Download Drug Interaction and Food - KSU Faculty Member websites

Introkjljduction
Plants have always provided an important source of medicines. The use of herbs
to treat disease emanates from the ancient Greek, Egyptian and Chinese civilizations
(Ioannides, 2002). They generally were used by natives in folk medicine and later
adopted by conventional western medicine as their efficacy was confirmed. The progress
of pharmacology in the 20th century created the misconception that there is a pill for
every ill, while at the same time faith in science was undermined by disasters such as the
thalidomide tragedy (Angell, 2003). Consequently, a mistaken belief emerged that all that
is natural is superior to all that is synthetic. The recent increase in the popularity of herbal
medicine, especially during the preceding several years has flooded the world's
pharmaceutical markets with over 20,000 herbal and other natural products (De Smet,
1995).
In 2005 studies estimated that 42% of Americans use some type of
complementary and alternative medicine (CAM) and herbal therapy is among the most
prevalent types (Eisenberg et al, 2001). On the other hand an estimated one third of
adults in developed nations and more than 80% of the population in many developing
countries use herbal medicines in the hope of promoting health and to manage common
maladies such as colds, inflammation, heart disease, diabetes and central nervous system
diseases (Braun, 2000). Furthermore, as Western medicines become more expensive and
fewer people carry health insurance, the use of herbal supplements with their promise of
wonderful results can only increase (Philip, 2004). Large variety of herbal preparations
and products is used by people all over the world, and the selection of a particular herb
reflects the diverse ethnic backgrounds of the users (Bush et al, 2007).
1
Problems Associated with the Use of Herbal
Remedies
2
I. Problems associated with the use of herbal remedies
While the public perception is that herbal remedies are safe, many published
reports and scientific researches have been presented about the potential problems
associated with the use of herbal remedies. Some of these problems will be presented,
briefly, in the following points
I.1. Scarcity of established regulatory standards and safety concerns for herbal
drugs
In both the United States and Canada, herbs are currently classified as dietary
supplements. The law, declared by the Dietary Supplements Health and Education Act
(DSHEA) in 1994, defines a dietary supplement as a vitamin, mineral, amino acid, herb
or other botanical combination (Noonana and Noonan, 2006). Dietary supplements do not
require premarket approval and, therefore, are sold without undergoing extensive testing
for safety and efficacy. To be removed from the market, a herb must be proven unsafe
and the proof submitted to the Secretary of Health and Human Services. The Food and
Drug Administration (FDA) has no authority to test dietary supplements, but can stop the
sale of supplements that pose a “significant unreasonable risk of illness or injury” or that
make unsubstantiated claims (Soller, 2000). In contrast, Germany appears to be the only
developed country to have established a comprehensive legislative body to deal with
herbal remedies, Commission E, a committee of doctors, pharmacists, scientists and
herbalists to evaluate data regarding the efficacy and safety of herbal remedies and
publishes monographs on these judgments (Valli and Giardina, 2002). Products on
Germany, can only be registered if based on approximately 300 monographs on herbs
with concise information on dose, indications, contraindications, interactions and
3
mechanisms (De Smet, 2002). In Saudi Arabia, survey of available literature revealed the
lack of quality control and product standardization of the majority of the used herbal
preparations which makes it difficult to establish safe administration of herbal products.
I.2. The complex nature of herbal drugs
Herbal products, as taken by the general population, are usually complex mixtures
of many molecular entities and often a complete characterization of all the chemical
constituents from a natural product is not possible (Pal and Mitra, 2006). Additionally,
chemical constituents of natural product may vary depending on the part of the plant
processed (stems, leaves, roots), seasonality, growing conditions and finally the
manufacturing process. What complicate matters further is the fact that many marketed
herbal drugs are combination products composed of multiple natural extracts and a single
herbal preparation may contain more than 100 components (Hu, 2005).
Because herbal products are not regulated by the FDA, as previously mentioned,
there are no standards for herbal products (Mary et al, 2005). Indeed, some products have
been found to be misidentified, substituted and/or adulterated with other natural products
or unwanted substances including microbes, microbial toxins, environmental pollutants,
or heavy metals (Seth and Sharma, 2004). Testing the quality of more than 1200 dietary
supplement products by the independent laboratory Consumerlab.com found that 1 in 4
dietary supplement products lacked the labeled ingredients or had other serious problems
such as unlisted ingredients or contaminants (Con, 2005).
I.3. The lack of accurate information sources
Although the safety concern and the awareness regarding allopathic drugs are
increasing rapidly, up to day it is hard for the consumer to find trustworthy and reliable
4
sources for balanced information about this emerging field regarding their safety profile,
the exact constituents of the conventional herbal formulations, adulteration in the drug
formulations, manufacturing standards, etc. (Percival, 2000).
1.4. Toxicity and adverse effects of herbal drugs
As herbs are considered natural products, evaluation of the toxicity and adverse
reaction of the herbal preparation has been a neglected area for a long time. This lack of
information makes it difficult to compare the benefit-risk profile of herbal medicines.
Even with the increased awareness regarding the adverse herb reaction reporting and
evaluation, the long term toxicity, mutagenicity and genotoxicty studies are still deficient
(Seth and Sharma, 2004).
1.5. The interaction between complementary herbal drugs and conventional
medicines
The interaction of drugs with herbal medicines is a significant safety concern, as
the consequence of some of these interactions may be severe and even life threatening
(Fugh-Berman, 2001).
The focus of this review article will be on the interactions of some herbal
phytochemicals with conventional drugs. It is important to recognize herbs with high
potential to interact with conventional medications through detailed investigation of the
mechanisms involved in this process.
5
Mechanisms for Herbal Interactions with
Prescription Drugs
6
II. Mechanisms for herbal interactions with prescription drugs
There are numerous ways in which pharmacologically active agents can interact,
regardless of whether they are prescription medications, proprietary medicines or herbal
preparation (Goldman, 2001).
A herb-drug interaction is defined as any pharmacological modification caused by
a herbal substance(s) to another exogenous-chemical (e.g. a prescription medication) in
the diagnostic, therapeutic or other action of a drug in or on the body (Brazier and
Levine, 2003). This relates to drug-drug interactions, herb-herb interaction or drug-food
interaction. A herb can potentially mimic, increase, or reduce the effects of coadministered drugs and the consequences of these interactions can be beneficial,
undesirable or harmful effects (Fugh-Berman, 2000). It should be pointed out that both
the putative active ingredient(s) and other constituents present in that herbal mixture have
the potential to interact with various classes of drugs (Venkataramanan et al, 2003)
The underlying mechanisms for most reported drug interactions with herbal
medicines have not been fully elucidated. However, as with drug-drug interactions, both
pharmacokinetic and pharmacodynamic mechanisms are implicated in these interactions.
II.1. Pharmacokinetic (PK) herb-drug interactions
PK interactions result from alteration of absorption, distribution, metabolism or
elimination of a conventional drug by a herbal product or a dietary supplement (Zhou et
al, 2007). As known herbal components are chemicals and, like drugs, they are
metabolized by phase I and phase II pathways (Woolf, 1999).
7
II.1.A. Phase I pathway
Phase I processes include oxidation, reduction, hydrolysis and hydration resulting
in the formation of functional groups (OH, SH, NH2 or COOH) that impart the metabolite
with increased polarity compared to the parent compound (Gibson and Skett, 2001). In
phase I processes, the cytochrome P450 (CYP) super family is responsible for the
metabolism of a variety of xenobiotics and endobiotics (Venkataramanan et al, 2003).
The effect of phase I enzymes on the drug’s activity depends on the nature of the drug.
Some drugs (e.g., cyclophosphamide, ifosfamide) are introduced into the body as
prodrugs, whose structure must be altered by phase I enzymes to become active. Drugs
that are introduced into the body in their active forms, on the other hand, are de-activated
by phase I enzymes as a part of the process of their clearance or removal from the body
(Block and Gyllenhaal, 2002).
II.1.B. Phase II pathway
Phase II processes include sulfation, methylation, acetylation, glucuronidation
glutathione conjugation and fatty acid conjugation (Gibson and Skett, 2001). In
conjugation, a new chemical entity is attached to a drug’s functional group to make the
drug more polar, facilitating its removal from the body (Block and Gyllenhaal, 2002).
Glucuronidation is catalyzed by uridine diphosphoglucuronosyltransferases (UGTs) and
involves the transfer of the glucuronic acid residue from uridine 5--diphosphoglucuronic
acid to a hydroxyl or a carboxylic acid group on the compound (Meech and Mackenzie,
1997). As the case with CYPs, UGTs metabolize a broad range of endogenous and
exogenous substances (Radominska-Pandya et al, 1999). Phase II enzymes are also
8
considered to have a significant role in disabling and exporting chemical carcinogens
(Kensler et al, 2000).
It is important to note that not all drugs go through the phase II metabolizing
enzymes; many are removed after metabolism by phase I cytochrome P450 enzymes. The
activities of phase I and phase II enzymes on active drugs and prodrugs are summarized
in Table 1.
Table 1. Functions of phase I and phase II enzymes on prodrugs and drugs
administered in active form
Drug Type
Phase I Enzymes
Phase II Enzymes
Active drugs
Deactivation, clearance
Conjugation, clearance
Prodrugs
Activation, clearance
Conjugation, clearance
II.2. Role of drug metabolizing enzymes and transporters in herbal-drug interaction
Herbal or even dietary phytochemicals can cause induction of drug metabolizing
enzymes (DME’s: phase I and phase II) and transporters via nuclear hormone receptors,
as well as non-hormonal receptors (Mandlekar et al, 2006). In the following section the
role of DME’s and efflex proteins and transporters in the mechanism of drug-herbal
interactions will be discussed.
II.2.A. Role of CYP450 in herbal-drug interaction
A recent study showed that 82% of the drugs that were reported to interact with
herbs are substrates for various cytochrome P450s (CYPs) (Rendic, 2002). The CYPs are
a group of enzymes found primarily in the liver and the gut mucosa; and lower levels
may be found in the lungs, the kidneys and brain. The enzymes catalyze phase I
biotransformation of a variety of compounds including most drugs (Wong et al, 1991).
