Chaste Tree and
Melatonin
The role of melatonin in human health and disease is being extensively
investigated. In particular, melatonin functions in the regulation
of circadian rhythms, mood and tumor growth.1 Since the effects
of melatonin can be biphasic, for example some concentrations can
inhibit tumor growth while other concentrations have a stimulating
effect, it makes sense to investigate natural means of manipulating
the melatonin output by the pineal gland. The circadian rhythm
of melatonin secretion was measured in 20 healthy males aged 20
to 32 years after the intake of placebo or various doses of an
extract of Vitex agnus-castus (chaste tree) for 14 days. In an
open, placebo-controlled study, the doses investigated were 120
to 480 mg per day of this extract (corresponding to approximately
0.6 to 2.4 g of dried berries). The concentration of melatonin
in serum showed the typical nocturnal increase, beginning approximately
1 hour after the light was turned off. Administration of chaste
tree caused a dose-dependent increase of melatonin secretion, especially
during the night (compared to placebo treatment). Total melatonin
output was approximately 60% higher in the group receiving chaste
tree. The authors observed that the feeling of fatigue or the promotion
of sleepiness observed by some patients taking chaste tree during
the trial might be a result of the stimulation of endogenous melatonin
secretion.
Commentary: The authors speculated that chaste tree may have value
in the treatment of insomnia and jetlag. If chaste tree does significantly
improve nocturnal melatonin release, it could also be particularly
valuable in the treatment of the type of insomnia linked to fibromyalgia,
which shows a pattern suggestive of disturbed circadian rhythm.
In the meantime, in what could probably be regarded as ultimately
futile research, a number of investigative teams are examining chaste
tree for possible estrogenic activity. One study identified the common
fatty acid linoleic acid as an estrogenic compound from chaste tree2
and another identified the relatively common flavonoid apigenin as
the most active phytoestrogen in this herb.3 Since these compounds
are widely found in the plant kingdom, they can hardly explain the
unique clinical applications of chaste tree recognized by most Western
herbalists. No doubt this sort of research will lead to a mistaken
belief among the misinformed that the therapeutic effects of chaste
tree can be explained in terms of its possessing estrogenic properties.
References
1. Dericks-Tan JS, Schwinn P, Hildt
C. Dose-dependent stimulation of melatonin secretion after administration
of agnus castus. Exp
Clin Endocrinol Diabetes 2003;
111: 44–46
2. Liu J, Burdette JE, Sun Y et al. Isolation of linoleic acid
as an estrogenic compound from the fruits of Vitex agnus-castus
L. (chaste-berry). Phytomedicine 2004; 11(1):
18–23
3. Jarry J, Spengler B, Porzel A et al. Evidence for estrogen receptor
b-selective activity of Vitex agnus-castus and
isolated flavones. Planta Med 2003; 69: 945–947
Ginger and Nausea of Pregnancy: More Evidence of Safety and Efficacy
The use of ginger by pregnant women to treat nausea and vomiting
is widespread, however concerns have been expressed in some circles
about the safety of such a practice. In particular, the clinical
trials that have been conducted in the past have only observed
the use of ginger over a 4-day time period, which does not lend
confidence to the safety of the extensive use of ginger during
the first trimester of pregnancy.
Recently the results of three studies (two of them from Australia)
have been published which provide further evidence for the safety
and efficacy of ginger during pregnancy. The first study was conducted
at the Royal Hospital for Women in Randwick NSW.1 The effect of a
ginger extract on the symptoms of morning sickness was investigated
in 120 women in a double-blind, randomized, placebo-controlled trial.
Participants were less than 20 weeks pregnant who had experienced
morning sickness daily for at least a week and had experienced no
relief of symptoms through dietary changes. They received 125 mg
of ginger extract (equivalent to 1.5 g of dried rhizome) or placebo
four times per day for 4 days. The nausea experience score was significantly
less for the ginger extract group relative to placebo after the first
day of treatment and this difference was observed for every treatment
day. While retching was reduced to some extent, there was no significant
effect observed on vomiting. Follow-up of the pregnancies revealed
normal ranges of birth weight, gestational age, Apgar scores (see
footnote below) and frequencies of congenital abnormalities. Four
participants in the ginger group withdrew from the trial due to reflux
and heartburn caused by the relatively high dose of ginger used.
In the second Australian study, the effect of 1.05 g of ginger or
75 mg of vitamin B6 per day were compared using a randomized, double-blind
design.2 The trial involved 291 South Australian women less than
16 weeks pregnant and either treatment was given for 3 weeks. Differences
from baseline in nausea and vomiting scores were estimated for both
groups at days 7, 14 and 21 of the trial. The trial found that ginger
was equivalent to vitamin B6 in reducing nausea, retching and vomiting.
