO.
Inotropic
effect. Flavonoid
fraction of the dried aerial part, at a concentration of 0.1 mcg/mL, had a
positive effect on the heartHP0 144 .
Insecticide
activity. Water
extract of the aerial part was inactive on Blatella germanica and Oncopeltus
fasciatusHroz 39 •
lnterleukin-1-alpha
release inhibition. Water
extract of the entire plant was active on the human monocytes vs
lipopolysaccharide stimulationHrozsJ.
lnterleukin-1-beta
release inhibition. Hydro-
alcoholic extract of the dried aerial part was equivocal on the human blood vs
phytohemagglutinin or lipopolysaccharide-induced releaseHPo 166 .
lnterleukin-6
release. Hydro-alcoholic
extract of the dried aerial part was active on the human blood vs
phytohemagglutinin or lipopolysaccharide-induced releaseHPo 166 .
Leukotriene B-4
production inhibition. Water extract of the entire plant was active on
the human polymorphonuclear leukocytes vs calcium ionophore
A23187-phorbol-12-myristate-13-acetate stimulationHrom.
Monoamine
oxidase inhibition (Types A and B). Carbon dioxide extract of the dried flower,
at a concentration of 50.0 mcg/mL, was inactiveHrozs 1. Methanol and petroleum
ether extracts of the dried aerial part, at a concentration of 1.0 mmol,
produced weak activityHP 0170 .
Muscarinic
antagonist activity. Hydroalcoholic
extract of the aerial part, at a concentration of 1.0%, was active on mouse brainHPOI67.
Mutagenic
activity. Chloroform,
ethyl acetate and ethanol (95%) extracts of the dried aerial part, on agar
plate at a concentration of 20.0 microliters/plate, were active on Salmonella
typhimurium TA98Hro 188. Ethanol (100%) extract of the dried flower, at
variable concentrations on agar plate, was active on Salmonella typhimurium TA100
and TA98. Metabolic activation was required for activityHrozoz. Ethanol (95%)
extract and the essential oil of the dried leaf were active on Salmonella
typhimuriumHroz 04 • Tincture of the aerial part, on agar plate at a
concentration of 160.0 microliters/disc, was active on Salmonella typhimurium
TA100 and TA98. Metabolic activation had no effect on the resultsHP0187.
Narcotic
activity. Ethanol
(95%) extract of the dried aerial part, administered intragastrically to mice,
was activeHP0146.
Norepinephrine
uptake inhibition. Carbon
dioxide extract of the dried flower and leaf was active on synaptosomesHrozs 1.
Phagocytosis
stimulation. Ethanol
(95%) extract and unsaponifiable fraction of the dried leaves, administered
intraperitoneally to mice at a dose of 0.5 mL/animal, were inactiveHP 0243 .
Pharmacokinetic
study. In
a pharmacokinetic study, 1 mg of the hydro-alcoholic extract was administered
as a single dose to human adults, and blood samples were taken. From 3.5 to 8
hours after dosing, the level of the extract increased from 0.45 ng/ mL to 4.21
ng/mL. Maximum resorption time was 6 hoursHP 0145 .
Photosensitizer
activity. Fluid
extract of the entire plant, on agar plate, was inactive on Candida
albicansHPo 117 • The aerial part, in the ration of sheep, was active.
Sheep with fully pigmented skin were insensitive to the action of the
plantHr0119.
Phototoxicity. The aerial part,
in the ration of cattle of both sexes at a dose of 1.0 gm/ kg, was inactive.
The animals were dosed after exposure to sunlight. A dose of 3.0 gm/kg, administered
intragastrically, was active. When the animals were dosed after exposure to
sunlight, the temperature and respiration of the animals rose 3 to 4 hours later
and the animals were restless and
passed soft
fecesHro 143.
Prophage
induction. Ethanol
(95%) extract of the dried entire plant, on agar plate at variable concentrations,
was inactive. The assay system was intended to predict for antitumor
activityHroz17.
Reverse
transcriptase inhibition. Acetone and ethanol ( 70%) extracts of the dried entire
plant, at a concentration of 10.0 mcg/mL, were inactive. The ethanol (95%) extract
was activeHroz54.
Serotonin
receptor blocking effect. Hydroalcoholic extract of the aerial part, at a
concentration of 0.1 %, produced weak activity on a mouse brain vs 5-HT-IAA
receptorHP0167.
Serotonin uptake
inhibition. Carbon
dioxide extract of the dried flower and leaf was active on synaptosomesHroz51.
Hydro-alcoholic extract of the aerial part, at a concentration of 0.01 %, was
active on the mouse brain vs re-uptake of synaptosome preparationsHr0167.
Serotonin uptake
stimulation. Methanol
extract of the aerial part was active on the rat synaptosome, IC50 6.2 mcg/mLHro150.
Sleep
potentiation. Ethanol/water
(1: 1) extract of the dried aerial part, administered intragastrically to mice
at a concentration of 13.25 mg/kg, produced weak activity vs influence on the
sleep duration induced by pentobarbital. The activity was decreased with
dosage, results significant at p <0.005 levelHPoi49. The aerial part,
administered intragastrically to male mice, extended narcotic-induced
sleepHP0141 .
Smooth muscle
relaxant activity. Ethyl
acetate extract of the dried aerial part, at a concentration of 0.1 mg/mL, was
active on pig arterial muscle vs histamine-induced contractions, and on the coronary
artery vs prostaglandin F2 alpha-induced contractionsHP0148. Water extract of
the aerial part, at a concentration of 1 :5, and tincture at a concentration of
1:20, were active on cat and mouse intestinesHroizJ.
Smooth muscle
stimulant activity. Hot
water extract of the stem was active on the guinea pig ileum. The spasms were
blocked by atropineHPOIOO.
Spasmolytic
activity. Ethanol/water
( 1:1) extract of the entire plant was inactive on a rat uterusHrom.
Toxic effect. The aerial
partHP0154 and its hydro- alcoholic extract HPOI71, when taken orally by adults
of both sexes at a dose of 900.0 mg/ day, were inactive. In an open study of
3250 patients treated with St. John's Wort, observed side effects were
gastrointestinal (0.6%) and fatigue (0.4o/o)HPOI51 . The aerial part, administered
orally to pigs, was active. Symptoms include temperature increase to about 105
degrees Fahrenheit, rapid pulse and respiration, diarrhea and dermatitis in the
white animals after exposure to sunlight. Blistering and necrosis of the skin
and subcutaneous tissue was observed. Intestinal and stomach inflammations were
sometimes seenHro178.
Toxicity
assessment. Ethanol/water
(1: 1) extract of the entire plant, administered intraperitoneally to mice,
produced L050 > 1 000 mg/kgHPOZJZ •
Tumor necrosing
factor inhibition. Hydroalcoholic
extract of the dried aerial part was active on human blood vs
phytohemagglutinin or lipopolysaccharide-induced releaseHPOI66.
Uterine
relaxation effect. Hot
water extract of the stem was active on a non-pregnant rat uterus Hrowo.
Uterine
stimulant effect. Hot
water extract of the stem, at a concentration of 50.0 mL/liter, was active on guinea pig uterus. A
concentration of 100.0 mL/liter was active on human uterus. A dose of 2.0 mL/kg,
administered intravenously to dogs, was in- Choline content in some medicinal plants.
activeHPowo. Water extract of the leaf was
active on nonpregnant rat uterus HPOtoz.