9
CYP3A is the most abundant isozyme in the human liver; representing approximately
30% of total hepatic CYP and more than 70% of intestinal CYP activity. Moreover
CYP3A is responsible for the metabolism of more than 50-70% of all prescribed drugs
(Kaminsky and Zhang, 1997). A congener of CYP family is CYP3A4, the most abundant
form that account with the isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A3
for the metabolism of almost half of all clinically used drugs (Figure 1)
Relative Levels of P450 isozymes
in human liver
28%
30%
7%
13%
CYP 3A4
CYP2C
CYP2D6
CYP1A2
CYP2E1
Other
20%
2%
Fig. 1. Relative levels of P450 isozymes in human liver
10
Xenobiotics, drugs and a variety of naturally occurring dietary or herbal
constituents can interact in several ways with the CYP450 system (Lehmann, 1998)
resulting in altered drug clearance and effect (Rendic, 2002).
• A compound may be a substrate of one or several CYP isoforms. If the main isoform is
saturated, it becomes a substrate for the secondary enzyme(s).
• A compound can be an inducer of a CYP isoform, either of the one it is a substrate for,
or may induce several different enzymes at the same time. The process of induction
increases the rate of metabolism of substrates of that enzyme.
• A compound may also be an inhibitor of CYP450 enzymes. There are several
mechanisms of inhibition, and a compound may inhibit several isoforms including others
than those for which it is a substrate (Zhou, 2003).
In humans, there is a wide range of variation in expression of CYP450 enzymes.
This accounts for the inter-individual variability in responses to drugs, as well as in the
occurrence and severity of adverse effects and drug interactions. Some of the underlying
factors affecting individual variation in CYP450 expression are age; genetics including
gender and race; disease, including both general infection as well as specific hepatic
conditions (Bourian et al, 1999).
Importantly, the expression of CYP3A4, CYP3A5, CYP2B6 and CYP2C8 is
tightly regulated by the nuclear factor pregnane x receptor (PXR/NR112), which is
activated by a number of structurally distinct ligands, including certain herbal
components such as hyperforin from St John’s wort (Matic, 2007).
A funded research, performed in Germany, identified the following herbal
remedies as, in vitro, inhibitors of the various CYP isozymes with IC50 values between 20
11
and 1000 g/mL The herbs identified were: devil's claw root (Harpagophytum
procumbens),
feverfew
herb (Tanacetum parthenium), fo-ti
root
(Polygonum
multiflorum), kava-kava root (Piper methysticum), peppermint oil (Mentha piperita),
eucalyptus oil (Eucalyptus globulus) and red clover blossom (Trifolium pratense) (Frank
and Unger, 2004).
II.2.B. Role of efflex proteins and transporters in drug-herbal interaction
On the other hand, 29.4% of the drugs that interact with herbs have been
identified as substrates for P-glycoprotein (P-gp) and multiple resistance proteins (MRPs)
(Evans, 2000; Pal and Mitra, 2006). P-gp and MRPs are members of the ATP binding
cassette family (ABC), responsible of transporting compounds against a steep
concentration gradient (efflux) (Pizzagalli et al, 2001). A well-known drug transporter, Pgp, is found in the intestines, liver and kidneys. It plays important roles in the absorption,
distribution or elimination of drugs from various tissues (Gerloff et al, 1998). The
multidrug resistance-associated protein (MRP) is another famous ATP-binding cassette
transporter involved in biliary, renal, and intestinal secretion of numerous organic anions,
including endogenous compounds such as bilirubin and exogenous compounds such as
drugs and toxic chemicals (Faber et al, 2003).
Evidence suggests that the transporter interacts directly with non-polar substrates
within the membrane environment of the cell and may act as drug flippest, facilitating the
efflux of the drug from the enterocytes to the intestinal lumen. As a result of such efflux,
drug absorption is reduced and bioavailability of xenobiotics is decreased at the target
organs. In common with CYPs, P-gp and MRPs can be induced and inhibited by several
xenobiotics, including drugs and herbal medicines (Zhou, 2004) and is also regulated by
12
PXR (Synoid, 2001). Several herbs and naturally occurring compounds are found to
modulate P-gp (Zhou, 2004). Curcumin, ginsenosides, piperine, sylimarin and catechins
are thought to affect P-glycoprotein-mediated drug transport (Zhou, 2004). Flavonoids
may induce or inhibit P-gp, for example tangeretin inhibits P-gp (Takanaga et al, 2000),
whereas quercitin and kaempferol are P-gp inducers (Bock et al, 2000).
II.2.C. Combined effects
Interestingly, 23.5% of the reported drugs that interact with herbs are dual
substrates for both CYP3A4 and intestinal efflux proteins, and therefore, they have a
much higher potential for interaction with herbs that also modulate CYP3A4 and Pgp/MPRs (Matic, 2007). Thus the modulation of intestinal and hepatic efflux proteins and
CYP3A4 by herbal medicines represents a potentially important mechanism by which the
bioavailability of co-administered drugs can be modulated (Fugh-Berman, 2001). Any
inhibitory effect of herbs on efflux proteins and CYP3A4 may result in enhanced plasma
and tissue concentrations leading to toxicity, while any inductive effect may cause
reduced drug concentration leading to decreased drug efficacy and treatment failure (Pal
and Mitra, 2006).
II.2.D. Some dietary phytochemical modulators of metabolizing enzymes
There are many non drug inducers and inhibitors of CYP450, among the best
known are grapefruit juice which inhibits intestinal CYP3A4 activity (Bourian et al,
1999). Grapefruit constituents that appear to promote this effect are furanocoumarins
(psoralens), such as bergamottin and its derivative 6`,7`-dihydroxy- bergamottin (figure
2), and dimers derived from them. On the other hand, Cruciferous vegetables, (e.g.,
cabbage family, including Brussels sprouts, kale, mustard greens, cauliflower, broccoli
13
etc.) induce CYP1A2 through its glucosilinated indole-3-carbinol contents (Fontana et al,
1999) and increase the activity of phase II enzymes; they are thus important as
anticarcinogenic agents (Kensler et al, 2000). Other common foods that appear to upregulate cytochrome P450 expression include tea which is found to induce CYP1A2,
CYP2B and also to stimulate the activity of some phase II conjugation enzymes
(Ioannides, 2002).
CH 3
CH 3
O
CH 3
CH 3
CH 3
O
OH
CH 3
OH
O
Bergamottin
O
O
O
O
O
6`,7`-dihydroxy- bergamottin
Fig. 2. Components of grapefruit juice that contribute to its interactions with drugs.
14
II.3. Pharmacodynamic (PD) herb-drug interactions
PD interactions may occur when constituents of herbal products have either
synergistic or antagonist activity in relation to a conventional drug. As a result,
concentration-dependent activity of a therapeutic molecule is altered at the site of action
at the drug-receptor level (Chavez et al, 2006). Displacement from plasma protein
binding sites may increase the availability of an agent to its active site. Competition at
receptor sites, by active agents in the herb, may interfere with the pharmacological
response, agents with similar actions but by different mechanisms may be additive,
whereas those with opposite actions by different mechanisms may be pharmacologically
antagonistic (Braun, 2001). Possible mechanisms for drug interactions with combined
herbal medicines are shown in Figure 3 (Zhou et al, 2007).
Fig. 3. Possible mechanisms for drug interactions with combined herbal medicines
(Zhou et al, 2007)
15
II.4. Other factors influencing drug-herb interactions

Interference with absorption: Another mechanism by which drugs and herbal
medicines may interact is the interference of any laxative or bulk-forming herb
with the absorption of almost any intestinally absorbed drug by speeding
intestinal transit (Philip, 2004). The most popular stimulant laxative herbs are the
antharnoid-containing plants including senna (Cassia senna and C. angustifolia)
and cascara sagrada (Rhamnus purshiana) bark, the dried exudate from the aloe
vera (Aloe barbadensis) leaf and soluble fibers including guar gum and psyllium
(Fugh-Berman, 2000).

Therapeutic index: Many of the drugs identified as interacting with herbal
medicines have narrow therapeutic indices, thus a small change in their plasma
concentration could lead to a marked alteration in their therapeutic effect and/or
toxicity. Warfarin, digoxin, theophylline and cyclosporine are examples of these
drugs (Izzo, 2004). On the other hand, less clinically relevant interactions are also
possible for drugs with large therapeutic index (Hu, 2005).

Inter-individual differences: Drug–herbal interactions in human are likely to be
highly variable because of inter-individual differences in drug metabolism
enzymes and transporters, food habits, age, health status and genetic make up
(Zhou, 2003; Breidenbach et al, 2000).

Effect of multiple medications: The use of multiple medications will
significantly increases the risk of potential herb-drug interaction, especially in the
elderly or certain groups of consumers, such as cancer patients (Izzo, 2004). The
risk of interaction increases with the number of products consumed, for example,
16
the risk for potential interactions when consuming two products is 6%, five
products 50%; the risk increases to 100% when consuming eight or more products
(Mathewson, 1998). As will be discussed later, clinical implication of drug-herbal
interactions is persuaded by variety of factors such as herb type and species,
timing of herbal intake, dose and dosing regimen, route of drug administration
and therapeutic range (Hu, 2005).
17
Popular Herbal Products and Their Interactions
with Therapeutic Drugs
18
III. Popular herbal products and their interactions with therapeutic drugs
The search is focusing on herbs with high potential for drug interactions, as
suggested by published reports, and it is limited to herbs present on the ten top selling
herbal products list provided by Courtesy of Information Resources, Inc., Chicago, IL
III.1. St. John's Wort
Among the more popular herbal products used worldwide and in the U.S. are St.
John's Wort (Hypericum perforatum L., Hypericaceae) (Figure 4). St. John's Wort
accounted for 9 million U.S. dollars in sales in 2005, making it the ninth highest selling
botanical (FDM Market Sales Data for Herbal Supplements, 2005).
Fig. 4. Hypericum perforatum L.
1.1. Preparations, contents and uses
Marketed St. John's Wort (SJW) is an extract of the dried flowering portion of the
plant Hypericum perforatum. It is available from numerous manufacturers, presented in
different forms (tea, tincture, tablet or capsule) alone or in combination products and
under many trade names (e.g. St. john’s Wort High Potency, St. john’s Wort Preferred,
Tension Tamer, Hypercalm and St. john’s Wort Time Release) (Nathan, 1999).