There was no evidence of different effects between the two treatments
at each of the three assessment points of the trial. Morning sickness
improved in little more than half of the women in each group. No
differences in congenital abnormalities were detected between the
study groups and the overall risk of pregnancy complications did
not differ. In addition, there were no differences found for any
other birth outcomes. The authors concluded that, because of the
relatively small size of the study, firm evidence of the safety of
ginger in pregnancy is still required and further systematic research
on the risks and benefits of ginger during pregnancy would be of
great clinical relevance.
The third study was conducted in Canada.3 Rather than
being a clinical trial, it was a comparative observational study
where pregnant women
who took ginger were compared to a control group. The outcome of
187 pregnancies where women took ginger for nausea and vomiting were
compared with 187 pregnancies where no antiemetic medications were
used. The study found that there were no statistical differences
in pregnancy outcomes between the ginger group and the comparison
group, with the exception of more infants weighing less than 2.5
kg occurring in the comparison group (12 versus 3, p £ 0.001).
In addition, a total of 66 women who had used ginger alone for a
minimum of 3 days completed an effectiveness score for the treatment.
The mean score of 3.3 ± 2.9 indicated mild effectiveness for
the ginger in the treatment of nausea and vomiting of pregnancy.
However, various types of ginger were consumed by the women including
capsules, ginger tea, fresh ginger, pickled ginger, candied ginger
and so on. A total of 49% of the women used capsules, with the rest
using the various other preparations. When the authors compared the
effectiveness of the different forms of ginger they found that the
capsules were significantly more effective than all the other preparations
combined (4.2 ± 3.1 versus 1.7 ± 0.7, p < 0.001).
No information was provided concerning the length of time that ginger
was used by the women. Again the authors stressed that conclusions
about the safety of ginger during pregnancy were limited by the relatively
small size of their survey.
Commentary: These studies are timely given the widespread use of ginger by
pregnant women throughout the world. For example, a recent survey of 400 women
found that 36% had used herbal products during their pregnancy with an average
of 1.7 products per woman.4 The proportion of women using herbs increased throughout
the first, second and third trimesters. The most commonly used herbs were Echinacea,
herbal-based iron supplements, ginger, chamomile and cranberry. The South Australian
study is particularly significant because of the longer time period over which
ginger was used by the pregnant women. The results of the Canadian study are
also useful because the survey observed the actual usage of ginger and (although
not stated), presumably ginger was used by these pregnant women for substantial
periods of time.
Footnote
The Apgar score was introduced in
1973 and is a method developed by Dr. Virginia Apgar to evaluate
a newborn's adjustment
to extrauterine life (life outside the uterus). Five items (heart
rate, respiratory effort, muscle tone, reflex irritability, and
color) are evaluated 60 seconds after birth and again five minutes
later on a scale of 0–2, 0 being the lowest, 2 being normal.
The five numbers are added for the Apgar score. A score of 0–3
represents severe distress, 4–7 indicates moderate distress,
and a score of 7–10 predicts an absence of difficulty in
adjusting to extrauterine life.
References
1. Willetts KE, Ekangaki A, Eden
JA. Effect of a ginger extract on pregnancy-induced nausea: a randomised
controlled trial. Aust N
Z J Obstet Gynaecol 2003; 43: 139–144
2. Smith C, Crowther C, Willson K et al. A randomized controlled
trial of ginger to treat nausea and vomiting in pregnancy. Obstet
Gynecol 2004; 103: 639–645
3. Portnoi G, Chng, LA, Karimi-Tabesh L et al. Prospective comparative
study of the safety and effectiveness of ginger for the treatment
of nausea and vomiting in pregnancy. Am J Obstet Gynecol 2003;
189: 1374–1377
4. Nordeng H, Havnen GC. Use of herbal drugs in pregnancy: a survey
among 400 Norwegian women. Pharmacoepidemiol Drug Saf 2004;
13(6): 371–380
Ginkgo and Glaucoma
While the alkaloid pilocarpine from the herb Pilocarpus
jaborandi has established itself
as an effective topical treatment for glaucoma, there is to date
little evidence that the oral use of any herbs
can help this condition. In this context, the publication of a
recent clinical trial on the effect of Ginkgo biloba extract
on pre-existing visual field damage in normal tension glaucoma
is
noteworthy.1 Normal tension glaucoma is a form of primary
open-angle glaucoma in which damage to the optic nerve and visual
field are
present despite intraocular pressure measurements being within
statistically normal ranges. The exact mechanisms behind the anatomic
and functional damage in this disease are unknown, but there are
two main theories: reduced blood flow to the optic nerve versus
relatively high intraocular pressure. Because some patients with
normal tension glaucoma can continue to experience a loss of visual
field despite conventional medical treatment, the value of other
treatments is worthy of investigation. Since Ginkgo biloba has
been shown to improve blood flow at a tissue level, it was an obvious
candidate for selection in such investigations.