Wound healing acceleration. Ethanol ( 60%)
extract of the dried leaf, administered intragastrically to rats at a dose of
0.1 mL/animal, increased wound strength and
rate of contraction and epithelization in excision woundsHP 0209 • Hot
water extract of the aerial part, applied externally to rabbitsHPo233 and
guinea pigs at a dose of 20.0%, was active
vs experimentally-induced wounds HP0129 •
INDICATIONS
Adenopathy
(f; CRC; JLH); Alcoholism (1; MAB); Alopecia (f; CRC); Anorexia (1; CAN);
Anuria (f; CRC); Anxiety (2; APA; KOM; PH2; PNC); Apoplexy (f; MAD); Asthma (f;
CRC; PH2); Bacteria (1; CRC; FAD; MAB; PH2; VVG); Bite (f; CRC); Bladder Stone
(f; CEB); Bleeding (f; CRC; DEM; MAD); Bronchosis (f; CRC; PH2); Bruise (2;
APA; BGB; FAD; MAB); Bunion (f; CRC); Burn (2; APA; KOM; MAD; PH2; SHT); Calcification
(f; PH2); Cancer (1; CRC; MAB); Cancer, breast (f; JLH); Cancer, lymph (f;
JLH); Cancer, ovary (f; JLH); Cancer, stomach (f; JLH); Cancer, uterus (f;
JLH); Cardiopathy (f; MAD); Catarrh (f; CRC); Cerebrosis (f; CRC; PH2);
Chickenpox (1; MAB); Childbirth (f; CRC); Cholecystosis (f; APA; FAD; PH2); Climacteric
(f; MAD); Cold (f; APA; PNC); Cold Sore (1; MAB); Concussion (f; CRC);
Congestion (1; APA); Crohn’s Disease (f; CRC); Cough (f; APA; DEM; PNC);
Coxalgia (f; CRC; MAD); Cramp (f; APA; HHB; MAD); Cut (f; FAD); Cyanosis (f;
MAD); Cystosis (f; CRC); Cytomegalovirus (1; MAB); Depression (2; APA; BGB;
CRC; FAD; KOM; PH2; SHT; WAM); Dermatosis (2; APA; PHR; PH2); Diarrhea (f; APA;
FAD; MAB; PH2); Duodenosis (f; MAD); Dysentery (f; CRC; FAD; MAB); Dysmenorrhea
(f; APA CRC; MAD; PNC); Dyspepsia (2; APA; KOM; PHR; PH2); Dysuria (f; CEB;
CRC); Eczema (1; PH2); Endometriosis (f; MAD); Enterosis (f; DEM); Enuresis (f;
CRC; MAB; PH2); Epilepsy (f; MAD); Epistaxis (f; DEM); Fever (f; DEM);
Fibrososis (f; CAN); Flu (1; CAN); Gas (f; MAD); Gastroduodenosis (1; CAN);
Gastrosis (1; CAN; CRC; PH2); Gout (f; MAD; PH2; VVG); Headache (f; CRC; MAD);
Hematuria (f; CEB); Hemoptysis (f; CRC; MAD); Hemorrhagia (1; CRC; MAB);
Hemorrhoid (1; APA; CRC; HHB; MAD); Hepatosis (1; CAN; MAB; MAD; MAN); Herpes
(1; MAB); High Blood Pressure (1; CAN); HIV (1; CAN; JAD); Hydrophobia (f;
CRC); Hysteria (f; BGB; CRC; MAB); Immunodepression (1; CAN); Impotence (f;
CRC); Induration (f; CRC; JLH); Infection (1; APA; CAN; MAB); Inflammation (1;
APA; CRC; FAD; PIP; PH2); Insomnia (1; CAN; CRC; FAD; FNF; MAD; PH2); Jaundice
(f; CRC; MAB; MAD); Lumbago (f; MAD); Lymphosis (f; JLH); Mania (1; FNF; MAD);
Mastosis (f; CRC; JLH; MAD); Melancholy (1; FNF; MAD); Menopause (1; CAN; MAB);
Menorrhagia (f; MAB); Migraine (f; MAD); Myalgia (2; KOM; PHR; PH2; SHT); Neck
(f; CRC); Nephrosis (f; APA); Nerve (f; CRC); Nervousness (1; APA; CAN; CRC;
FAD; MAD; PH2; PNC); Neuralgia (1; BGB; CAN; MAB); Neurasthenia (f; CRC);
Neurofibromatosis (f; MAD); Neurosis (1; BGB; CAN; PH2); Noctambulism (f; MAD);
OCD (1; WAF); Oliguria (f; CRC); Otosis (1; SKY); Oxyurid (f; HHB); Pain (1;
CAN; CRC; EFS); Paralysis (f; CRC); Parasite (f; MAB); Pertussis (f; CRC);
Phthisis (f; CRC); Pulmonosis (f; APA; CEB); Rabies (f; CRC); Radiation (f;
AIL); Rheumatism (1; MAB; PH2; PNC); SAD (2; MAB); Sciatica (1; CAN; CRC; MAB);
Shingles (1; MAB); Snakebite (f; DEM); Sore (f; CRC; DEM; FAD); Sore Throat (f;
CEB); Spine (f; CRC); Sprain (1; BGB; WAM); Staphylococcus (1; PH2); Sterility
(f; DEM); Stimulant (f; EFS); Stomatosis (f; CEB); Strain (1; WAM);
Streptococcus (1; PH2); Stress (1; CAN); Sunburn (1; AIL); Swelling (1; CAN;
CEB; MAB; MAD); Tetanus (f; CRC); Tonsilosis (f; PH2); Tuberculosis (f; CRC); Ulcer
(1; CAN; CRC; MAB; MAD); Ulcus cruris (f; MAD); Uterosis (f; JLH; MAD); VD (f; DEM);
Viral Hepatitis (1; MAB); Virus (2; APA; PH2; SKY; VVG); Vitiligo (1; CRC;
SKY); Water Retention (f; BGB; DEP; EFS; MAD; VVG); Worm (f; CEB; CRC; DEP;
EFS; FAD); Wound (2; APA; KOM; PH2; WAM).
INDICATIONS AND USAGE
Approved by
Commission E: "' '-
• Anxiety
• Depressive moods
• Inflammation of the skin
• Blunt injuries
• Wounds and burns
Internally, the drug is used for psychovegetative
disturbances, depressive moods, anxiety and nervous unrest.
Externally, the oily Hypericum preparations are
used for . treatment and post-therapy of acute and contused injuries and for
first-degree burns.
Unproven uses: The herb has been
used for worm infestation, bronchitis and asthma, gallbladder disease,
gastritis (also diarrhea), nocturnal enuresis, gout and rheumatism. Oily
Hypericum preparations are used internally for dyspeptic complaints, and
externally for the treatment of myalgia.
Chinese Medicine: In a gargle
solution, the herb is used externally for tonsillitis. The herb is also
administered externally as a lotion for dermatoses.
Homeopathic Uses: The herb has
been used for treatment of peripheral and central nervous system injuries,
depressive moods, asthma and cerebral-vascular calcification.
INDICATIONS
– Internal use: Depressive
mood, anxiety
– External use (oily
preparations): Contusions, wounds, burns
PRODUCT AVAILABILITY
Cream; sublingual capsules;
solid forms: 100, 300, 500 (0.3% hypericin), 250 (0.14% hypericin) mg; tincture
PLANT PART USED: Flowers
DOSAGES
DOSAGES
·
Adult PO: 300 mg hypericum
extract, standardized to 0.3% hypericin, tid
·
Adult topical: apply prn
DOSAGES
Dosages
for oral administration (adults) recommended in standard herbal reference
texts(G6, G7) are the same for several traditional uses; examples are given
below.
·
DRIED HERB 2–4 g as an infusion three times daily.(G7)
·
LIQUID
EXTRACT 2–4mL (1 : 1 in 25%
alcohol) three times daily.(G7)
·
TINCTURE 2–4mL (1 : 10 in 45% alcohol) three times
daily.(G7)
·
Doses of St John's wort extracts used in clinical trials
involving patients with mild to moderate depression generally range from
240–1800 mg daily (equivalent to varying concentrations of hypericin and
hyperforin, depending on the extract), typically for four to six weeks.(24)
DOSAGES
·
2–4 g dry herb (0.2–1 mg hypericin)/day (JAD); 2–5 g dry herb/day
(MAB); 2–4 mL liquid herb extract (PNC); 2–4 g dry shoot, or in tea, 3 x/day
(CAN); 1–2 tsp (2–4 g flowers)/cup water 1–2 /day for 4–6 wk (APA);
·
2–4 mL liquid flowering tops extract (1:1 in 25% ethanol) 3 x/day
(CAN); 2–4 mL flowering tops tincture (1:10 in 45% ethanol) 3 x/day (CAN); 1–2 mL
flowering tops tincture 3 x/day (SKY);
·
1–2.7 mg/day hypericum (MAB);
0.2–1.0 mg total hypericin (PIP); 500 mg StX (0.2% hypericin) (SKY);
·
1 (430 mg) capsule (StX with 300 mg certified potency extract
with at least 0.3% hypericin in a synergistic base of St. John’s-Wort powder) 3
x/day with a large glass of water (NH).
DOSAGES
MODE OF ADMINISTRATION: Comminuted drug,
herb powder, liquid and solid preparations for internal use; liquid and semi-solid
preparations for external use; preparations made with fatty oils for external
and internal use.
HOW
SUPPLIED:
CAPSULES—(standardized at 0.3% hypericin) 125mg,
150mg, 250mg, 300mg, 350mg, 370mg, 375mg, 400mg, 424mg, 434mg, 450mg, 500mg,
510mg Capsules, Extended Release—(standardized at 0.3% hypericin) 450mg, 900mg,
lOOOmg
DRIED HERB
Extract—I.T
Injection—1%
Liquid—300 mg/5mL, 250 mg/mL
Liquid Dilutions—3x,
6x, 30x,12c, 30c
Pellets—3x, 6x, 12x, 12c, 30c
Tablets—(standardized at 0.3% hypericin) lOOmg,
150mg, 300mg, 450mg
Tincture—1:10
Transdermal—900mg/24hr ' :-
PREPARATION: To prepare an
infusion, use 2 teaspoonfuls of drug in 150 mL boiling water and steep for 10
minutes.
DAILY DOSAGE: In general, a range
of 200 to 1000 micrograms/ day of hypericin is recommended for treatment of depression
(Anon, 1996). Total hypericin concentrations of Hypericum extracts may vary
widely, therefore caution should be taken in determining dosage (Fachinfo
Helarium Hypericum, 1996; Fachinfo Remotiv, 1996; Hansgen, 1993; -Schmidt &
Sommer, 1993; Vorbach, 1994; Woelk, 1994). - For depressive moods, it is
recommended the herb be administered for the duration of 4 to 6 weeks; if no improvement
is apparent, a different therapy should be initiated.
DEPRESSION:
Capsules/tablets
— 300 mg of the standardized extract should be administered three times daily
(Clausson & Muller, 1997; Fachinfo Helarium Hypericum, 1996).
Dried herb
— 2 to 4 grams taken 3 times daily (Fachinfo Helarium Hypericum, 1996; Fachinfo
Remotiv, 1996; Hansgen, 1993; Schmidt & Sommer, 1993; Vorbach, 1994; Woelk,
1994).
Tea — St. John's Wort as a tea is the traditional
method of administration, with a single dose of 2-3 grams dried herb placed in
boiling water. If dried herb of 2 grams is used, and the dried herb to extract
ratio is 6, a usual dose of the extract .- would be 300 milligrams (Schultz,
1997).
Liquid extract
1:1 in 25% ethanol — 2 to 4 milliliters taken 3 times daily (Fachinfo Helarium
Hypericum, 1996; Fachinfo * Remotiv, 1996; Haensgen, 1993; Schmidt &
Sommer, 1993; Vorbach, 1994; Woelk, 1994).
Tincture: (1:10) in 45% ethanol — 2 to 4
milliliters, 3 times a day (Fachinfo Helarium Hypericum, 1996; Fachinfo Remotiv,
1996; Hansgen, 1993; Schmidt & Sommer, 1993; Vorbach, 1994; Woelk, 1994). Wounds,
bruising and swelling: The herb is applied topically and locally for treatment.
The activity of the topical preparations is based on the hyperforin content,
which is highly variable depending on the method of oil preparation. The
preparation may be stable for a few weeks up to 6 months. (Maisenbacher &
Kovar, 1992)
HOMEOPATHIC DOSAGE: The daily dosage
for homeopathic indications is 5 drops, 1 tablet or 10 globules every 30 to 60 minutes
for acute therapy, and 1 to 3 times daily for chronic use. Parenterally, 1 to 2
mL subcutaneously administered three times daily for acute therapy and once
daily for chronic therapy. The ointment is applied 1 to 2 times daily for acute
and chronic use (HAB1).
STORAGE: Store at room
temperature, away from heat, moisture and direct light. Hyperici oleum has a
limited shelf life. One study showed that a sample containing 62 milligrams of
hyperforin (the active ingredient in the oil) contained no hypericin in 14 days.