19
The marketed extract is a mixture of a number of biologically active, complex
compounds
including
hyperforin
(a
prenylated
phloroglucinol),
hypericin
(a
naphthodianthrone) –these are believed to be the major constituents of pharmacological
interest- as well as other components such as pseudohypericin, adhyperforin, biapigenin,
quercetin, quercitrin, isoquercitrin, hyperoside and rutin (Figure 5) (Nelson and Perrone,
2000). Commercial preparations are often standardized to 0.3 mg per capsule hypericin.
St. John’s Wort is purported to have sedative, anxiolytic and astringent properties.
It is commonly consumed internally for the relief of depression, anxiety and applied
topically for wounds, minor burns, inflammation and blunt injuries (Barnes et al, 2001).
Several clinical studies have demonstrated the potential benefits of St. John's Wort
compared with conventional therapy in the treatment of mild to moderate depression
(Linde et al, 1996).
20
Fig. 5. Chemical structure of major components of St. John's Wort.
1.2. Pharmacology
Studies conducted in vitro and in animals have shown that the phloroglucinol,
hyperforin, the most plentiful lipophilic compound in the extract, has a binding affinity
for a variety of neurotransmitter receptors, including receptors for serotonin, aminobutyric acid, adenosine and other muscarinic receptors. It has also been shown to
be a potent inhibitor of synaptosomal uptake of 5-HT, norepinephrine and dopamine
(Nathan, 1999).
21
A number of clinical studies have shown that SJW is generally as effective as
tricyclic antidepressants in relieving the symptoms of mild to moderate depression.
However it has not been shown to be effective in severe depression (Lantz, 1999).
1.3. St. John’s Wort & interactions
St. John’s Wort is considered the most commonly used herbal product, which
causes severe drug–herbal interactions (Rodriguez-Landa and Contreras, 2003). Reports
of SJW interactions led the FDA to issue a public health advisory in 2000 informing the
public of the risk of drug-herb interactions with St. John’s Wort (http:
www.fda.gov/cder/drug/advisory/stjwort.htm). A number of clinical studies have
indicated that SJW lowered steady state plasma concentrations of variety of drugs such as
sedatives
and
antidepressants
(amitriptyline,
midazolam)
immunosuppressants
(cyclosporine, tacrolimus), anticoagulants (phenprocoumon, warfarin) cardiovascular
(digoxin), antihistamines (fexofenadine), anti-HIV agents (indanavir, nevirapine,
saquinavir), analgesics (methadone), cholesterol lowering drugs (simvastatin), asthma
medication (theophylline), oral contraceptives and many other drugs (Zhou et al, 2004).
However, the mechanism by which SJW interacts with all these medications is
somehow related and is explained in the following section.
1.3.A. SJW and CYP450 modulation
Preliminary conclusions from many studies that had directly investigated St
John's Wort extract interactions with the CYP450 system, suggest that St John's Wort
may under some circumstances modulate CYP450 isoforms, particularly 3A4 (Roby et
al, 2000). Several in vitro studies revealed that crude extract of SJW, competitively,
inhibits CYP3A4 (Patel et al, 2004). Another study had showed SJW extracts and its
22
major constituents to diminish enzyme activities of recombinant CYP1A2, 2C9, 2C19,
2D6 and CYP3A4 (Obach, 2000). Preliminary studies indicated that hydroxylation
mediated by CYP3A and CYP2B enzymes is the primary pathway of metabolism of
hyperforin, the major component in St. John's wort extract. The four major metabolites
that had been detected in vitro using rat liver microsomes indicated hydroxyl groups in
positions 19, 24, 29 and 34 (Figure 6) (Cui et al, 2004).
Hyperforin: R1=R2=R3=R4=CH3
M1 : R2=R3=R4=CH3, R1=CH2OH
M2 : R1=R3=R4=CH4, R2=CH2OH
M3 : R1=R2=R4=CH3, R3=CH2OH
M4 : R1=R2=R3=CH3, R4=CH2OH
Fig. 6. Chemical structure of hyperforin and its major metabolites
It was, also, reported that when plasma concentration of hyperforin in human
reach a maximum of 0.17-0.5 M potential drug interactions with several CYP substrates
can occur (Agrosi et al, 2000). Several other isolated constituents of SJW were also
found to be capable of competitively reducing CYP activities, with the biflavone 3`,8`biapigenin being the most potent inhibitor of CYP3A4 (IC50 =0.082mM).
23
Conversely, in 2000 Roby et al had proved that SJW is capable of inducing
CYP3A4 in healthy volunteers as demonstrated by a significant increase in 6-β-hydroxy
cortisol/cortisol ratio in the urine (Roby et al, 2000). In 2004 Patel et al had
experimentally proved that prolonged exposure of quercetin, hyperforin and kaempferol
cause a significant increase of CYP mRNA expression levels in Caco-2 cells (Patel et al,
2004). Other in vitro studies had also indicated that crude extract of SJW caused marked
induction of CYP3A4 expression in primary human hepatocytes (Moore et al, 2000).
Results of several animal (Bray et al, 2002) and human studies (Dresser et al, 2003) had
indicated that SJW after 4 to 14 days of administration resulted in higher activity of
CYPs along with increased clearance of the drugs fexofenadine and cyclosporine.
Therefore, it appears that higher levels of CYP enzymes are expressed upon prolonged
exposure to SJW herb (Agrosi et al, 2000).
A recent study demonstrated that SJW induces CYP3A4 by negatively acting on
interleukin-6, which is known to inhibit the pregnane X receptor that in turn, as
mentioned previously, may be involved in the expression of the CYP class of enzymes
(Fiebich et al, 2001).
All these in vitro and in vivo studies suggest that SJW possesses both CYP
inductive and inhibitory properties. However, the induction for CYP activity requires
appropriate dose and duration of herbal exposure. This long-term effect in turn can
elevate metabolism of xenobiotics, consequently reducing their bioavailability, whereas
in short-term SJW inhibitory effect on CYP may actually raise steady state drug levels
(Dresser et al, 2003).
24
1.3.B. SJW and efflex proteins modulation
In vitro studies have showed four to seven folds elevation in the expression of Pgp in LS180 intestinal carcinoma cells by hypericin or SJW total extract treatment
(Fiebich et al, 2001). In vivo studies have also indicated that long-term (14 days)
exposure to SJW leads to higher expression of MDR1 and a significant increase in P-gpmRNA expression in rat intestine (Durr et al, 2000). The same group of researchers
performed a clinical study, where SJW was taken as 900 mg/day for 14 days and resulted
in 1.4 fold increase of P-gp expression in healthy volunteers (Durr et al, 2000).
Results obtained from several clinical studies concluded that simultaneous
administration of SJW with drugs like erythromycin, saquinavir and ritonavir, can
enhance drug absorption due, primarily, to competitive inhibition of P-gp/MRP-mediated
efflux on short-term exposure. Conversely, SJW, upon chronic exposure induces
intestinal P-gp resulting in reduced intestinal absorption possibly through enhanced drug
efflux (Hennessy et al, 2002). It is evident from the clinical studies that the action of SJW
is dose-and exposure dependent. In the following section some reported cases, presented
by sources with reliable evidence for an interaction, of drugs concomitantly used with
various SJW preparations will be outlined.
SJW & anticoagulants: A clinical study showed that 11–day medication of St.
John’s wort resulted in a significant decrease of the area under the curve (AUC) of the
free phenprocoumon, an anticoagulant chemically related to warfarin, compared with
placebo (Yue et al, 2000).
SJW & antineoplastics: The use of SJW is very popular among patients with
HIV or cancer as a complementary therapy, to cope with mental and physiological
25
instability. Recently Piscitelli et al found that the anti HIV drugs (Indinavir and
Saquinavir) concentrations were reduced to 57% by SJW consumption (Piscitelli, 2002).
Another study found that serum concentration of the active metabolite SN-38 in cancer
patients receiving irinotecan was also reduced by SJW consumption (Zhou et al, 2004).
Obviously, such interaction could alter the outcome of anti-HIV therapy and lead to the
development of drug resistance strains and may cause treatment failure in HIV patients.
SJW & immunosuppressive drugs: Several case reports have indicated that
SJW consumption subsequent to transplantation resulted in subtherapeutic plasma
cyclosporine levels leading to organ rejection (Breidenbach et al, 2000; Zhou et al, 2004).
SJW & oral contraceptives: Several clinical studies, conducted to investigate the
effect of concomitant use of SJW and oral contraceptives, (OC) found a significant 1316% increase in the oral clearance of norethindrone and ethinyl estradiol. The studies,
also, discussed the demonstrable effects of SJW on the pharmacokinetics of contraceptive
steroids and warned of the risk of intermenstrual bleeding and unplanned pregnancies
caused by concomitant use of St. John’s Wort and a low-dose OC (Murphy et al, 2005;
Hall et al, 2003).
SJW & selective serotonin-reuptake inhibitors: Development of serotonin
syndrome occurred when SJW and selective serotonin-reuptake inhibitors (sertaline and
paroxetine) were coadministered (Ioannides, 2002).
List of the most important drugs that interact with SJW and the assumed
mechanism involved is presented in table 2.
26
Table 2. Clinical interactions between St. John’s Wort and other conventional drugs
conventional
drug
Result of
interaction
Possible
mechanism
Pharmacological comment
Clinical comment
SJW may reduce efficacy of digoxin
and make a patient a nonresponder.
(John et al, 1999)
numerous cases of
approximately 50% decrease in
INR). (Yue et al, 2000)
Interactions with Cardiac drugs
Digoxin
Decreased plasma
digoxin concentration
Induction of Pglycoprotein
Anticoagulants
Warfarin
Decreased
anticoagulant effect
Hepatic enzyme
induction
Digoxin is a substrate of P-glycoprotein which
is induced by St. John’s Wort resulting in
increased digoxin renal excretion
Warfarin is metabolized by CYP1A2 in the
liver, which is induced by SJW
Phenprocoumon
Increased ‘’QuickWert‘’ test (indicating
decreased
anticoagulant effect)
Hepatic enzyme
induction
SJW could reduce Phenprocoumon on plasma
levels throughout Hepatic enzyme induction
Possible loss of activity since
Phenprocoumon has a narrow
therapeutic window. (Donath et al,
2003)
Simvastatin
Decreased plasma
Simvastatin
concentration
Hepatic enzyme
induction
Simvastatin is extensively metabolized by
CYP3A4 in the intestinal wall and liver,
which are induced by SJW
Minimal significance, no clinical
reports available.