In a randomized, double-blind, placebo-controlled, crossover trial,
27 patients with bilateral visual field damage resulting from normal
tension glaucoma received either 120 mg of Ginkgo biloba extract
(equivalent to 6 g herb) or placebo. Since it was a crossover trial,
patients acted as their own placebo controls. Visual field tests
were performed at baseline and at the end of each 4-week treatment
phase. The main outcome measured was any change in the visual field
and the development of any ocular or systemic complications. After
Ginkgo biloba treatment, a
significant improvement in visual field indices was recorded, but
there were no significant changes found
in intraocular pressure, blood pressure or heart rate. No ocular
or systemic side effects were noted in any patient during the trial.
The authors concluded that their results suggest that Ginkgo
biloba extract can improve pre-existing
visual field damage in some individuals with normal tension glaucoma.
However, they observed that the exact
explanation for this effect is not currently understood.
Commentary: The results of this trial are promising, but as the authors pointed
out, a longer treatment period needs to be investigated to determine whether
the effects of Ginkgo biloba extract
are temporary or will continue with prolonged treatment. Based on this finding,
it is suggested that Ginkgo biloba may
be valuable in all patients suffering from visual field damage irrespective
of
the type of glaucoma. However, it should be emphasized that Ginkgo biloba on
its own is not an adequate treatment where intraocular pressure is significantly
raised.
Reference
1. Quaranta L, Bettelli S, Uva MG
et al. Effect of Ginkgo biloba extract
on preexisting visual field damage in normal tension glaucoma. Ophthalmology 2003; 110: 359–364
Valerian: The Hunt for the 'Active Constituent' Continues
The sedative and anxiolytic effects of valerian have over the years
been attributed to a number of phytochemicals found in the root
of this plant.1 While early research concentrated on the effects
of the essential oil, it is generally believed that this makes
only a minor contribution to its activity (about one-third). Research
on valerian in the 1950s demonstrated that the essential oil was
not primarily responsible for the sedative activity. This led to
the search for other components and the valepotriates were discovered
about 10 years later. Attention then focused on the valepotriates
and later their decomposition products. Research in the past decade
has focused on the component valerenic acid and its derivatives
as important sedative components unique to the European valerian.
These compounds may explain the activity of a water-extracted valerian,
which was noted in some clinical trials.
However, much has been made in a recent press release concerning
the discovery of new components in valerian that may contribute to
its sedative effect.2 The researchers say that a compound
in the phytochemical class known as lignans in valerian latches onto
specific
receptors in the brain which control the body's sleeping and
waking rhythms. Caffeine affects the same type of receptor but has
the opposite effect according to the researchers.3
On the face of it, this new research suggests that valerian works
on adenosine receptors targeting specifically A1 receptors and thereby
triggering drowsiness. In the press release, Christa Müller,
Professor of Pharmaceutical Chemistry at the University of Bonn,
said: “We repeated the experiments and were able to confirm
that aqueous alcoholic full extracts from the valerian root can attach
themselves to the A1 receptor, at least in the brains of rats . .
. What is more, we were able to show for the first time that the
extract activates the receptors rather like adenosine does. Experiments
with genetically produced human receptors had a similar result.”
Commentary: As can be seen from the above, the press release2in fact contains
additional developments to the paper previously published in the Journal
of Natural Products.3 In the published
paper, the lignans in valerian were identified as mainly occurring as glycosides.
These lignan glycosides would have extremely
low bioavailability and would be highly unlikely to cross the blood-brain barrier.
Hence this is another case of where in vitro or test tube research on herbs
has been extrapolated out of proportion to the test results. In other words,
due to the poor bioavailability of these compounds and the limited relevance
of in vitro models, it must be concluded that any inferences drawn from this
research are highly tentative. More research in both clinical and experimental
models is required to validate the assertion that the lignans are partly responsible
for the sedative effect of valerian. The press release also contains reference
to a Swiss research team which measured the effects of valerian on the brain
waves of around 50 test subjects. After caffeine was ingested the alpha waves
leveled out, signalling relaxation. By contrast, the beta waves, signs of nervousness,
became more marked. When valerian extract was administered, this effect of
caffeine was neutralized. This could be explained in terms that the herb does
in fact affect the A1 adenosine receptor, but these findings could equally
be explained in terms of the general calming effect of valerian. A possible
future direction for this research would be to identify the bioavailable forms
of the valerian lignans and test these compounds in the in vitro models
of the adenosine receptor.