If sunlight is not used to prepare the oil, then the breakdown is slower, but
still less than 30 days. Various oil preparation methods have been described,
including one with eutanol G, which showed stability for 6 months. Researchers
evaluated^ 6 commercial samples of oil of Hypericum containing 2.2 to 20.8 milligrams/deciliter.
All hyperforin was gone by the end of five weeks (Maisenbacher, 1992).
DOSAGE
AND DURATION OF USE
·
TINCTURE:
Extract 20 g of the herb in 100
g of 70 % ethanol and filter. Store away from light. Take 3–4 mL three times a
day. The mean daily dose should be 0.2–1 mg total hypericin in any dosage form.
·
FOR
DEPRESSIVE MOOD: The herb preparations should be
taken for a period of at least 4 to 6 weeks to assess benefit. Solid and liquid
hypericum preparations should be given at doses corresponding to 300 mg native
extract (standardized to 0.3 % hypericin, and/or 2–3 % hyperforin), 2 to 3
times a day.
PRECAUTIONS AND ADVERSE REACTIONS
General: No health hazards
are known in conjunction with the proper administration of designated
therapeutic dosages. The tannin content of the drug can lead to digestive complaints,
such as feeling of fullness or constipation. Patients with a previous history
of photosensitization to various chemicals should be cautious of direct sun
exposure (Wheatley, 1998).
Central Nervous System Effects: Restlessness
(0.3%) and fatigue (0.4%) occurred in 3250 patients in one study of depressed
patients (Woelk, 1994). In another study, fatigue/ tiredness was reported in 5%
of subjects, and restlessness in 6% (Vorbach, 1997). Symptoms are difficult to
evaluate since the herb is being used to treat depression, which may have
similar symptoms. Headache was noted in 7% of studies reviewed (Wheatley,
1998).
Fertility Effects: High
concentrations of St. John's Wort in vitro, was mutagenic to sperm cells
and adversely effected oocytes. The data suggests St. John's Wort given
at high concentrations damages reproductive cells (Ondrizek, 1999).
Gastrointestinal Effects: Gastrointestinal
effects were noted in 0.6% of patients in one study. Anorexia occurred in 0.55%
(n=18), diarrhea occurred in 0.55% (n=18), nausea occurred in 0.55% (n=18), and
gastrointestinal pain or stomachache occurred in 0.55% (n=18) of 3250 patients
taking Hypericum extract 300 milligrams 3 times daily (Woelk, 1994). Three percent
of patients in one study developed dry mouth and 5% had gastrointestinal
complaints Vorbach, 1997). Constipation was reported in 5% of cases reviewed
(Wheatley, 1998).
Dertnatologic Effects: Photosensitization
has been observed in animals following intakes of large quantities of the drug (starting
at 3 g per kg body weight, which would be 150 g for a person weighing 50 kg).
St. John's Wort photosensitization is dose-related, and has occurred with
plasma concentrations of 50 meg of hypericin per mL, according to Schulz'
Rational Phytotherapy—six orders of magnitude above that of patients taking an
extract of 300 mg of 0.6% hypericin three times a day. Hypericism is defined as
a sensitivity to light seen in animals who have ingested certain Hypericum
species. The Hypericum pigments are carried to the skin, and in the unpigmented,
unhaired portions of the skin of sheep, cattle, horses, goats and swine may
produce sunlight induced rash and blisters (Giese, 1980; Southwell & Campbell,
1991). However, such a reaction is unlikely with administration of therapeutic
dosages in humans.
1. Hypericum
extract, especially at higher doses or with long-term use, may cause photosensitivity
with sunburn-like lesions and inflammation of the mucous membranes, at least in
animals (Duran & Song, 1986). Photosensitization has been demonstrated in a
controlled clinical trial using metered doses of hypericin and subsequent
exposure to UVA/UVB radiation (Roots, 1996).
2. Significant
phototoxicity did occur in HIV-infected persons administered intravenous
hypericim, 0.25-0.5 mg/kg twice weekly, or 0.25 mg three times weekly, or oral hypericin
0.25 mg/kg daily (Gulick, 1999).
3. Pruritus and
exanthema occurred in 17 of 3250 patients (0.52%) taking Hypericum extract 300
milligrams three time a day (Woelk, 1994). Pruritus was found in 2% of patients
taking Hypericum for depression (Wheatley, 1998).
4. A case report
involved one patient taking St. John's Wort who developed subacute polyneuropathy
after sun exposure (Bove, 1998).
Drug Interactions:
MAOI—Although there is poor documentation,
concomitant administration of St. John's Wort and a MAOI , such as tranylcypromine,
phenelzine, may lead to increased effects and possible toxicity (hypertensive
crisis)-See~Contraindications (Hoelzl & Ostrowski, 1986; Mueller & Schaefer,
1996; Suzuki, 1984). It is prudent to avoid concomitant use with beta-sympathomimetic
amines, e.g., ma huang or pseudoephedrine (Miller, 1998).
SSRFs—St. John's Wort taken concomitantly
with an SSRI, such as fluoxetine, paroxetine, sertraline, fluvoxamine or citalopram,
may lead to an increased effect and possible toxicity "serotonin syndrome",
e.g., sweating, tremor, flushing, confusion and agitation. St. John's Wort has
slight serotonin reuptake properties. A case report suggests that
coadministration of St. John's Wort with paroxetine has resulted in a clinical
syndrome resembling a sedative/hypnotic intoxication (Gordon, 1998). Tannic
acids present in St. John's Wort may inhibit the absorption of iron (Miller,
1998). Concomitant use with other photosensitizers, such as tetracyclines, sulfonamides,
thiazides, quinolones, piroxicam and others should be avoided (Miller, 1998). Hypericum
extract has been reported to significantly prolong narcotic-induced sleeping
times and to antagonize the effects of reserpine (Okpanyi, 1987).
Cyclosporine — Decreased serum concentrations have occurred
with use of St. John's Wort (Bon, 1999). Acute cellular transplant rejection in
heart transplant patients due to an interaction between St. John's Wort and
Cyclosporine has been reported. St. John's Wort has been proven to induce the cytochrome
P450 enzyme system, the major pathway for cyclosporine metabolism. Heart
transplant rejection has been reported as soon as 3 weeks after St. John's Wort
is added to the drug regimen of heart transplant patients maintained on cyclosporine
therapy (Ruschitzka, et al., 2000).
Indinavir — An open label study was conducted
involving healthy volunteers that were administered 800 mg indinavir every 8
hours along with 300 mg St. John's Wort standardized to 0.3% hypericin 3 times
daily. Results showed a 57% reduction in the area under the curve for the
protease inhibitor and an 81% decrease of the extrapolated 8-hour indinavir
trough value. The authors concluded that a reduction of this magnitude could
lead to development of drug resistance and treatment failure (Piscitelli, et
al., 2000). Clinicians are warned that St. John's Wort may significantly affect
plasma concentrations of any drug that is metabolized by the cytochrome P450
system.
Ethinyloestradiol and desogestrel
(combined oral contraceptive) — Breakthrough bleeding has occurred with
concomitant use of St. John's Wort (Bon, 1999). Hypericin causes a reduction in
barbiturate-induced sleeping times (Ozturk, 1992).
Theophylline — The herb has decreased theophylline
levels on a patient stabilized on theophylline therapy (Nebel, 1999). Co-administration
of St. John's Wort extract (LI 160) with digoxin resulted in a significant
decrease in digoxin Grough, AUC (0-24), and Cmax values compared to placebo.
Therefore, St. John's Wort may reduce efficacy of digoxin and make a patient a
nonresponder, whereas increased toxicity may be anticipated after withdrawal of
the herb (Andreas, 1999). ... - St. John's Wort (600-900 mg/day) taken
concomitantly with sertraline (50-75 mg/day) after 2 to 4 days, resulted in a presumed
serotonin syndrome consisting of dizziness, nausea, vomiting, headache, epigastric
pain, anxiety, confusion, and/or feelings of restlessness and irritability.
Cyproheptadine was used to reverse the symptoms and after discontinuation of
the herb-drug therapy, all symptoms resolved (Lantz, 1999).
Nefazadine (100 mg BID) and St. John's Wort (300
mg TID) taken simutaneously resulted in nausea, vomiting and restlessness after
3 days of therapy. The symptoms improved after stopping the nefazadine and
continuing with St. John's Wort (Lantz, 1999).
Figure 2. Squill – dried drug substance (bulb).
(Barnes
et al., 2007)
OVERDOSAGE
Besides
the already-mentioned symptoms, overdosage can lead to cardiac rhythm
disorders, life-threatening .ventricular tachycardia, atrial tachycardia with
atrioventricular block, stupor, vision disorders, depression, confused states,
hallucinations and psychosis. Fatal dosages lead to cardiac arrest or asphyxiation.
Treatment
of poisoning includes gastric lavage and instillation of activated charcoal.
All other measures are to be carried out according to the symptoms. In case of
potassium loss, careful replenishment; for ectopic impulse formation in the
ventricle, administration of phenytoin as antiarrhythmic drug; lidocaine for
ventricular extrasystole; for pronounced bradycardia, atropine or orciprenaline.
The prophylactic use of a pacemaker is recommended. Hemoperfusion for
eliminating the glycosides or the administration of cholestyramine for
interrupting the enterohepatic circulation are possible.
CONTRAINDICATIONS, INTERACTIONS, AND SIDE
EFFECTS
CLASS 2D.
May potentiate MAOIs (AHP). Active ingredients may be photoactive, especially
in fair-skinned people. Reichert takes it even more seriously: Although
hypericum is not as strong as synthetic MAOIs, patients should still avoid the
things usually avoided: high tyramine foods (smoked or pickled), alcoholic beverages,
amphetamines, cold and hay fever remedies, narcotics, tryptophan, and tyrosine
(I no longer believe this caveat is desirable). Do not take during pregnancy or
intense sun exposure (Reichert, 1994; WAM). Commission E reports adverse effect
of photosensitivity. Other sources report flowering top permitted for external
use only; not to be used before exposure to sunlight (AEH). Foster (1996) is
moderate, suggesting that St. John’s-Wort should not be mixed with synthetic
antidepressants. Because it may inhibit MAO, taking it with SSRIs, such as
Prozac, could cause serious health damage. Although side effects have not been
reported in clinical studies, range animals eating the plant and then standing
in bright sunlight have experienced sunburn or blindness from
photosensitization. This treatment option should be discussed with your health
care provider (Foster, 1996). The Herbal PDR state that photodermatosis in animals
usually kicks in after high doses, such as 3000 mg per kg body weight (PHR).