(Sugimoto et al, 2001)
Immunosuppressnats
Cyclosporine/
Tacrolimus
Subtherapeutic plasma
Cyclosporine levels
Induction of
CYP3A4 and Pglycoprotein.
The combined up-regulation in intestinal Pglycoprotein and hepatic and intestinal
CYP3A4 impairs the absorption and
stimulated the metabolism of Cyclosporine.
Theophylline
Induction of
CYP1A2 enzyme
Theophylline is metabolized through catalytic
hydroxylation mediated by CYP1A2.
35 kidney and 10 liver recipients
whose
cyclosporine
blood
concentrations had dropped by an
average of 49%. Two reported cases
of tissue rejection (Breidenbach et al,
2000).
High dose of drug became necessary
to obtain therapeutic level (Fuhr et
al, 1992)
Decreased plasma
theophylline
concentration
27
Protease inhibitors
Indinavir/nevirapine
Subtherapeutic plasma
Protease inhibitors
levels
Induction of
CYP3A4
Protease inhibitors are metabolized by
CYP3A4 which is induced by SJW
No clinical reports. Generally avoid.
Coadministration requires specialist
supervision and monitoring of drug
levels. (Ioannides, 2002)
Oral contraceptives
Ethinylestradiol/
desogestrel
significant increase in
the oral clearance of
norethindrone,
Induction of
CYP3A4
Ethinylestradiol is metabolized through
CYP3A4 mediated hydroxylation
Reports of intermenstrual bleeding
and unintended pregnancies (Shader
and Greenblatt, 2002).
Tricyclic antidepressants
amitriptyline/
Decrease in the AUC of
midazolam/
amitriptyline/midazolam
by>20and 40%repectively.
Induction of
CYP3A4 and
CYP2C19 and
CYP2D6
The demethylation of / amitriptyline to
nortriptyline is catalysed by CYP2C19 and
CYP2D6, further metabolism of nortriptyline
is mediated by CYP3A4.
No clinical reports.
(Venkatakrishnan et al, 1999)
Selective serotonin- reuptake inhibitors
(SSRI)
Sertaline/paroxetine/
nefazodone
Herb may lead to
varying combined
pharmacokinetic
and
pharmacodynamic
interactions,
Additive effect on serotonin uptake inhibition
Several reports of varying reliability.
Delirium or mild serotonin syndrome
(Lantz, 1999;Breidenbach et al,
2000)
Induction of
CYP3A4
The drug is 3A4 substrate, which is induced
by SJW.
Possible compromise to targeted
anticancer therapy. No case reports.
(Dresser et al, 2003)
Anticancer drugs
Imatinib/Irinotecan
decreased drug
bioavailability
28
III.2.Echinacea
Echinacea plant (Family: Compositae) (Figure 7) is indigenous to the central and
eastern parts of United States and it has been used for centuries by Native Americans as an
antiseptic and analgesic (Percival, 2000). In 2005, it was the second most popular herb in the
United States with about 68 million U.S. dollars in sales (Turner et al, 2005).
E. angustifolia
E. purpurea
E. pallida roots
Fig. 7. Medicinally used Echinacea species
2.1. Preparations, contents and uses
Marketed Echinacea is prpared from the alcoholic extract of the root of the
narrow-leafed coneflower of E. angustifolia DC., the juice from the fresh aerial parts of
the purple coneflower of E. purpurea L. or the extract of E. pallida Nutt. root (fresh or
dried) (Figure 7). Echinacea is available in numerous forms, including teas, capsules,
prepared beverages, and chewing gum marketed under various trade names by many
companies (Melchart et al, 1995). It is, also, combined frequently with conventional
over-the-counter cold medications such as dextromethorphan (Benylin®) (Philip, 2004).
The composition of the different preparations is similar, with slight variations in
the amount of active components. However the composition of the root extract when
29
compared with that prepared from the upper plant is very different. Root parts have more
volatile oils (such as caryophyllene and humulene) (Percival, 2000), pyrrolizidene
alkaloids (such as tussilagine and isotussilagine) and alkamides than the above-ground
parts. The active components of the upper plant are thought to be caffeic and ferulic acid
derivatives (such as cichoric acid and echinacoside) and complex polysaccharides (acidic
arabinogalactan,
rhamnoarabinogalactans,
and
4-O-methylglucuronylarabinoxylans)
(Figure 8 & 9) (Grimm and Müller, 1999). Many other active components have been
identified in the water-soluble, ethanol-soluble, alkaline, lipophilic and polar fractions of
different Echinacea species (Barrett et al, 1999).
Generally the herb is used, internally, for treating common cold, cough,
bronchitis, and inflammation of the mouth and pharynx. It is used, topically, to treat
snake bites (PDR for Herbal Medicines, 1998). In 1998, the German Commission E
monograph, a consensus statement of expert opinions has approved the oral use of
Echinacea purpurea herb for colds, respiratory tract infections, and urinary tract
infections, and its topical use for poorly healing wounds (Gorski et al, 2004).
30
COOCH 3
COOCH 3
OH
N
N
Tussilagine
Isotussilagine
Main alkaloids of Echinacea roots
O
OH
OH
HO
H
O
OH
O
H
O
HO
O
O
OH
Cichoric acid
HO
COOH
HO
O
OH
HO
O
OH
Cholorogenic acid
GLo-O
O
H2C
HO
O
O
O
OH
Rha-O
HO
OH
OH
Echinacoside
Fig. 8. Some of the hydrophilic components of E. purpurea extract.
31
Humulene
Caryophyllene
Some volatile constituents of Echinacea roots
Fig. 9. Some of the major alkamides (isobutylamides) of E. purpurea extracts
32
2.2. Pharmacology
Echinacea may be best known as an immunostimulant. Several clinical German
studies reviewed by Barrett et al suggested that the benefit of Echinacea lies in its ability
to shorten the duration and lessen the symptoms of an illness by boosting the phagocytic
immune cell response and stimulation of tumor necrosis factor (Barrett et al, 1999).
Another clinical study performed by Kim, L. and coworkers found no clinically relevant
effects on phagocytic activity of granulocytes or on lymphocyte subpopulations, after
administration of Echinacea extract (Kim et al, 2002).
Melchart et al suggested that Echinacea may be beneficial to those already having
immune disorders and therefore may show little to no effect on a healthy immune system.
Because of supposed Echinacea effect on phagocytes, chronic ingestion of Echinacea
may potentially do more harm than good. Increased reactivity of the phagocytic system
may result in the potential generation of free radicals, which in turn, may cause damage
to the host (Melchart et al, 1995).
Some researches concerning the pharmacological effects of Echinacea
constituents has showed Cichoric acid to possess in vitro and in vivo phagocytosis
stimulatory activity, while echinacoside has antibacterial and antiviral activity (Bauer and
Wagner, 1991). Cichoric acid has also recently been shown to inhibit hyaluronidase and
to protect collagen type III from free radical induced degradation, while the lipophilic
alkamide (isobutylamides), polyacetylenes, and glycoproteins/polysaccharides have been
shown to possess immunomodulatory activity (Bauer and Wagner 1991). Alkamides have
been also shown to posses anti-inflammatory activity, attributed to their ability to inhibit
both cyclooxygenase (COX-1 and COX-2) enzymes (Mullin and Heddle, 2002).
33
2.3. Echinacea & interactions
Echinacea & CYPs: Although evidences from in vitro and in vivo studies suggest
potential interactions with substrates of cytochrome P450 CYP3A4 and CYP1A2 (Gorski
et al, 2004), no clinical studies have assessed the potential nature of such interactions
(Kligler, 2003).
Echinacea & immunosuppressives: Due to the potential immunostimulatory
nature of Echinacea, a great concern relates to the probable interference with
immunosuppressive therapy, exacerbation of autoimmune disorders such as systemic
lupus erythematosus and the unknown effects in immunocompromised individuals such
as those with human immunodeficiency virus infection (Gorski et al, 2004). Based on the
fact, the German Commission E monograph, recommends that Echinacea not be taken by
patients receiving immunosuppressive medications or patients with autoimmune
conditions or HIV infection (Messina, 2006).
Echinacea & hepatotoxic drugs: In addition, long term use (>8 weeks) of
Echinacea has been associated with hepatotoxicity, hence, many studies warn of
concomitant use of Echinacea and other hepatotoxic drugs such as methotrexate and
anabolic steroids (Kaur and Kapoor, 2001).
34
III.3. Gingko
Gingko biloba L. (Family Ginkogoaceae) (Figure 10) is about 40 m high
dioecious tree, indigenous to China, Japan and Korea . It is among the most sold
medicinal plants in the world with estimates of worldwide annual sales of over 1 billion
dollars. Most of the sales concern special standardized extracts from the leaves (Ernst,
2002).
Fig. 10. Ginkgo fruits, leaves and stem
3.1. Preparations, contents and uses
Ginkgo biloba is available from numerous manufacturers and in different
liquid or solid pharmaceutical forms for oral intake and also parenterally for
homeopathic use. G. biloba special extract EGb 761® is registered in Germany and
many other countries for the treatment of dementia disorders (Kanowski et al, 1996).
35
The standardized leaves extract contains a large number of constituents from
various classes. Chemical analysis of some of the standardized products found in the
market revealed the presence of terpene trilactones (6.0%), flavonol glycosides (24.0%),
biflavones and proanthocyanidins (7.0%) (Camponovo and Soldati, 2000). Currently
flavone glycosides (quercetin, kaempferol, isorhamnetin), and diterpene trilactones
(ginkgolides A, B, C and the closely related C-15 bilobalide) are considered the two
pharmacologically most important groups present (Ellnain-Wojtaszek et al, 2003). The
biflavone, Ginkgetin, is also a powerful antiinflammatory compound. On the other hand,
some alkylphenol compounds (ginkgolic acids, ginkgols and bilobols) occurring in
various parts of G. biloba, are found to posses cytotoxic, mutagenic and slight neurotoxic
properties and their presence is considered undesirable in Ginkgo marketed extracts
(Haster, 2000). (Figure 11)
Few published reports warned of the risk of presence of the neurotoxic compound
ginkgotoxin (4`-O-methylpyridoxine) in some marketed extracts (Arenz et al, 1996).