Until more information is available we should resist the temptation to declare
that the active components in valerian have finally been elucidated. Indeed,
on current evidence, valepotriates, valerenic acid derivatives and the essential
oil are still the most important quality markers for this herb.
References
1. Mills S, Bone K. Principles
and Practice of Phytotherapy: Modern Herbal Medicine.
Churchill Livingstone, Edinburgh, 2000, p 583.
2. [no author listed]. Scientists unravel mechanism behind valerian's
calming effect. NutraIngredients.com News 13/2/2004. Available: http://nutraingredients.com/news/printnews-NG.asp?id=49878.
Accessed 21 April 2004.
3. Schumacher B, Scholle S, Holzl J et al. Lignans isolated from
valerian: identification and characterization of a new olivil derivative
with partial agonistic activity at A(1) adenosine receptors. J
Nat Prod 2002; 65(10): 1479–1485
Herb-Drug Interactions
HDI Scares: Survey Does Not Confirm the Fears . . .
From time to time there have appeared various media articles and
papers in medical journals written in alarmist terms about the
dangers of herb-drug interactions. So it is refreshing to find
a study which
examined the reality of the potential of such interactions, rather
than exaggerated concerns. The US study explored the potential
incidence and severity of interactions between prescription medications
and
dietary supplements (including herbal products) at two outpatient
practices.1
A survey was conducted on dietary supplement use by 458 veteran
outpatients currently taking prescription medications. Self-reported
dietary
supplement use was cross-referenced with each patient's prescription
medication list, and potential interactions were identified from
several texts and medical literature searches.
It was found that 197 patients (43%) were currently taking at least
one dietary supplement with prescription medication(s). The most
common products included vitamins and minerals, garlic, Ginkgo
biloba, saw palmetto, and ginseng.
Among these, 89 (45%) had a theoretical
potential for drug-dietary supplement interactions of any significance.
Most of these potential interactions (n=84 (94%)) were not serious,
based on limited available evidence, giving an incidence of 6%
(5/89) of potentially severe interactions among patients taking
interacting
drugs and dietary supplements and 3% (5/197) among patients taking
coincident dietary supplements and medications.
Commentary: While this study is valuable, it has a major shortcoming.
The potential or theoretical interactions identified were not investigated
further to ascertain
whether an actual interaction had occurred. One suspects, if they had done
this, that the number of actual serious interactions would be lower than
even a few percent, maybe even zero.
.
. . And Our Knowledge Continues to Grow
A number of clinical studies
and case reports on the topic of herb-drug interactions have appeared
in the literature.
One of these examined
the potential interaction between digoxin and hawthorn (Crataegus
oxyacantha).2 It found that hawthorn
had no effect on the pharmacokinetic profile of digoxin. Similarly,
saw palmetto (Serenoa repens)
did not alter cytochrome P450 2D6 and 3A4 in healthy volunteers,
as
assessed by the test drugs dextromethorphan (CYP2D6) and alprazolam
(CYP3A4).3 Neither did Ginkgo biloba using
the same test drugs.4
In terms of case reports, an interaction between the anticoagulant
drug phenprocoumon and ginger was recently described.5 This was
reported to result in an elevated international normalized ratio
(INR) of
up to 10 and episodes of epistaxis. The INR returned to normal
levels when the ginger (consumed as ginger tea, dosage not specified)
was
stopped. The basis of this possible interaction (pharmacodynamic
or pharmacokinetic) is not known, but since ginger is not thought
to possess anticoagulant activity, it was probably pharmacokinetic
in nature. That is, more phenprocoumon reached the patient's
bloodstream as a result of the patient taking ginger tea.
References
1. Peng CC, Glass PA, Trilli LE et
al. Incidence and severity of potential drug-dietary supplement interactions
in primary care
patients. Arch Intern Med 2004;
164: 630–636
2. Tankanow R, Tamer HR, Streetman DS et al. Interaction study
between digoxin and a preparation of hawthorn (Crataegus oxyacantha).
J Clin
Pharmacol 2003; 43: 637–642
3. Markowitz JS. Donovan JL, Devane CL et al. Multiple doses of saw
palmetto (Serenoa repens) did not alter cytochrome P450 2D6 and 3A4
activity in normal volunteers. Clin Pharmacol Ther 2003;
74(6): 536–542
4. Markowitz JS. Donovan JL, DeVane CL et al. Multiple-dose administration
of Ginkgo biloba did not affect cytochrome P-450 2D6 or 3A4 activity
in normal volunteers. . J Clin Psychopharmacol 2003;
23(6): 576–581
5. Krüth P, Brosi E, Fux R et al. Ginger-associated overanticoagulation
by phenprocoumon. Ann Pharmacother 2004;
38: 257–260
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