CAN cautions that hypericin is phototoxic.
“Mice given 0.2–0.5 mg of the
herb were found to develop severe photodynamic effects. Delayed hypersensitivity
or photodermatosis has been documented for St. John’s-wort, following the
ingestion of a herbal tea made from the leaves” (CAN). ESCOP recommends a
limited daily intake of 1 mg total hypericin (QRNM, 1997:292). Because of slight
uterine activity in vitro, its use in pregnancy and lactation is to be
avoided (CAN). No contraindications or drug drug interactions reported (PIP). A
recent Internet message cautions about the potential for serotonin syndrome. Symptoms
include chills, confusion, fever, myoclonus, hyperactive reflexes, myoclonus,
speech difficulties, and sweating. Cannot be mixed with an SSRI. That is likely
to produce serotonin syndrome—severe headache, tachycardia, and
diaphoresis—which resembles neuroleptic malignant syndrome (O’Brien, 1998).
Recently found to detoxify all the same drugs that grapefruit potentiates. It
induces cytochrome P3A4 450, which speeds up metabolism of several drugs. Nierenberg
et al., 1999 kindly remind us that, like synthetic antidepressants, this herbal
antidepressant may rarely induce hypomania in manic patients. Poorly designed
Loma Linda studies (Ondrizek) suggest that hypericum may interfere with
fertility. But this was based on soaking “skinned human sperm” for 24 hours in
hypericum tea as I recall.
CONTRAINDICATIONS
Simultaneous
use of a MAO inhibitor: St. John's Wort contains some weak monoamine oxidase
inhibitor (MAOI) properties that may add to the effects of other MAOI drugs, therefore
theoretically increasing the risk for hypertensive crisis (Hoelzl &
Ostrowski, 1986; Muller & Schaefer, 1996; Suzuki, 1984).
SIDE
EFFECTS/ADVERSE REACTIONS
CNS: Dizziness, insomnia, restlessness, fatigue (PO)
GI: Constipation, abdominal cramps (PO)
INTEG: Photosensitivity, rash, hypersensitivity
INTERACTIONS
Drug
ACE inhibitors,
hormonal contraceptives, loop diuretics, NSAIDs, sulfonamides, sulfonylureas,
tetracyclines, thiazide diuretics: St.
John’s wort combined with these products may lead to severe photosensitivity; avoid
concurrent use.
Alcohol, MAOIs: St. John’s wort may increase MAO inhibition (suggested
by early studies); do not use alcohol, MAOIs and St. John’s wort concurrently
until research is available.
Amphetamines,
antidepressants, trazodone, tricyclics: St.
John’s wort used with these products may cause serotonin syndrome.
Antiretrovirals,
nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors: Studies indicate that St. John’s wort taken PO in combination with indinavir may decrease the
antiretroviral action of this drug. Cytodrome P450 1A2, 2C9, 3A4: St. John’s wort induces these enzyme systems.
Immunosuppressants:
Rejection of transplanted
hearts has occurred when St. John’s wort was taken PO with cyclosporine, an
immunosuppressant. Other immunosuppressants may have the same drug interaction
in heart transplants, as well as other transplants.
Paroxetine: Increased sedation may result when paroxetine is
combined with St. John’s wort (Gordon, 1998).
SSRIs: Serotonin syndrome and an additive effect may occur
when SSRIs are combined with St. John’s wort. Concurrent use may lead to coma.
Do not use concurrently.
INTERACTIONS—CONT’D
Food
Catecholamines,
tyramine: Limit foods high in tyramine or
cat e chol amines until further research confi rms or denies the MAOI action of
St. John’s wort taken PO.
Lab Test
Growth hormone: St. John’s wort may cause increased growth hormone (somatotropin,
GH).
Digoxin, serum
iron, serum prolactin, theophylline: St.
John’s wort may cause decreased serum prolactin, theophylline (aminophylline),
serum iron, and digoxin (peak and trough concentrations).
Pharmacology
Pharmacokineticss
Very little is known about the pharmacokinetics in
humans. St. John’s wort is thought to cross the blood-brain and placental
barriers and possibly enter breast milk.
SIDE-EFFECTS, TOXICITY
CLINICAL DATA
Data relating to the frequency and type of adverse effects associated
with treatment with St John's wort extracts are available from randomised
controlled trials, systematic reviews and meta-analyses of such trials, and
from post-marketing surveillance and other observational studies. Collectively,
the data indicate that certain St John's wort extracts are well-tolerated when
taken at recommended doses for shorter periods of time (around eight
weeks).(131, 166) Data from the small number of longer-term (one year) studies
support the tolerability of certain St John's wort extracts, although further
investigation of long-term use is warranted. Adverse events/effects reported
are generally mild and most commonly gastrointestinal symptoms. These observations,
however, are based on data collected in the settings of formal randomised or
observational studies, usually where H. perforatum has been prescribed under
the supervision of a physician, not taken as self-treatment.
A small number of studies has explored the effects of
selftreatment with St John's wort products. In a cross-sectional study involving
452 members of a depression self-help group (response rate = 17%), 63 of the
452 respondents (28%) reported adverse effects, including psychological symptoms,
allergic reactions and visual disturbances, that they believed to be related to
use of St John's wort.(167) The safety of St John's wort products taken as self-treatment
without supervision by a healthcare professional requires further study.
A Cochrane systematic review included 37 randomised,
doubleblind, controlled clinical trials of monopreparations of H. perforatum
and involving a total of 4925 patients with depressive disorders (see
Therapeutic effects, Depression).(24) Of the 26 placebo-controlled trials
included in the review, data for analysis of the number of participants withdrawing
for any reason were available from 19 trials, for withdrawing due to adverse
effects from nine trials and for numbers of patients reporting adverse effects
from 16 trials. Compared with placebo recipients, slightly fewer H. perforatum
recipients withdrew from trials for any reason (odds ratio, 95% CI: 0.82, 0.64–1.06),
withdrew due to adverse effects (odds ratio, 95% CI: 0.61, 0.28–1.31), and
reported adverse effects (odds ratio, 95% CI: 0.79, 0.61–1.03). Compared with
SSRIs, H. perforatum extracts were associated with a slightly lower probability
of withdrawing from the study due to adverse effects (odds ratio, 95% CI: 0.60,
0.31–1.15; data from six trials) and reporting of adverse effects (odds ratio,
95% CI: 0.75, 0.52– 1.08; data from five trials), whereas overall withdrawal
rates were similar (odds ratio, 95% CI: 0.95, 0.65–1.40; data from six trials).(24)
Compared with older antidepressant agents, H. perforatum extracts were associated
with a lower probability of withdrawing for any reason (odds ratio, 95% CI:
0.65, 0.46–0.92; data from seven trials), withdrawing due to adverse effects
(odds ratio, 95% CI: 0.25, 0.14–0.45; data from six trials) and of reporting
adverse effects (odds ratio, 95% CI: 0.39, 0.31–0.50; data from seven trials).
It is important to consider that there is qualitative and quantitative variation
in the composition of different manufacturers' products and the results of the
analyses above should not be extrapolated to other H. Perforatum preparations.
The review described above(24) was an update, with tighter inclusion
and exclusion criteria, of a previous Cochrane systematic review of 27
randomised controlled trials of H. perforatum preparations in depressive
disorders.(129) The previous review reported that, in the trials comparing St
John's wort with standard antidepressants, the proportions of patients reporting
side-effects were 26.3% and 44.7%, respectively (rate ratio 0.57 and 95% CI
0.4–0.69).(129) Another meta-analysis which employed tight inclusion criteria
reported that tricyclic antidepressants were associated with a higher proportion
of side-effects than were St John's wort preparations (47% versus 26.4%,
respectively, relative risk 1.72 and 95% CI 1.30–2.14).(130)
A randomised, double-blind, multicentre trial comparing the effects
of a hydroalcoholic extract of H. perforatum herb (WS-5570, drug to extract
ratio 3–7 : 1, standardised for hyperforin 3–6% and hypericin 0.12–0.28%;
Schwabe Pharmaceuticals) with those of paroxetine in the acute treatment of
moderate to severe depression has been published since the revised Cochrane review(24)
was completed. In the study, 251 participants with acute major depression
received H. perforatum extract 300 mg three times daily (increased to 1800 mg
daily in non-responders), or paroxetine 20 mg daily (40 mg daily for
non-responders), for six weeks.(128) During the study, 55% of H. perforatum recipients
reported a total of 172 adverse events and 76% of paroxetine recipients
reported a total of 269 adverse events, representing incidences of 0.035 and
0.060 adverse events per day of exposure for H. perforatum and paroxetine,
respectively. Gastrointestinal adverse events were the most common adverse
events reported for both groups. Data were not provided on numbers and types of
adverse events considered to be related to treatment.
A systematic review of large-scale observational studies of H. perforatum
extracts in patients with depressive disorders also provides data on adverse
events. The review included 16 nonrandomised studies (involving a total of 34
804 patients) each involving at least 100 participants with depressive
disorders who were treated with H. perforatum preparations for at least four weeks
(see Therapeutic effects, Depression).(131) Overall, 13 studies reported data
on proportions of participants withdrawing due to adverse events; these ranged
from 0% to 2.8% in shortterm studies and from 3.4% to 5.7% in longer-term (one
year) studies. Twelve studies reported data on proportions of participants with
adverse events (range 0–49.3%) and 12 (not the same 12 studies) reported data
on proportions of participants with sideeffects (range 0–5.9%). These data,
however, should be interpreted cautiously as most of the studies did not
describe adequately how these data were collected, clear definitions for the
terms adverse events and adverse effects were not always provided, and as no
serious adverse events were reported among the 30 000 patients, this raises questions
about the methods used to collect data.(131) The most frequently reported
adverse events or side-effects were gastrointestinal symptoms, followed by increased
sensitivity to light and other skin reactions.