Ginkgo biloba is approved in Germany for the treatment of cerebral circulatory
disturbances that result in reduced functional capacity and vigilance. It has also been used
to treat peripheral arterial circulatory disturbance, high altitude sickness and equilibrium
disorders like tinnitus of vertigo (Tesch, 2003).
36
OH
OH
OH
HO
O
R
OCH3
OH
OH
OH
O
O
CH3O
O
HO
O
R
HO
HO
OH
OH
O
OH
OH
Procyanidin
R=H
Pridelphinidin R=OH
Ginkgetin
HO
H3CO
N
H3C
Ginkgolide
G-A:
G-B:
G-C:
G-J:
G-M:
Bilobalide
OH
4`-O-methylpyridoxin
R1= OH, R2=R3=H
R1= R2=OH, R3=H
R1= R2= R3= OH
R1= R3=OH, R2=H
R1=H R2= R3=OH
OH
OH
COOH
HO
R
R
Ginkgolic acid
R=C13H27
HO
Cardanols
R=Saturated or unsaturated
n-alkyl chain from C13-17
Ginkgol, R=C13H27
R
Bilobols
Fig. 11. Some pharmacologically active constituents of G. biloba
37
3.2. Pharmacology
Although many diverse actions contribute to the overall effectiveness of Gingko,
not all of these mechanisms have been elucidated. Contributing actions include direct and
indirect antioxidant activity, neurotransmitter/receptor modulation, platelet activating
factor antagonism, and neuroprotective actions (Tesch, 2003). The combined therapeutic
effects are probably greater than that of an individual mechanism and are perhaps the
result of the synergistic effects of multiple constituents of the total extract (Rosenblatt
and Mindel, 1997). It has been found that the flavone glycosides posses antioxidants and
platelet aggregation-inhibiting properties, reduce capillary fragility and increase the
threshold of blood loss from capillaries (Hadley and Petry, 1999). Several animal studies
found the antagonism of platelet-activating factor (PAF) by ginkolides improves cerebral
metabolism and increases cerebral tolerance to hypoxia (Schulz et al, 2003). On the other
hand clinical trials have demonstrated the effectiveness of EGb 761 in managing mild-tomoderate dementia of the Alzheimer’s disease patients (Curtic-Prior et al, 1999).
3.3. Gingko & interactions
Gingko & CYPs: A controlled trial on healthy volunteers was conducted by Yin
and co workers to study the probability of G. biloba-CYP 450 interactions. The patients
were administered omeprazole 40 mg a day, a widely used CYP2C19 substrate, prior to
and 1 day following a regimen of 140 mg G. biloba extract twice daily for 12 consecutive
days. A 67.5% decrease on the ratio of omeprazole to 5-hydroxyomeprazole
concentrations and a decrease in urinary excretion of 5-hydroxyomeprazole were
recorded. The authors assumed that G. biloba extract induced CYP2C19 mediated
hydroxylation of omeprazole, and concomitantly reduced urinary excretion of 5-
38
hydroxyomeprazole (Yin et al, 2004). Another study showed that the biotransformation
of androstendione and the urinary steroid profile, in human subjects, was not affected
after intake of EGb 761 for 28 days (240 mg daily) (Schwabe, 2005). However, the
published studies on effect of G. biloba on CYP-3A4, 2C9 or 2D6 are conflicting and
inconclusive of definite interaction.
Gingko & anticoagulants/NSAI: Several case reports of possible herbal-drug
interactions, involving patients concurrently taking a regimen of about 40 mg of G.
biloba with aspirin, ibuprofen, and warfarin, were discussed. In all cases the adverse
effect was bleeding that led to eye hemorrhage, cerebral hemorrhage and coma
(Rosenblatt and Mindel, 1997; Meisel et al, 2003). The interaction was possibly of
pharmacodynamic nature as ginkgolide B, a constituent of G. biloba has been shown to
decrease platelet aggregation and displace platelet-activating factor from its binding sites,
thus potentially decreasing blood coagulation. These data suggest that ginkgo should not
be taken with oral anticoagulants, preparations containing non-steroidal antiinflammatory drugs or other platelet-inhibiting drugs such as ticlopidine (Ticlid®),
clopidogrel (Plavix®) and dipyridamole (Persantine®). Caution also should be used when
ginkgo is taken in conjunction with other agents that could compromise hemostasis, such
as vitamin E or oils containing omega III fatty acids (Ernst, 2002).
Gingko & antidepressants: A case report of a patient, who lapsed into reversed
coma after taking 20 mg trazodone (an antidepressant drug) twice daily with the addition
of 80 mg G. biloba daily, was evaluated. It was suggested that G. biloba may act as an
antagonist of gamma-aminobutyric acid (GABA) activity at benzodiazepine binding sites
resulting in increased sedation effect (Mary et al, 2005)
39
III.4. Ginseng
Ginseng is a perennial herb native to Korea and China (Figure 12). It is one of the
most widely utilized herbs in the world because of its long-term traditional use and its
scientifically-proven benefits for treating and preventing numerous conditions
(Thompson and Edzard, 2002). In the US it is estimated to be the seventh top-selling
herbal supplement, with $62 million in annual sales. It has been used in Asia for over
2,000 years and has the most extensive body of scientific literature of any medicinal herb.
Its scientific name, Panax ginseng, alludes to its purported panacea-like quality (Mar and
Bent, 1999).
American (white, Panax quinquefolium
Fresh ginseng root
ColdFx
Asian (red, Panax ginseng)
Fig. 12. Ginseng plant, roots and pharmaceutical preparations
40
4.1. Preparation, contents and uses
The name ginseng is applied to herbs prepared from the root of several different
species, Asian (red, Panax ginseng C.A. Meyer), American (white, Panax quinquefolium
L.), Japanese (Panax japonicus M.), Sanchi (Panax notoginseng B.), and Eleuthero or
Siberian ginseng (Eleutherococcus senticosus) formerly known as (Acanthopanax
senticosus). All are members of the plant family Araliaceae and they differ in their
content of ginsenosides and slightly in biological activity (Lui and Staba, 1989). Ginseng
is marketed in many forms such as slices, tonics, powders, tablets, teas, extracts, fruit and
mineral drinks. The dose is about 100 to 300 mg of ginseng extract 3 times a day (Tesch,
2003).
Ginsenosides are the major active components of Panax ginseng. They are a
diverse group of steroidal saponins. The amount of ginsenosides can vary with the age of
the plant, method of preservation and season of harvest. Since different forms of ginseng
may contain varying amounts of ginsenosides, studying the effects of ginseng in humans
can be difficult (Lieberman, 2001). Ginsenosides also differ from one another by the type
of sugar moieties, their number and their site of attachment (Chuang et al, 1995).
According to the number and position of sugar moieties, ginsenosides are divided into
two main categories (i) the 20(S)-protopanaxadiols e.g.,Ra, Rb1, Rc, Rg3, Rh2 (ii) 20(S)protopanaxatriols e.g., Re, Rf, Rg1 (Figure 13). More than 30 ginsenosides have been
isolated, and new ones are being found in P. quinquefolium and P. japonicus (Attele et
al, 1999).
41
Ginseng is used to treat a variety of symptoms such as anxiety, weakness,
dyspnea, forgetfulness, fatigue, decreased libido, nausea (Li and Harries, 1996) and
diseases as type II diabetes, HIV, cancer, and hyperlipidemia (Attele et al, 1999).
It was approved by Commission E in 1981 as a tonic to counteract weakness and
fatigue, a restorative for declining stamina and impaired concentration, and as an aid to
convalescence (The Complete German Commission E Monographs, 1998). In 2006, CV
Technologies, Inc. received clearance by the Food and Drug Administration (FDA) to sell
COLD-fX® as a new dietary ingredient in the United States. COLD-fX® is a highly
purified ChemBioPrint product derived from the roots of North American ginseng
(Panax quinquefolius). It is a patented natural compound of poly-furanosyl-pyranosylsaccharides that is claimed to be effective in enhancing cell-mediated (antiviral)
immunity (Predy et al, 2005). In general, people use ginseng to enhance physical
performance and to improve vitality, immune function, sexual function and fertility.
42
Fig. 13. Structure of ginsenosides. Glc: ß-D-glucopyranosyl; Arap: -Larabinopyranosyl; Araf:
-D-arabinofuranosyl; Rha:
-L-rhamnopyranosyl.
Numerical superscripts indicate the carbon in the sugar ring that links the two
carbohydrates.
4.2. Pharmacology
In Chinese medicine, ginseng is described as an “adaptogen” because it is reputed
to restore homeostasis and to increase the body’s resistance to physical, chemical and
biological stress (Gillis, 1998).
Ginsenosides, the major active components of ginseng, have shown the ability to
target a myriad of tissues producing a variety of pharmacological responses (Li and
43
Harries, 1996). They were reported to cause an increase in insulin blood levels, have a
mild estrogen effect possibly by promoting the synthesis of endogenous estrogens (Rude,
1997), scavenge free radicals and possess calcium channel blocking activity (Vogler et al,
1999). Both inhibitory and excitatory effects on the central nervous system have been
reported, as well as protection of neurons from ischemic damage and enhancement of
learning abilities (Attele et al, 1999). There, also, is experimental evidence for
antineoplastic and immunomodulatory effects. The steroid nature of the ginsenosides
imparts high lipid solubility and the ability to pass through cell membranes, possibly
interacting with cytosolic steroid receptors and nuclear receptors, including those for
glucocorticoids with downstream genomic consequences (Lui and Staba, 1989). Other
clinical
studies
have
shown
that
American
ginseng
attenuated
postprandial
hyperglycemia in both normal and diabetic subjects (Vuksan et al, 2000). Ginseng also
has been reported to exert cardioprotective effects through the release of nitric oxide
(Chen, 1996).