Photosensitivity Sensitivity to sunlight following the ingestion
of hypericum or hypericin, the photosensitising agent in H. perforatum,(168,
G33) is known as hypericism. Several studies have explored the photosensitising
potential of hypericin-containing H. perforatum extract following oral
administration. In a double-blind, crossover, single-dose study involving 13
healthy volunteers who received placebo or St John's wort extract (LI 160)
(900, 1800 and 3600 mg containing 0, 2.81, 5.62 and 11.25 mg total hypericin,
respectively), no evidence of photosensitivity was observed with or without St
John's wort following skin irradiation with both UV-A and UV-B light 4 hours after
dosing.(169) In a multiple-dose study in which 50 volunteers received St John's
wort (LI 160) (600 mg) three times daily (equivalent to 5.6 mg total hypericin
daily) for 15 days, a moderate increase in UV-A sensitivity was observed.(169)
However, the doses used were higher than those recommended therapeutically. In another
single-dose study, administration of St John's wort (LI 160) (1800 mg,
equivalent to 5.4 mg total hypericin) to 12 healthy volunteers resulted in a
mean serum total hypericin concentration of 43 ng/mL and a mean skin blister
fluid concentration of 5.3 ng/mL.(170) After
administration of St John's wort (300 mg) three times daily for seven
days in order to achieve steady-state concentrations, the mean serum total
hypericin concentration was 12.5 ng/mL and the mean skin blister fluid
concentration was 2.8 ng/mL; these concentrations are below those estimated to
be phototoxic.(170) Further randomised, controlled, single- (six or 12 tablets
of LI-160, equivalent to 5.4 and 10.8 mg hypericins, respectively; n = 48) and
multiple-dose studies (three tablets of LI- 160 daily, equivalent to 2.7 mg
hypericins daily, for seven days; n = 24) found no statistically significant
differences in minimum erythema threshold doses (of light irradiation),
erythema index and pigmentation index between treated and untreated skin areas (p
> 0.05 for each).(171, 172)
Collectively, the evidence indicates that the threshold for phototoxicity
of hypericin is between 100 and 1000 ng/mL.(171) Since serum and skin
concentrations of hypericin after oral administration of recommended doses are
below 100 ng/mL, photosensitivity seems unlikely. However, caution is advised
as it is possible that there may be unusual absorption of hypericin in some
individuals and, particularly in fair-skinned individuals and after extended
periods of solar irradiation, there may be increased susceptibility to the
photosensitising properties of hypericin.(171)
A study reported that HIV-positive patients treated with oral hypericin
(0.05 mg/kg) for 28 days developed mild symptoms of photosensitivity on
exposure to sunlight and that two patients developed intolerable symptoms of
photosensitivity when the dose was increased to 0.16 mg/kg.(173) In a
dose-escalating study involving 30 HIV-infected patients treated with oral (0.5
mg/kg daily) or intravenous hypericin (starting dosage 0.25 mg/kg twice or
three times weekly), 16 patients discontinued treatment before completing eight
weeks of therapy because of moderate or severe phototoxicity; severe cutaneous phototoxicity
was observed in 11 out of 23 evaluable patients.(142) Other serious clinical or
laboratory adverse events were infrequent: elevation of alkaline phosphatase
and hepatic aminotransferase concentrations to more than five times normal
values was noted in two and three patients, respectively.
The effects of topical application of H. perforatum extract on skin
sensitivity have also been investigated. In a randomised controlled trial, 16
healthy volunteers with no history of skin disease or photosensitivity were
treated with H. perforatum oil (containing hypericin 110 mg/mL) or H.
perforatum ointment (containing an alcoholic H. perforatum extract with a final
hypericin concentration of 30 mg/mL). The oil or ointment was applied to a two
centimetre test area on one forearm of participants for 24 hours. Controls were
an untreated test area of the same forearm, and the untreated other forearm.
After removal of the oil or ointment, both forearms of participants received
increasing doses of solar simulated irradiation (24, 48, 96 and 144 J/cm2). No
phototoxic reactions were observed in any of the participants, and there was no
change in the minimal erythema dose in either the oil or the ointment
group,(174) although data to support the latter statement were not shown.
There was a significant increase in the erythema index following
treatment with H. perforatum oil (which contained the higher concentration of
hypericin) but not after H. perforatum ointment (p < 0.01 and p > 0.05,
respectively, compared with values for untreated skin), although this may not
be clinically relevant since the minimal erythema dose did not change. The
phototoxic potential of topical application of the H. perforatum preparations tested
appears to be low, although caution is necessary, particularly as hypericin may
penetrate more highly through broken or lesional skin, and there may be
increased susceptibility to the photosensitising properties of hypericin in
fair-skinned individuals and after extended periods of solar irradiation.(174)
A case report describes a 45-year-old woman who developed blisters
on two occasions at the treatment site following laser therapy to her legs for
multiple solar keratoses.(175) It was stated that the patient revealed that she
was taking St John's wort, although a sample of the product was not obtained
and, therefore, no analysis was undertaken. The blisters resolved and, after stopping
treatment with St John's wort, the patient underwent a further session of laser
treatment without experiencing adverse effects. Delayed hypersensitivity or
photodermatitis has been documented for St John's wort following the ingestion
of a herbal teamade from the leaves.(176) Psychiatric effects Cases of mania(177,
178) and hypomania(179, 180) have been reported in individuals taking St John's
wort preparations. Two cases of mania were reported in patients with bipolar
depression who began self-treatment with standardised St John's wort extract
(900 mg) daily(178) and one in a patient experiencing a moderate depressive episode
who was taking both sertraline and St John's wort (dosage not known).(177) A case
of hypomania was reported in a woman with panic disorder and unipolar major
depression who had discontinued sertraline treatment one week before starting
St John's wort tincture.(179)
Two cases of hypomania were reported in individuals with no history
of bipolar disorder.(180) A man who had received electroconvulsive therapy and
who had previously taken various antidepressant drugs, including venlafaxine,
fluvoxamine, moclobemide and nortriptyline, experienced a hypomanic episode six
weeks after starting St John's wort (dosage not stated). A man with symptoms of
post-traumatic stress disorder was diagnosed with an acute manic episode after
three months of self-treatment with St John's wort (dosage not stated).(180)
The cases described above, along with five other cases of mania,
one of hypomania, two of schizophrenia, two of delirium and one of acute
anxiety, were included in a review of psychotic events associated with administration
of St John's wort products. Across the 17 cases, the onset of symptoms ranged
from two days to six months after initiation of St John's wort treatment.(181)
The dosage of St John's wort taken was stated in only six of these cases; this
was within recommended dosages except in one case where an excessively high
dose was reported to have been taken (18 g; no further details provided). All
these reports stated that the symptoms had resolved after stopping treatment
with St John's wort, although in one case the patient improved but initially remained
agitated despite cessation of St John's wort.(180) None of the cases involved
rechallenge with St John's wort. Typically, these cases have involved
self-treatment with St John's wort products, rely on self-report of St John's
wort use, have not obtained blood samples for analysis of constituents of H.
perforatum and/or their metabolites and have not obtained samples of the
product for analysis. Also, in most cases, there were other pharmacological factors
and/or underlying illnesses that could have been responsible for or contributed
to the observed events. Other effects A case of subacute toxic neuropathy
possibly related to the use of St John's wort and subsequent exposure to sunlight
has been reported.(182)
Awoman developed stinging pains in areas exposed to the sun (face
and hands) four weeks after starting treatment with St John's wort (500 mg/day,
extract and hypericin content not stated); the report did not state whether the
woman was using any other products. Her symptoms improved three weeks after
stopping St John's wort and disappeared over the next two months. There have
been reports of sensory nerve hypersensitivity occurring in individuals who
have taken St John's wort preparations (tablets or tinctures).(183) There is an
isolated report of confusion, disorientation and hypertensive crisis (blood
pressure 210/140 mmHg) in a 41-yearold man seven days after he began taking a
St John's wort product for work-related stress. It was reported that the man
had consumed aged cheese and red wine before onset of the delirium, which is
suggestive of hypertension associated with the use of a monoamine oxidase
inhibitor.(184) However, although previous in vitro experiments have indicated
that H. perforatum extracts had monoamine oxidase inhibitory activity, this has
not been confirmed in subsequent in vitro studies (see Pharmcological Actions,
In vitro and animal studies), and consensus is that St John's wort is not a
monoamine oxidase inhibitor.(118) In addition, no analysis of blood samples or
of the St John's product appears to have been undertaken, thus alternative
explanations for the event cannot be ruled out. St John's wort extract (BNO-1385,
containing 255–285 mg extract equivalent to hypericin 900 mg) 255 to 285 mg
three times daily taken for 14 days had no significant effect on heart rate variability,
cognitive performance and parameters of autonomic function (vasoconstrictory
response of cutaneous blood flow and skin conductance response following a
single deep inspiration) according to the results of a randomised, double-blind,
placebocontrolled, three-arm, crossover trial involving 12 healthy male volunteers.
(Decrease in heart rate variability is an effect observed with chronic administration
of tricyclic antidepressant agents, although the implications of this for
morbidity and mortality in patients with depression are not yet
understood.)(185, 186)
In contrast, amitriptyline 25 mg daily significantly decreased
heart rate variability and significantly influenced the parameters of autonomic
function. The effects of another St John's wort herb extract (Hyperiforte, 300
mg extract containing hypericin 990 mg, pseudohypericin 526 mg and hyperforin
9–15 mg) 900 mg or 1800 mg as a single dose on cognitive and psychomotor performance
were compared with those of amitriptyline 25 mg in a randomised,
placebo-controlled, crossover study involving 13 healthy volunteers. Recipients
of H. perforatum extract, compared with placebo, experienced a dose-dependent
impairment in one of the eight tests (digit symbol substitution test), whereas
amitriptyline recipients showed statistically significant impairments in performance
in seven of the eight tests.(187)
In a case–control study, 37 patients with raised serum
thyroidstimulating hormone (TSH) concentrations (7–20 mU/mL) matched for age
and sex to 37 individuals with normal TSH concentrations (1–3 mU/mL) selected
from the same set of patient records, were interviewed regarding their exposure
to St John's wort products and other prescription and non-prescription medicines.