4.3. Ginseng & interactions
Ginseng & CYPs: A study carried out in 20 volunteers found that 100 mg of
Asian ginseng standardized to 4% ginsenosides administered twice daily for 14 days did
not significantly change urinary 6-β-OH-cortisol/cortisol ratio, which suggests that Asian
ginseng does not induce CYP3A4 (Anderson et al, 2003). Another study performed in
2004, investigated the inhibitory effects of ginsenosides Rb1, Rb2 and Rd on hepatic
CYP2C9 and CYP3A4 catalytic activities. Tolbutamide 4-methylhydroxylation and
testosterone 6-hydroxylation were used as index reactions of CYP2C9 and CYP3A4
catalytic activities, respectively. The herbal components investigated were capable of
44
inhibiting the activities of the tested enzymes with varying potencies (IC50: 38105mol/L) (Nu and Timi, 2004). In 2006, Liu et al performed another in vitro study
using human liver microsomes and cDNA-expressed human CYP3A4. Their results
showed that the naturally occurring ginsenosides exhibited no inhibition or weak
inhibition against human CYP3A4, CYP2D6, CYP2C9, CYP2A6, or CYP1A2 activities
(Liu et al 2006). However, the intestinal metabolites of ginsenosides demonstrated a wide
range of inhibition of P450-mediated metabolism against CYP2C9 (IC50 value of 32.0 ±
3.6µM-33.7 ± 2.7µM). CYP2C9 is important in the metabolism of many drugs including
the anticoagulant drug warfarin and a number of nonsteroidal anti-inflammatory drugs
(Vuksan et al, 2000).
Ginseng & warfarin: Two randomized clinical trials in healthy young volunteers
had investigated the effect of ginseng on the pharmacokinetics and pharmacodynamics of
warfarin. The outcome showed conflicting results. In the search performed by Jiang et al,
7-day treatment with Asian ginseng did not affect the PK and PD of the anticoagulant in
healthy subjects (Jiang et al, 2004). By contrast, Yuan et al reported American ginseng to
antagonize the efficacy of warfarin by causing a modest reduction in International
Normalized Ratio (INR), peak warfarin levels and warfarin area under the curve (Yuan et
al, 2004). However, the use of different species (Panax ginseng vs. Panax quinquefolius)
and a different time of administration (1 week vs. 2 weeks) may explain such apparent
discrepancy.
Ginseng & digoxin: A possible interaction of Siberian ginseng (Eleutherococcus
senticosus) and digoxin was presented and discussed by McRae in a case report. The
observed effect was mainly elevated serum digoxin level without symptoms of toxicity.
45
The authors speculated that the high drug level was caused by cardiac glycoside-like
constituents such as eleutherosides, one of the Siberian ginseng components, that may
had interfered with digoxin assay (McRae, 1996).
Ginseng & diuretics: Several cases of interaction between ginseng and loop
diuretics (furosemide), resulting in hypertension and edema, had been reported. Although
the exact nature of the interaction was unknown, it was hypothesized that the germanium
component found in some ginseng products may had resulted in the interaction. Longterm use of germanium had been associated with chronic renal failure. Therefore, careful
monitoring with concomitant use of the two products is necessary (Becker et al, 1996).
Ginseng & other medications: Based on the multiplicity of active agents, the
potential for interactions with many other drugs has been noted. These include
interference with antipsychotic drugs by affecting neurotransmitter transport (McRae,
1996); interference with monoamine oxidase inhibitors resulting in symptoms ranging
from manic-like episodes to headache and tremulousness; increasing the stimulant effect
of caffeine, with possible hypertension as a result (McRae, 1996); interference with
estrogen hormone therapy resulting in symptoms of estrogen excess or interference
(Angell, 2003); and interference with hypoglycemic medication (Sievenpiper et al, 2003)
resulting in dangerously low blood sugar levels.
46
III.5. Phytoestrogens containing herbs
Phytoestrogens are secondary plant metabolites with estrogenic properties found
in several hundred plants (Sabine et al, 2002).
Since it has been hypothesized that the use of phytoestrogen-rich diet, as seen in
traditional Asiatic societies, is associated with a lower risk of breast, colon and prostate
cancer, the consumption of phytoestrogens containing dietary products and herbal
preparations has gained increasing popularity (Rose et al, 1986). The published results, in
2002, of the Women’s Health Initiative randomized controlled trial of hormone
replacement therapy (HTR), warned of the negative side effects of HRT and as a
consequence, many are turning to phytoestrogen supplements as perceived-safer
alternative to manage postmenopausal estrogenic deficiency symptoms (Philip, 2004). In
2005, according to sales data compiled by Information Resources Inc. (IRI) of Chicago,
pharmaceutical preparations containing plant derived phytoestrogens/isoflavones were
among the five top-selling herbal supplements (FDM Market Sales Data for Herbal
Supplements, 2005).
47
Black cohosh
(Cimicifuga racemosa)
Alfalfa
(Medicago sativa)
Red clover
(Trifolium pratense)
Chaparral
(Larrea tridentata)
Dong quai plant & prepatation
(Angelica sinensis)
Fig. 14. Some herbs, plants and pharmaceutical preparations containing
Phytoestrogens
48
5.1. Preparations, contents and uses
Phytoestrogens are present in both foodstuffs (e.g., cereal grains, soy milk and
protein and vegetables or fruits) and herbal remedies (e.g., alfalfa, black cohosh, red
clover, chaparral, dong quai, fenugreek, licorice and wild yam) (Farnsworth et al, 1975).
(Figure 14) Most of these herbs as well as other isoflavone-containing plant extracts are
available in market as nutritional supplements (nutriceuticals) in different forms and
names.
The phytoestrogens have been categorized according to their chemical structures
as isoflavones, lignans and coumestans (Price and Fenwick, 1985). The major isoflavones
are genistein and daidzein, which most commonly occur in plants as inactive glucosides
(Barrett, 2002). They may also be derived from the precursors biochanin A and
formononetin, which are metabolized to genistein and daidzein, respectively, after
breakdown by intestinal glucosidases. Daidzein may be further metabolized to equol and
O-desmethylangiolensin (Sabine et al, 2002). (Figure 15)
Lignans are present in whole grains, flax seed, and variety of fruit and vegetables.
Secoisolariciresinol and matairesinol (Figure 15) are plant lignan precursors, and when
ingested, they are metabolized, by intestinal bacteria, to the mammalian lignans,
enterodiol and enterolactone (Rowland et al, 2003).
Coumestans, the third class, include the most potent of the phytoestrogens,
coumestrol (Figure 15). Coumestans are found in mung beans (bean sprouts) and other
sprouting beans as well as in clover and alfalfa sprouts (Anderson et al, 1999).
49
HO
HO
O
O
O
HO
O
OCH 3
Daidzeien
Equol
HO
O
OH
OH
OH
Formonetin
HO
O
O
O
OH
OCH3
O
OH
Biochanin A
Genistein
H3CO
H3CO
OH
OH
OH
OH
HO
HO
OH
OCH 3
OH
OH
Secoisolariciresinol
Enterodiol
H3CO
H3CO
O
O
HO
HO
O
O
OH
OCH 3
OH
OH
Matairesinol
HO
Enterolactone
O
O
OH
O
O
O
O
Coumestrol
Coumestan
Fig. 15. Compounds with phytoestrogenic properties
50
5.2. Pharmacology
Some of the phytoestrogens (particularly genistein) are able to inhibit tyrosine
kinases and DNA topoisomerases, which would promote cell differentiation and, hence,
inhibit cancer cell proliferation (Rowland et al, 2003). Additionally, phytoestrogens
(particularly genistein and daidzein) can act as antioxidants and are expected to affect cell
signaling depending on phosphorylation pathways and redox reactions (You, 2004).
However, phytoestrogens and isoflavones are mainly recognized due to their estrogenic
activity. Phytoestrogens exert estrogenic effects in a manner similar to endogenous
estrogen, mainly through activation of the estrogen receptors (ER). The ability of
phytoestrogens to compete with estrogen at its receptor (ER) was studied by a group of
researchers. The six plants with the highest ER-binding characteristics were soy, licorice,
red clover, thyme, tumeric, hops and verbena. Among these, genistein and daidzein
isoflavones had the most demonstrable estrogenic activities (Sava et al, 1998). Genistein,
in particular, is an agonist for both ER and ER (Casanova et al, 1999; Kuiper et al,
1998). It binds to ER (which is highly expressed in both reproductive and other human
tissues) with high binding affinity that is comparable to estradiol. While genistein acts as
an estrogenic agent by itself; it displays certain antiestrogenic characteristics in the
presence of estradiol (Ratna, 2002) which distinguish it as both estrogenic agonist and
antagonist.
5.3. Phytoestrogens & interactions
Confirmed reports of interactions between phytoestrogens and drugs are scarce,
and limited information of involved genes and receptors is documented. It is evident from
the conflicting research results published every day that much more data are required to
51
make
definitive
statements
about
the
long-term
hazards
of
concomitant
phytoestrogens/drugs use. Some of the published interactions will be mentioned.
Isoflavones & CYPs: In vitro studies have shown extracts of soy isoflavones to
activate cytochrome enzyme CYP3A4, although no clear correlation between in vitro and
in vivo activation has yet been established (Messina, 2006).
Isoflavones & levothyroxine: A case report presented by Bell and Ovalle found
that concurrent administration of levothyroxine with soy proteins resulted in decreased
therapeutic concentration of levothyroxine and the need for higher dose to attain
therapeutic serum thyroid hormone level (Bell and Ovalle, 2001). Soy isoflavones have
been found to inhibit the activity of thyroid peroxidase, an enzyme required for thyroid
hormone synthesis in cell culture and animal studies (Bell and Ovalle, 2001).
Isoflavones & tamoxifen: It was found that high intake of the soy isoflavone,
genistein, interfered with the ability of tamoxifen to inhibit the growth of ER+ breast
cancer cells implanted in mice (Allred et al, 2001). This was explained by the ability of
isoflavones to stimulate the growth of estrogen receptor positive (ER+) breast cancer
cells. Although very limited data from clinical trials showed that increased consumption
of soy isoflavones (38-45 mg/d) can have estrogenic effects in human breast tissue, some
experts think that women with a history of breast cancer, particularly ER+ breast cancer,
should not increase their consumption of phytoestrogens, including soy isoflavones
(MacGregor et al, 2005)
52
III.6. Garlic
Medicinal use of garlic (Allium sativum Linne., Fam. Liliaceae) (Figure 16) goes
back to Greek and Egyptian antiquity. Hippocrates prescribed it for leprosy, toothache,
and chest pain. Galen considered it a cure-all readily accessible to everyone (Koscielny et
al, 1999). Recently and since the passage of the Dietary Supplement Health and
Education Act (DSHEA) of 1994 by the U.S. Congress, it has been claimed that garlic
dietary supplements possess health benefits (Staba et al, 2001). In 2004, it was designated
as the herb of the year by the Herb Society of America.