Four participants with raised TSH concentrations and two with normal TSH concentrations
reported that they had taken St John's wort products within six months of the
TSH test (odds ratio, 95% CI for raised TSH concentrations associated with
self-reported exposure to St John's wort during the specified time period:
2.12, 0.36 to 12.36; p > 0.05).(188) The small sample size may mean that the
study lacked the statistical power to detect an association between St John's
wort exposure and raised TSH concentrations. Other methodological issues
include the possibility of confounding by indication, since individuals with hypothyroidism
may experience symptoms of depression and, therefore, be more likely to take St
John's wort.(188) Further research to assess the possibility of effects of H.
perforatum on thyroid function may be warranted. There are two isolated reports
of sexual dysfunction, including decreased libido and erectile dysfunction, associated
with use of St John's wort products. In one man, previous symptoms of sexual dysfunction,
possibly related to use of a conventional antidepressant agent which had
resolved on stopping treatment, reappeared one week after initiation of
treatment with St John's wort.(189) Another report describes a man who
experienced decreased libido whilst taking St John's wort for nine months.(190)
PRECLINICAL DATA
The consumption of large quantities of St John's wort by grazing
animals has been associated with the development of photosensitivity.( 191,
G22, G51) Mice given 0.2–0.5 mg of the herb were found to develop severe
photodynamic effects.(G22) Studies using cell cultures of human keratinocytes
incubated with hypericin or St John's wort extract and exposed to UV-A resulted
in a reduction in the LC50 (lethal concentration) with hypericin, but only a
mild reduction with hypericum.(192) From these findings it has been estimated
that at least 30 times the therapeutic dose would be necessary to produce
phototoxic effects in humans.(192) It has been shown in in vitro experiments
using a human keratinocyte cell line and quercitrin-free and
quercitrin-containing extracts of H. perforatum that quercitrin reduces the
phototoxicity of H. perforatum extracts.(193)
Experimental evidence has suggested that a solution of hypericin
can react with visible and UV light to produce free radical species and that
this may lead to damage of proteins in the lens of the eye.(194) Up to October
2005, there were no spontaneous reports of cataract formation in individuals
who have taken St John's wort.(195)
A hydromethanolic extract of St John's wort flowering tops (containing
0.3% hypericin) at concentrations of 1–300 mg/mL reduced experimentally induced
contractions in rat vas deferens smooth muscle in a concentration-dependent
manner.(196) The St John's wort extract and hyperforin also produced a
concentrationdependent inhibition of phenylephrine-induced contractions in human
vas deferens in vitro; mean (standard error of mean) IC50 values for the
extract and hyperforin were 13.9 (2.0) and 0.45 (0.04) mg/mL, respectively.
A number of experimental studies has investigated the genotoxic
potential and mutagenic activity of St John's wort extracts in vitro and in
vivo. In vivo studies and most in vitro studies provided negative results,
indicating a lack of mutagenic potential with defined St John's wort
extracts.(G52) Mutagenic activity observed in an in vitro Ames test was
attributed to the presence of quercetin, although other studies have found no mutagenic
potential with a St John's wort extract and it has been stated that there is no
valid evidence for the carcinogenicity of quercetin in humans.(G21,G52)
Dietary administration of St John's wort to rats was found to have
no effect on various hepatic drug-metabolising enzymes (e.g. aminopyrine,
N-demethylase, glutathione S-transferase and epoxide hydrolase) or on copper
concentrations in the liver (see Contra-indications, Warnings, Drug
interactions). No major effects were observed on hepatic iron or zinc
concentrations and no significant tissue lesions were found in four rats fed St
John's wort in their daily diet for 119 days (10% for first 12 days and 5% thereafter
because of unpalatability).(197) Cytotoxic constituents related to hyperforin
have been isolated from two related Hypericum species (see Pharmacological Actions,
In vitro and animal studies).
ADVERSE EFFECTS
Photosensitization (hypericism)
has been observed in animals that consume large quantities of the herb, but
this is unlikely to occur in humans following administration of the designated therapeutic
doses. Nonetheless, fair-skinned individuals should take due precaution when
using Hypericum.
EFFECTS
The
main active principles of the herb are the flavone and flavonol derivatives,
xanthones and naphthodianthrone (hypericins). A mild antidepressant, sedative
and anxiolytic action of the herb and its preparations has been documented in
clinical studies. Historically, hypericin was thought to have a weak MAO inhibitor
effect. However, recent literature suggests hypericin is devoid of MAO
inhibitory activity (Bladt, 1994).
More
recent studies have indicated that the antidepressive effect may be largely due
to the ability of the herb to inhibit the reuptake of serotonin and other neurotransmitters.
The activity of the herb could be attributable to the combined contribution of
several mechanisms, each one too weak by itself to account for the overall
effect (Bennett, 1998). A study concluded that hydroalcoholic hypericum extract
inhibits the reuptake of serotonin, norepinephrine and dopamine with similar
affinities, which leads to a significant down-regulation of cortical beta-
adrenoceptors and serotonin (5HT-2) receptors. This data suggested hyperforin
is the active principle of hypericum extracts in biochemical models of
antidepressant activity (Muller, 1998).
The
antidepressive action not only results from the effect on adrenergic transmitter
systems (norepinephrine, dopamine, serotonin), but also from an endocrine
effect (melatonin). Oily Hypericum preparations demonstrate an
anti-inflammatory action due to their high flavonoid content. Antiviral (retroviruses)
properties of the herb have not been proven. No antiretroviral activity determined
by virologic markers and CD4 cell count of hypericin was seen in a study of
HIVinfected patients (Gulick, 1999). The
antibacterial effect of hyperforin was demonstrated in a recent study.
Hyperforin inhibited the growth of gram positive bacteria, such as Streptococcus
pyogenes and Streptococcus agalactiae. Hyperforin also demonstrated efficacy
against penicillin-resistant Staphylococcus aureus (PRSA) and
methicillin-resistant Staphylococcus aureus (MRSA). These data indicate
the possible use of the herb for local treatment of infected wounds and
eczematous skin lesions (Schempp, 1999).
CLINICAL TRIALS
A
meta-analysis of 23 randomized trials consisting of 1757 outpatients with mild
to moderately severe depressive disorders was conducted to determine the
effectiveness of Hypericum perforatum. Although Hypericum was significantly superior
to placebo with fewer adverse effects (19.9% with Hypericum compared to 52.8% with
standard antidepressants), there was little standardization and a lack of information
with regard to the diagnostic criteria, compliance control, and dosage regimen
of Hypericum and standard antidepressants (Linde K, 1996).
The
equivalence between St. John's Wort and fluoxetine was demonstrated in a randomized,
double-blind, comparative trial involving 149 outpatients with mild or moderate
depressive episodes (according to International Statistical Classification of
Diseases and Related Health Problems). Patients were treated for 6 weeks. A
daily dose of 800 mg St. John's Wort extract LoHyp-57 (dry extract of St.
John's Wort, drug .extract ratio 5-7:1, solvent, ethanol 60% [w/w]) was found
to be equivilent in efficacy to 20 mg fluoxetine (Harrer, 1999).
The
effectiveness and tolerance of Hypericum extract LI 160 with a dosage of 300 mg
three times daily was compared to imipramine 25 mg three times daily in a
double-blind, clinical study. The study involved 135 depressed patients (according
to DSM-III-R criteria) treated over a 6-week period. The analysis demonstrated
comparable results between the treatment groups, with fewer and milder side effects
in the Hypericum group (Vorbach, 1994).
CONTRA-INDICATIONS, WARNINGS
Individuals with sensitivity towards St John's wort may
experience allergic reactions. The use of St John's wort is not advised in known
cases of photosensitivity and, in view of the potential of hypericin as a
photosensitising agent, therapeutic UV treatment should be avoided whilst using
St John's wort.(G1) It has previously been suggested that excessive doses of St
John's wort may potentiate monoamine oxidase inhibitor therapy.(198) However,
as monoamine oxidase inhibitory activity has not been reported in vivo with St
John's wort, this warning is no longer considered necessary. In addition,
avoidance of foodstuffs, such as those containing tyramine (e.g. cheese, wine,
meat and yeast extracts) and medicines containing sympathomimetic agents (e.g.
cough/cold remedies), which interact with MAOIs, is
not considered necessary.
Drug interactions There are important pharmacokinetic interactions
and potential for important pharmacodynamic interactions between St John's wort
preparations and certain other medicines.(118, 199, 200) Evidence for
pharmacokinetic interactions between St John's wort preparations and certain
other medicines, leading to a loss of or reduction in the therapeutic effect of
those medicines, includes spontaneous reports(199) and published case
reports.(200, G79) Drugs that may be affected include certain anticonvulsants,
ciclosporin, digoxin, indinavir (and other HIV protease inhibitors, and HIV non-nucleoside
reverse transcriptase inhibitors), oral contraceptives, theophylline and
warfarin. A report involving four cases describes reduced plasma methadone
trough concentrations in addicts who received St John's wort extract 900 mg
daily before methadone maintenance treatment.(201) There have also been reports
of increased serotonergic effects (i. e. pharmacodynamic interactions) in
patients taking St John's wort products concurrently with selective serotonin
reuptake inhibitors (e.g. sertraline, paroxetine).(202, 203) There are isolated
reports of hypotension during general anaesthesia(204) and delayed emergence
following general anaesthesia.(205) In both cases, patients had been taking St
John's wort before receiving several anaesthetic agents, including fentanyl and
propofol. It has been suggested that treatment with St John's wort preparations
should be stopped at least five days before undergoing elective surgery.(206) In
the year 2000, the UK Committee on Safety of Medicines (CSM) issued advice to
pharmacists, doctors, other healthcare professionals and patients on the use of
St John's wort products with certain other medicines.(207, 208) The CSM's
advice for healthcare professionals regarding patients taking St John's wort and
other medicines concurrently can be summarised as follows.
Warfarin, ciclosporin, digoxin, theophylline and anticonvulsants
(carbamazepine, phenobarbital and phenytoin) There is a risk of
reduced therapeutic effect, e.g. risk of transplant rejection, seizures and
loss of asthma control. Advice is to check plasma drug concentrations (with
warfarin, the patient's International Normalised Ratio should be checked) and
to stop St John's wort therapy. In addition, dose adjustment may be necessary.
HIV protease inhibitors (indinavir, nelfinavir, ritonavir and saquinavir)
and HIV non-nucleoside reverse transcriptase inhibitors (efavirenz and
nevirapine) There is a risk of reduced
blood concentrations with possible loss of HIV suppression.
Advice is to measure HIV RNA viral load and to
stop St John's wort.
Oral contraceptives There is a risk of reduced
blood concentrations, breakthrough bleeding and unintended pregnancy.
Advice is to stop St John's wort. Triptans
(sumatriptan, naratriptan, rizatriptan and zolmitriptan) and selective
serotonin reuptake inhibitors (citalopram, fluoxetine, fluvoxamine, paroxetine
and sertraline) There is a risk of increased serotonergic effects with the possibility
of an increased risk of adverse reactions. Advice is to stop
St John's wort. Patients already taking any of the above drugs should be advised
not to start taking St John's wort and users of other medicines should be
advised to seek professional advice before using St John's wort. Topical
medicines and non-psychotropic medicines that are excreted renally are not
likely to interact with St John's wort. In addition, topical or homeopathic preparations
of St John's wort are not likely to interact with prescribed
medicines.
There is further evidence from prospective pharmacokinetic studies
involving patients who have received St John's wort preparations and other
medicines concurrently that there are interactions which result in altered
pharmacokinetics, including reduced plasma concentrations, of amitriptyline,(209)
ciclosporin,(210, 211) tacrolimus,(212) and irinotecan.(213) These studies have
typically been open-label studies (although two involved a randomised,
crossover design) involving small numbers of patients undergoing treatment with
the respective conventional medicines and who were also treated with single and/or
multiple doses (600 to 900 mg extract daily for around two weeks) of St John's
wort preparations. In one randomised, crossover study, 10 patients who had
undergone renal transplants were treated concurrently with ciclosporin and St John's
wort extract with a low or high hyperforin content. Patients experienced
altered ciclosporin pharmacokinetics and required ciclosporin dose increases
only whilst taking the extract with the high content of hyperforin.(211)
Studies with different designs (and varying methodological quality)(214)
and involving healthy volunteers have provided supporting evidence of
pharmacokinetic interactions between St John's wort preparations and
digoxin,(215) imatinib,(216, 217) oral contraceptives,(218, 219)
phenprocoumon,(220) quazepam,(221) simvastatin,(222) tacrolimus,(223)
verapamil(224) andwarfarin.(225) These and other studies provide evidence
indicating that St John's wort preparations induce the cytochrome P450 (CYP) drug-metabolising
enzyme CYP3A4,(220, 226–229) as well as affecting P-glycoprotein (a transport
protein).(200, 230) As with other medicines, whether or not clinically
important drug interactions occur with St John's wort preparations depends on several
factors, including the dosage regimen, route of administration and
pharmaceutical quality of St John's wort preparations and co-administered medicines.
As CYP3A4 is involved in the metabolism of at least half of all medicinal
agents, and as Pglycoprotein is involved in the transport of many drugs, it is possible
that St John's wort preparations interact with other medicines in addition to
those listed above.(231)S
There is also evidence from studies involving healthy volunteers,
albeit less extensive, that St John's wort preparations induce CYP2C19.(232) Effects
on certain other CYP drug metabolising enzymes are less clear: one study
reported no effect on CYP2C9 activity,(229) whereas another study found that a
St John's wort extract did induce CYP2C9 as determined by effects on the
pharmacokinetics of S-warfarin;(225) conflicting results have also been reported
for CYP1A2 with respect to induction(225) or a lack of induction(229) by St
John's wort preparations.
In contrast, similar studies have reported a lack of pharmacokinetic
interaction between St John's wort preparations and carbamazepine,(233)
pravastatin,(222) and theophylline,( 234) and several others have reported a lack
of significant effects on CYP isoenzymes,(235–237) although the numbers of volunteers
may have been too small and the duration of St John's wort administration too short
to exclude definitively an inductive effect.(236, 237) There is evidence from
several studies involving healthy volunteers that St John's wort preparations do
not influence CYP2D6 activity to an extent likely to be clinically relevant.(200,
228, 229, 238)
Randomised, placebo-controlled studies involving healthy volunteers
who received an ethanol extract of St John's wort with a low hyperforin content
(Esbericum capsules containing 60 mg extract, drug to extract ratio 3.5–6.0 : 1,
equivalent to 0.25 mg total hypericins and 0.88 mg hyperforin) 240 mg extract
daily found no statistically significant effects on the pharmacokinetics of
drugs used as substrates for CYP3A4, CYP1A2 and CYP2C9. It is not clear whether
the lack of effect is due to the preparation having a lowhyperforin content, or
to the low dose of extract used in the studies.(239) The suggestion that the
occurrence of CYP enzyme induction, or the extent of induction, may vary
depending on the particular St John's wort preparation is a valid one, since
the profile of constituents, including those influencing CYP enzyme activity, varies
qualitatively and quantitatively between products (see Quality of plant material
and commercial products).
A further randomised, double-blind, placebo-controlled study
involving healthy volunteers (n = 33) explored the effects of the CYP enzyme inhibitor cimetidine and
the CYP enzyme inducer carbamazepine on the pharmacokinetics of certain constituents
of St John's wort extracts. Participants received St John's wort extract
(LI-160) 300 mg three times daily for 11 days, followed by a further seven days'
administration together with cimetidine 1000 mg daily in divided doses,
carbamazepine 400 mg each night, or placebo. No statistically significant differences
in the plasma concentration versus time curves from hours 0 to 24 (AUC0–24)
were observed between groups; statistically significant intragroup differences
in the AUC0–24 were observed for hypericin during cimetidine administration and
for pseudohypericin during carbamazepine administration, although these effects
are unlikely to be of clinical relevance.(240)
A number of in vitro and animal studies have also explored the effects of St John's wort preparations on
CYP drug metabolising enzymes. In vitro studies have reported induction of the
CYP enzymes CYP3A4 and CYP1A2 by St John's wort extracts,(200, 231) and of
CYP2C9 by hyperforin.(241, 242) Results from in vivo (mice) experiments
indicate that hyperforin is important for induction of CYP3A in the liver.(243)
In vitro experiments have shown that hyperforin induction of CYP2C9 is mediated
by the pregnane X nuclear receptor.(242) Induction of P-glycoprotein by St
John's wort extract(244) and hyperforin( 245) has been reported following in vitro
experiments using LS180 intestinal carcinoma cells, whereas there are conflicting
results on the induction of P-glycoprotein by hypericin.(244, 245) A number of
in vitro experiments have described inhibition of the CYP enzymes CYP3A4 and
CYP2C19 by St John's wort extracts,(246, 247) and inhibition of P-glycoprotein
by hypericin and hyperforin.(248) A series of in vitro experiments explored the
effects of hypericin on human DNA topoisomerase II activity. Hypericin appeared
to interact with DNA in a manner which precluded topoisomerase II DNA binding
activity and antagonised the formation of topoisomerase II-covalent cleavage
complexes mediated by the topoisomerase II poisons etoposide and amsacrine. The
effects of hypericin and St John's wort extracts on topoisomerase II cancer
chemotherapy require further investigation.(249) Certain groups of users may
have little knowledge of safety aspects,
such as drug interactions, related to use of St John's wort products, and may
be particularly vulnerable to certain adverse effects.(250–253)
Pregnancy and lactation Information on the use of H. perforatum
preparations during pregnancy and breastfeeding is summarised below. In view of
the lack of toxicity data, St John's wort preparations should not be used
during pregnancy and lactation.
CLINICAL DATA
In a prospective, cohort study, 33 breastfeeding women who had
made enquiries about the safety of St John's wort during breastfeeding to a
teratogen/toxicology advice service (and who took St John's wort products) were
compared with 33 age- and parity-matched controls and 101 diseasematched controls
(who had enquired about the safety of St
John's wort products but who did not take any). Three of the women
in the first group had initiated St John's wort treatment during pregnancy
(stage not stated), and the mean (standard deviation) of infant exposure to St
John's wort through breastfeeding was 2.1 (3.5) months.(254) There were no statistically
significant differences in maternal or infant demographics, and in women's reasons
for enquiring about use of St John's wort, although significantly more women
who took St John's wort were using conventional antidepressants, compared with
women who inquired about St John's wort but who did not use it (42.4% versus
17.8%; p < 0.01). No maternal adverse events were reported in any of the
women and there were no statistically significant differences in the proportions
of women reporting decreased milk volume (12.1%, 6.9% and 6.1% for St John's
wort consumers, disease-matched controls, and age-/parity-matched controls, respectively;
p = 0.58).(254) Five infants born to St John's wort consumers experienced
colic, drowsiness or lethargy, compared with one report in each of the other
two groups, although two of the former five infants were also exposed to
conventional antidepressant agents during breastfeeding.
The study described above provides only limited information on
the safety of St John's wort products during breastfeeding (and, to a even
lesser extent, pregnancy) as it involved only small numbers of women so had the
statistical power to detect only very common, acute adverse events. In addition,
a report of the study did not provide any details of the St John's wort products
consumed by the participants. It is likely that several, perhaps many,
different St John's wort products were involved, all of which are likely to
differ in their pharmaceutical quality and, therefore, in their potential
effects on the infant. There is a report of a 38-year-old woman who started
taking St John's wort (900 mg/day) at her 24th week of pregnancy, taking the
last dose 24 hours before delivery.(255) The pregnancy was unremarkable except
for late onset of thrombocytopenia. Another report described a 43-year-old
woman who discontinued fluoxetine and methylphenidate upon becoming pregnant and
started taking St John's wort (900 mg/day). The report does not state the
outcome of the pregnancy,(255) although it is assumed that had adverse events
occurred, they would have been stated. Another case report describes a
33-year-old woman who presented with post-natal depression at a German
psychiatric service and who had been taking an extract of H. Perforatum (Jarsin)
300 mg three times daily from five months postpartum. Analysis of breast milk
samples indicated that hyperforin is excreted into breast milk at
concentrations below the lower limit of quantification (0.50 ng/mL).(256) No
adverse effects were observed in the infant or the mother, however, further
investigation of the pharmacokinetics of constituents of H. perforatum extract
in breast milk and in mothers' and infants' plasma is required.