Fig. 16. Garlic and one of its pharmaceutical preparations
6.1. Preparations, contents and uses
Garlic is available in many forms, including fresh bulbs, oil-based extracts, dried
powder and steam-distilled extracts. Most commercially available products, for medicinal
purposes, are composed of dried garlic powder standardized for allicin content, in doses
of about 650 mg/day (Valli and Giardina, 2002).
Garlic is characterized by a high content of organosulfur. In the bulb, the sulfur is
primarily -glutamyl peptides and allylcysteine sulfoxides. When the bulb is cut, chopped
or squeezed, alliin, the main allylcysteine sulfoxide, is metabolized to allicin through the
53
action of alliinase. Allicin is a self-reactive constituent and it is converted readily to more
stable compounds such as polysulfides (Lawson, 1998). In addition to allicin, other active
compounds in garlic include methyl allyl trisulfide, diallyl trisulfide, diallyl disulfide,
ajoene and trace minerals as germanium and selenium (Ali et al, 2000). (Figure 17)
Garlic derivatives and preparations are frequently used for antiplatelet,
antioxidant, and fibrinolytic effects as well as for treatment of common cold (Bordia et
al, 1998).
S
S
Diallyl trisulfide
S
O
S
Ajoene
S
S
Fig. 17. Chemical structures of organosulfur compounds of garlic
54
6.2. Pharmacology
Although garlic has been used for its medicinal properties for thousands of years,
investigations into its mode of action are relatively recent (Harris et al, 2001).
The widespread efficacy of this plant extract as an antimicrobial, antifungal and
antiviral agent has been attributed to its main constituent, allicin, and it has been linked to
the ease by which its molecules pass through cell membranes and react biologically at the
low level of thiol bonds in amino acids (Miron et al, 2000). No example of acquired
microbial resistance to garlic has been reported and this could be explained by its diverse
modes of action and the multiplicity of intracellular targets that each bioactive component
inactivates (Harris et al, 2001).
Garlic is believed to inhibit cholesterol biosynthesis at several enzymatic steps. It
was able to lower the levels of free and esterified cholesterol in cultured human cells and
to decrease fatty streak development in rabbits. Several clinical studies, with different
inclusion criteria, had confirmed a moderate cholesterol-lowering effect in patients with
hypercholesterolemia (Yamasaki et al, 2006). The results were consistent across
analyses: garlic modestly reduces lipids 15 to 25 mg/dl (5% to 15%) (Stevinson et al,
2000; Ackermann et al, 2001). Inhibition of lipid peroxidation was another effect
observed for garlic in clinical trials performed on subjects with atherosclerotic conditions
(Koscielny et al, 1999).
In vitro studies suggest garlic to reduce blood pressure by inhibiting platelet nitric
oxide synthase. Clinical trials, evaluating hypertensive subjects, reported a modest
systolic reduction of 7.7 mm Hg and diastolic reduction of 5.0 mm Hg (McMahon and
Vargas, 1993).
55
Garlic is known to have blood-thinning properties, attributed to enhanced
fibrinolytic and antiplatelet activity. It was suggested that diallyl disulfide and diallyl
trisulfide (Fig. 17) inhibit thromboxane synthesis (Ali et al, 2000), possibly by inhibiting
phospholipase-A and mobilizing arachidonic acid (Bordia et al, 1998). Additionally, it
was found that extract of raw garlic contains compounds that inhibit cyclooxygenase
(Ali, 1995).
Recently, epidemiological studies have proved that high consumption of garlic is
associated with reduced cancer risk in humans, primarily stomach and colon cancer
(Fleischauer and Arab, 2001). In addition, experimental studies have demonstrated the
ability of garlic to reduce chemical carcinogenesis in several tissues of different animal
models and against a broad range of carcinogens (Gail and You, 2006).
6.3. Garlic & interactions
Until recently, garlic supplements were thought to be well tolerated and relatively
safe. Adverse interactions between garlic supplements and several narrow therapeutic
index drugs have been reported within the past years (Gallicano et al, 2003)..
Garlic & CYPs/P-gp: Several in vitro and in vivo studies of organosulfur
constituents of garlic, as well as garlic extracts, showed simultaneous inhibitory and
inducing effect on several CYP enzymes (1A, 2B, 2C, 2E and 3A subfamilies) in the
liver, as well as the efflux transporter P-gylcoproptein (Pgp) in the intestinal mucosa
(Foster et al, 2001). In vivo, a single dose of garlic oil, administered to rats, significantly
decreased hepatic CYP activity. However, daily administration for 5 days significantly
increased hepatic CYP activity (Haber et al, 1994). In conclusion, studies suggest that
56
garlic can act as an enzyme inhibitor during acute dosing and an enzyme inducer during
chronic dosing.
Garlic & phase II enzymes: In 2004, Fukao et al studied the effect of the
principal constituents of garlic oil, diallyl sulfide, diallyl disulfide and diallyl trisulfide on
phase II drug-metabolizing enzymes, and on the rat model of acute liver injury induced
by carbon tetrachloride (CCl4). They found that hepatic phase II enzymes glutathione Stransferase (GST) and quinone reductase (QR); were induced strongly by the trisulfide, at
a dose of 10 μmol/kg, and weakly by the disulfide, but not by diallyl sulfide. Moreover,
diallyl trisulfide significantly reduced the liver injury caused by CCl 4. The authors
suggested that the trisulfide may be one of the important factors in garlic oil that protects
our body against the injury caused by radical molecules (Fukao et al, 2004).
Garlic & protease inhibitors: Ritonavir, a protease inhibitor, used in AIDs
management is mainly metabolized by CYP3A4 and has a high binding affinity to Pglycoprotein. At the same time, it inhibits and induces CYP3A4 and predominantly
induces other drug-metabolizing enzymes. Therefore, a possible interaction between
ritonavir and garlic, also a CYP3A4 modulator, is highly probable (Hsu et al, 2007). A
report, discussing two cases of HIV patients who developed GI toxicity after concomitant
use of garlic supplement and ritonavir, concluded that toxicity could have resulted from
either ritonavir effect on CYP3A4 leading to toxic concentration of compounds derived
from garlic, or the latter inhibiting the CYP-mediated metabolism or P-glycoproteinmediated transport of ritonavir leading to elevated levels of the drug (Gallicano et al,
2003). In another study, on healthy volunteers, a 3-week administration of a garlic
57
supplement decreased plasma concentrations of the protease inhibitor saquinavir by about
50% (Piscitelli et al, 2002).
Garlic & acetaminophen/chlorzoxazone: CYP2E1 is one of the isosymes
inhibited by garlic. CYP2E1 is also involved in the metabolism of acetaminophen
(Panadol, Tylenol, etc.) and the muscle relaxant chlorzoxazone (Parafon Forte®). These
drugs could possibly linger longer in people who are taking or eating garlic (Ali, 2000)..
Garlic & anticoagulants: An additive effect on coagulant effect is likely to be
the mechanism by which garlic causes increased INR in patients taking warfarin or other
anticoagulant treatment (Burnham, 1995).
Garlic & hypoglycemic agents: Animal and clinical studies imply hypoglycemic
effects of garlic which could explain the fall in glucose levels reported in several cases
regarding patients concomitantly taking dietary garlic supplement with diabetic
medication such as chlorpropamide (Izzo and Ernst, 2001).
58
Approaches to Evaluate and Minimize Toxic HerbDrug Interactions in the Drug Development
Process
59
IV. Approaches to evaluate and minimize toxic herb-drug interactions
in the drug development process
The prevalence of complementary and alternative medicine (CAM) is increasing
worldwide because of the growing public interest in natural or holistic therapies and
because of the flow of information through the Internet. However, there are many reasons
for the increased concern regarding the use of herbal medicines, among which the
following maybe mentioned:
1- A general misconception persists among most CAM users that herbal
medicines are of natural origin and therefore they are safe and free from side effects and
drug interactions (Pal and Mitra, 2006).
2- The fact that most herbal users do not inform their allopathic doctors about
CAM intake and this increases the likelihood that herb-drug interactions are not identified
and resolved in timely manner (Izzo et al, 2005).
3- Herbs are generally considered a traditional health aid which does not require
stringent preclinical and clinical assessments by appropriate regulatory agencies.
4- The paucity of proper surveillance procedures for quality control and for
monitoring adverse effects of herbs or herb-drug combinations.
5- The practice of including several herbs in a single preparation and the marked
variations in the potency of various preparations (Venkataramanan et al, 2003).
IV.1. Predicting a drug’s potential for interaction with herbal medicines
The screening of natural products has become an economically viable approach
for the drug industry especially with the advancement of new assay techniques and
automated screening technologies (Darshan and Doreswamy, 1998). A brief illumination
about the use of such approaches is discussed in the following section.
60
IV.1.A. The use of in vitro and in vivo models
To avoid or minimize toxic drug–herb interactions, it is important to identify
drugs that can interact with herbs using proper in vitro and in vivo models in the early
stages of drug development. These models may be used in combination to obtain enough
information that is useful for providing warning and proper advice to patients in clinical
practice. There is an increasing use of in silico methods to study CYPs, Phase II enzymes,
P-gp and their interactions with xenobiotics, including herbs (Ekins and Wrighton, 2001).
For metabolic interactions, the major models include subcellular fractions (liver
microsomes, cytosols and homogenates), precision-cut liver slices, isolated and cultured
hepatocytes or liver cell lines (Rodrigues, 1994). The use of primary cultures of human
hepatocytes (PCHH) in in vitro models, are necessary to make better predictions of drug–
herb interactions in humans (Venkataramanan et al, 2003). PCHH provide cellular
integrity with respect to enzyme architecture and allow the study of Phase I and II
reactions and transport in a cost and time efficient manner (Wentworth, 2000).
IV.2. Regulatory measures to minimize herb- drug interactions
Ever-increasing use of herbal remedies raises the need for more effective
regulations to put this class of therapeutics on the same evidence-based footing as other
medicinal products. Some of the suggested guidelines are listed below
1- The need for a comprehensive surveillance system for monitoring the adverse effects
of herbal medicines as well as well-controlled and randomized clinical trials to prove the
safety and efficacy of this type of medicines.