PRECLINICAL DATA
In a randomised experiment, 40 adult female mice were given food
bars containing 'hypericum herb' (no further details of plant material provided)
at a dose of 180 mg/kg body weight daily, or placebo, for two weeks before
conception and throughout the gestation period. At the end of the study, there were
no statistically significant differences between the 'hypericum' and placebo groups
in duration of gestation, number of live pups per litter, body length and head circumference
measurements, dam–pup interactions, physical maturation milestones and
reproductive capabilities of offspring.( 257) The only exceptions to this were
that male offspring in the hypericum-exposed group weighed significantly less
than those in the placebo group at birth (p < 0.02), but this difference was
not statistically significant by day three after birth, and male offspring in
the hypericum-exposed group experienced a temporary delay in appearance of the
upper incisors. Since multiple statistical tests were carried out, this number
of statistically significant results at a level of p < 0.05 is likely. In similar
experiments, 18 adult female rats were given a methanol extract of St John's
wort (containing 0.3% total hypericins) 100 or 1000 mg/kg, or placebo, by gavage
for two weeks before mating, throughout the gestation period and/or for three
weeks during breastfeeding. Histological alterations in the livers and kidneys
of rat pups exposed to St John's wort extract throughout gestation and/or
during breastfeeding; lesions were more severe in the offspring of rats treated
with the higher dose and in offspring exposed to St John's wort extract during
both the gestation period and breastfeeding.(258) Slight in vitro uterotonic
activity has been reported for St John's wort (see Pharmacological Actions, In
vitro and animal studies).
CLIENT CONSIDERATIONS
ASSESS
Antidepressant
Use
·
Assess the client’s mental
status: mood, sensorium, affect, memory (long, short), change in depression or
anxiety levels.
·
Assess for the use of MAOIs and
SSRIs, which should not be used with St. John’s wort (taken PO) until further
research is available.
·
Assess for other drugs, foods,
and herbs the client uses on a regular basis (see Interactions).
Antiretroviral
Use
·
Assess for signs of infection.
·
Assess CBC, blood chemistry,
plasma HIV, RNA, absolute CD4/CD8_/cell
counts/%, serum b-2 microglobulin, and serum ICD_ 24
antigen levels.
ADMINISTER
·
PO: use 2 tsp herb in 150 mL
boiling water. Steep 15 minutes to create infusion.
·
Topical: use oily hypericum
preparations to treat infl ammation or burns. Apply as needed.
TEACH
CLIENT/FAMILY
·
Inform the client that
pregnancy category is 2 and breastfeeding category is 3A.
·
Caution the client not to give
St. John’s wort to children.
·
Advise the client to avoid
high-tyramine foods such as aged cheese, sour cream, beer, wine, pickled
products, liver, raisins, bananas, fi gs, avocados, meat tenderizers, chocolate,
and yogurt and to avoid increased caffeine intake when using this herb PO.
·
Inform the client that the
therapeutic effect may take 4 to 6 weeks for the treatment of depression. If no
improvement occurs in that time, another therapy should be considered.
·
Advise the client to avoid the
use of alcohol or over-the-counter products that contain alcohol when using
this herb PO.
·
Advise the client to avoid the
sun or use sunscreen or protective clothing to prevent photosensitivity when
using this herb.
PREPARATIONS
PROPRIETARY SINGLE-INGREDIENT
PREPARATIONS
Argentina: Amenicil; Hipax; Hiperinat. Australia: Bioglan Stress-Relax;
Hyperiforte. Austria: Esbericum; Helarium; Hyperiforce; Jarsin; Johanicum;
Johni; Kira; Lunare; Perikan; Psychotonin; Remotiv; Solaguttae. Belgium: Hyperiplant;
Milperinol; Perika. Brazil: Adprex; Emotival; Equilibra; Fiotan; Hiperex;
Hipericin; Hiperico; Hiperifarma; Hiperil; Hipersac; Hyperico; Hyperigreen;
Iperisan; Jarsin; Motiven; Prazen; Triativ. Canada: Kira; Movana. Chile: Anxium;
Edual. Czech Republic: Deprim; Lubovnik; Nat Trezalky; Trezalka v Nalevovych
Sacchich; Trezalkova Nat; Trezalkovy Caj; Turineurin. France: Dermum;
Procalmil. Germany: Aristo; Aristoforat; Cesradyston; Digitalysat
Scilla-Digitaloid; dystolux; Esbericum; Felis; Helarium; Hewepsychon uno;
Hyperforat; Hypericaps; Hyperimerck; Hyperpur; Jarsin; Jo-Sabona; Kira; Laif;
Libertin; Lomahypericum; Nervei; Neuroplant; Neurosporal; Neurovegetalin;
Psychotonin; Sedovegan; Syxal; Texx; Tonizin; Turineurin. Hungary: Helarium;
Remotiv. Italy: Nervaxon; Proserem; Quiens; Remotive. Mexico: Hiperikan; Procalm;
Remotiv. Russia: Deprim (Деприм); Helarium (Гелариум); Negrustin (Негрустин);
Novo-Passit (Ново-Пас-сит). Spain: Animic; Arkocapsulas Hiperico; Hiperico; Hyneurin;
Quetzal; Vitalium. Switzerland: Hyperiforce; HyperiMed; Hyperiplant; Hyperval;
Jarsin; Lucilium; Re-Balance; Remotiv; Solevita; Yakona. UK: Kira. Venezuela: Kira.
PROPRIETARY
MULTI-INGREDIENT PREPARATIONS
Australia: Bioglan 3B Beer Belly Buster; Cimicifuga Compound; Feminine
Herbal Complex; Infant Tonic; Irontona; Joint & Muscle Relief Cream; Nappy
Rash Relief Cream; Nevaton; Skin Healing Cream; Vitatona. Austria: Eryval; Magentee
St Severin; Nerventee St Severin; Remifemin plus; Species nervinae; Wechseltee
St Severin. Canada: Bronco Asmol; Sirop Cocillana Codeine. Czech Republic: Alvisan
Neo; Cajova Smes pri Redukcni Diete; Cicaderma; Eugastrin; Fytokliman Planta;
Naturident; Novo-Passit; Species Nervinae Planta; Stomaran; Zaludecni Cajova
Smes. Germany: anabolloges; Gastritol; Gutnacht; Hyperesa; Me-Sabona plus;
Miroton; Neurapas; Remifemin plus; Sedariston Konzentrat; Sedariston plus. Hong
Kong: Coci-Fedra; Cocillana Christo; Cocillana Compound; Cocillana Compound;
Cocillana Compound; Mefedra-N; Mist Expect Stim. Italy: Hiperogyn; Mithen. Mexico:
Nordimenty. Portugal: Cicaderma. Russia: Prostanorm (Простанорм). South Africa:
Cocillana Co; Contra-Coff; Linctus Tussi Infans. Spain: Natusor Gastrolen; Natusor
Somnisedan. Switzerland: Gel a la consoude; Huile de millepertuis A. Vogel
(huile de St. Jean); Hyperiforce comp; The a l'avoine sauvage de Vollmer. UK: Allens
Chesty Cough; Balm of Gilead; Buttercup Syrup; Chest Mixture; Covonia Mentholated;
Galloway's Cough Syrup; Honey & Molasses; Modern Herbals Cough Mixture;
Potters Children's Cough Pastilles; Potters Gees Linctus; Sanderson's Throat
Specific; Sanderson's Throat Specific; St Johnswort Compound. Venezuela: Biomicovo.
EXTRACTS
A StX (600 mg wit, 0.24–0.32% hypericin 3 /day) produced erythema
in light-sensitive patients (AHP). Leaf extracts enhance mouse immune system
against Bordetella pertussis and Staphylococcus aureus.
Novoimanine is most effective against S. aureus, with water
soluble imanine being more effective than imamine or sulphanilamide. Herb extracts
are reportedly more active against Escherichia, Shigella, and Staphylococcus
than decoctions. Catechin and flavonoid containing fractions inhibit the
flu virus 83–100% (CAN). Amentoflavone is antiinflammatory and antiulcerogenic
(CAN). Total flavonoid fraction is analgesic in mice (CAN). Small amounts of
hypericin are tonic and tranquilizing in humans (CAN). Extracts inhibit
catechol-o-methyl-transferase at 100 M, modulate interleukin-6, block corticotropin-releasing
hormone, reduce the availability of serotonin receptors (IC50 = 6.2 g/mL) and
the associated inhibition of resorption of serotonin into the cell, and block
MAOA and B in vitro and ex vivo, and hypericin raises levels of melatonin,
all factors that may contribute to antidepressant activity.
No statistical evidence was shown in the antiinflammatory activity
of the extract and hydrocortisone (QRNM, 1997:292). With rats the IC50
was only 6.2 g/mL for inhibiting synaptosomal serotonin uptake (consistent
with doses of 900 mg extract in humans). LD50 = >5000 mg/kg. Phototoxic
reactions occur in some patients with AIDS given ivn injections of 30–40 mg
hypericin. “Not suitable for use as daily sedatives of sleep aids. Preparations
are no more effective than synthetic antidepressants,” but they are extremely well
tolerated by the patients. In observational studies or >3000 cases, there is
ca. a 3% incidence of minor side effects, cf 10–25% with modern nontricyclic
antidepressants (SHT). In Germany, the costs are about equal (tricyclics = 0.75
a day, hypericum 0.80 a day, cf $2.25 for nontricyclic antidepressants (SHT).
REFERENCE
Barnes, J., Anderson, L. A., and Phillipson, J. D.
2007. Herbal Medicines Third Edition. Pharmaceutical
Press. Auckland and London.
Braun, L and Cohen, M. 2010. Hebs and Natural
Supplements An Evidence Based Guide 3R D Edition. Elsevier Australia.
Australia.
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
Kraft, K and Hobbs, C. 2004 . Pocket
Guide to Herbal Medicine. Thieme. Stuttgart New York.
Linda S-Roth. 2010. Mosby’s Handbook Of
Herbs & Natural Supplements, Fourth Edition. Mosby Elsevier. USA
Ross, I. A. 2004. Medicinal
Plants of the World Vol. 2. Chemical Constituents, Traditional and Modern
Medical Uses. Human Press. Totowa, New Jersey.