2- Emphasis on experimental approaches and biotechnological studies used for
propagation of medicinal plants to genetically improve the reliability and quality of its
61
products. This can be achieved through tissue culture which holds much promise as a
method for creating cell lines capable of producing high yields of complex secondary
metabolites in cell suspension cultures (Rout et al, 2000).
3- The integration of herbal medicine into the curriculum of medical schools.
4- Continuing education programs.
5- The availability of reputable pharmacopoeias for referencing at public health
institutions are useful instruments that can be used to close this gap and promote
improved physician-patient communication.
6- Increase the awareness to quality assurance problems associated with herbal products,
such as mislabeling, adulteration or contamination. However, the involvement of drug
companies into the herbal marketplace may improve standardization of dosage for a few
products.
62
Conclusion
The idea that herbal drugs are safe and free from side effects is false. Plants
contain hundreds of constituents and some of them are very toxic, such as the most
cytotoxic anti-cancer plant-derived drugs, digitalis and the pyrrolizidine alkaloids, etc.
Herb-drug interactions are a reality and can present a serious threat to human health.
Harmonization and improvement in the processes of regulation is needed, healthcare
professionals should be aware of this potential and researchers should strive to fill the
numerous gaps in our present understanding of this problem.
Finally, the trend in the domestication, production and biotechnological studies
and genetic improvement of medicinal plants, instead of the use of plants harvested in the
wild, will offer great advantages, since it will be possible to obtain uniform and high
quality raw materials which are fundamental to the efficacy and safety of herbal drugs
63
Reference List
Ackermann,R.T.; Ramirez,G.; Gardner,C.D.; Lawrence,V.A.; Morbidoni,L. and
Mulrow,C.D. (2001). "Garlic shows promise for improving some cardiovascular
risk factors". Arch Intern Med 161: 813-824.
Agrosi,M.; Mischiatti,S.; Harrasser,P.C. and Savio,D. (2000). "Oral bioavailability of
active principles from herbal products in humans. A study on Hypericum
perforatum extracts using the soft gelatin capsule technology". Phytomedicine 7:
455-462.
Ali,M. (1995). "Mechanism by which garlic (Allium sativum) inhibits cyclooxygenase
activity. Effect of raw versus boiled garlic extract on the synthesis of
prostanoids". Prostaglandins Leukot Essent Fatty Acids 53: 397-400.
Ali,M.; Thomson,M. and Afzal,M. (2000). "Garlic and onions: their effect on eicosanoid
metabolism and its clinical relevance". ProstaglandinsLeukot Essent Fatty Acids
62: 55-73.
Allred,C.D.; Allred,K.F.; Ju,Y.H.; Virant,S.M. and Helferich,W.G. (2001). "Soy diets
containing varying amounts of genistein stimulate growth of estrogen-dependent
(MCF-7) tumors in a dose-dependent manner". Cancer Res 61: 5045-5050.
Anderson,G.D.; Rosito,G.; Mohustsy,M.A. and Elmer,G.W. (2003). "Drug interaction
potential of soy extract and Panax ginseng". Journal of Clinical Pharmacology
43: 643-648.
Anderson,J.J.; Anthony,M.S.; Washburn,S.A.; Garner,S.C. and Cline , J.M. (1999).
"Health potential of soy isoflavones for menopausal women". Public Health Nutr
2: 489-504.
Angell, D.(2003). Herb and drug interactions. Ohio State University extension fact sheet.
Ref Type: Internet Communication
Arenz,A.; Klein,M. and Fiehe,K. (1996). "Occurrence of neurotoxic 4`omethylpyridoxine in ginkgo biloba leaves. Ginkgo medications and Japanese
ginkgo food". Planta Med 62: 548-551.
Attele,A.S.; Wu,J.A. and Yuan,C.S. (1999). "Ginseng pharmacology: multiple
constituents and multiple actions". Biochem Pharmacol 58: 1685-1693.
Barnes,J.; Anderson,L.A. and Phillipson,J.D. (2001). "St. John's wort (Hypericum
perforatum): A review of its chemistry, pharmacology and clinical properties". J
Pharm Pharmacol 53: 583-590.
64
Barrett,B.; Kiefer,D. and Rabago,D. (1999). "Assessing the risks and benefits of herbal
medicine: An overview of scientific evidence". Altern Ther 5: 40-49.
Barrett,J. (2002). "Phytoestrogens: Friends or foes?" Environ Health Perspect 104: 478482
Bauer R. and Wagner H. (1991). "Echinacea species as potential immunostimulatory
drugs". Eds. Economic and medicinal plant research. New York, NY: Academic Press
Limited
Becker,B.N.; Evanson,J.; Chidsey,G. and Stone,W.J. (1996). "Ginseng-induced diuretic
resistance". J Am Med Association 276: 606-607.
Bell,D.S. and Ovalle,F. (2001). "Use of soy protein supplement and resultant need for
increased dose of Levothyroxine". Endocrin Pract 7: 193-194.
Block,K.I. and Gyllenhaal,C. (2002). "Clinical Corner: Herb-Drug Interactions in Cancer
Chemotherapy: Theoretical Concerns Regarding Drug Metabolizing Enzymes".
Integrative Cancer Therapies 1: 83-89.
Bock,K.W.; Eckle,T. and Ouzzine,M. (2000). "Coordinate induction by antioxidants of
UDP glucuronosyltransferase UGT1A6 and the apical conjugate export pump
MRP2 (multidrug resistance protein 2) in Caco-2 cells". Biochem Pharmacol 59:
467-470.
Bordia,A.; Verma,S.K. and Srivastava,K.C. (1998). "Effect of garlic (Allium sativum) on
blood lipids, blood sugar, fibrinogen and fibrinolytic activity in patients with
coronary artery disease". Prostaglandins Leukot Essent Fatty Acids 58: 257-263.
Bourian,M.; Runkel,M. and Krisp,A. (1999). "Naringenin and interindividual variability
in interaction of coumarin with grapefruit juice". Exp Toxicol Pathol 51: 289293.
Braun,L. (2000). "Herb-drug interaction guide". Aust Fam Physician 29: 1155-1156.
Braun,L. (2001). "Herb-drug interaction guide". Aust Fam Physician 30: 357-358.
Bray,B.J.; Perry,N.B.; Menkes,D.B. and Rosengren,R.J. (2002). "St. John's Wort extract
induces CYP3A and CYP2E1 in the Swiss Webster mouse". Toxicol Sci 66: 2733.
Brazier,N.C. and Levine,M.A.H. (2003). "Drug-herb interaction among commonly used
conventional medicines: a compendium for health care professionals". Am J Ther
10: 163-169.
Breidenbach,T.; Hoffmann,M.W.; Becker,T.; Schlitt,H. and Klempnauer,J. (2000)."Drug
interaction of St. John's Wort with cyclosporin". Lancet 355: 1912.
65
Burnham,B.E. (1995). "Garlic as a possible risk for postoperative bleeding". Plast
Reconstruc Surg 95: 213.
Bush,T.M.; Rayburn,K.S.; Holloway,S.W.; Sanchez-Yamamoto,D.S.; Allen,B.L.,
Lam,T.; So,B.K.; Tran,D.H.; Greyber,E.R.; Kantor,S. and Roth,L.W. (2007).
"Adverse interactions between herbal and dietary substances and prescription
medications: a clinical survey". Altern Ther Health Med 13: 30-35.
Camponovo,F. and Soldati,F. (2000). "Medicinal and Aromatic Plants-Industrial
Profiles". TA van Beek, Amsterdam: Harwood.
Casanova,M.; You,L.; Gaido,K.W.; Archibeque-Engle,S.; Janszen,D.B. and Heck,H.A.
(1999). "Developmental effects of dietary phyto-estrogens in Sprague-Dawley
rats and interactions of genistein and daidzein with rat estrogen receptors and 
in vitro". Toxicol Sci 51: 236-244.
Chavez,L.M.; Jordan,A.M. and Chavez,I.P. (2006). "Evidence-based drug-herbal
interactions". Life science 78: 2146-2157.
Chen,X. (1996). "Cardiovascular protection by ginsenosides and their nitric oxide
releasing action". Clin Exp Pharmacol Physiol 23: 738.
Chuang,W.C.; Wu,H.K.; Sheu,S.J.; Chiou,S.H.; Chang,H.C. and Chen,Y.P. (1995). "A
comparative study on commercial samples of ginseng radix". Planta Med 61: 459465.
ConsumerLab.com. (2005). "guide to buying vitamins and minerals".
Electronic Citation
Ref Type:
Cui,Y.; Ang,C.Y.; Beger,R.D.; Hu,L.; Heinze,T.M. and Leakey,J. (2004). "In vitro
metabolism of hyperforin in rat liver microsomal systems". Drug Metabolism
and Disposition 32: 28-34.
Curtic-Prior,P.; Ver,D. and Fray,P. (1999). "Therapeutic value of Ginkgo biloba in
reducing symptoms of decline in mental function". J Pharm Pharmacol 51: 535541
Darshan,S. and Doreswamy,R. (1998). "Medicinal plant patents scenario in the new era
of drug development". Ind Drugs 35:55-66.
De Smet,P.A. (1995). "Should herbal medicine-like products be licensed as medicines?"
BMJ 310:1024.
De Smet,P.A. (2002). "Herbal Remedies". N Engl J Med 347: 2046-2056.
Donath,F.; Roots,I.; Langheinrich,M. and Hubner,W.-D. (2003). "Interaction of
St John's Wort extract with phenprocoumon". Eur J Clin Pharmacol 55: A22.
66
Dresser,G.K.; Schwarz,U.I.; Wilkinson,G.R. and Kim,R.B. (2003). "Coordinate induction
of both cytochrome P4503A and MDR1 by St. John's Wort in healthy subjects".
Clin Pharmacol Ther 73: 41-50.
Durr,D., Kullak-Ublick,G.A.; Rentsch,K.M.; Steinert,H.C.; Meier,P.J.; Fattinger,K. and
Stieger,B. (2000). "St. John's Wort induces intestinal P-glycoprotein/MDR1 and
intestinal and hepatic CYP3". Clin Pharmacol Ther 68: 604.
Eisenberg,D.M.; Kessler,R.C.; Van Rompay,M.I.; Kaptchuk,T.J.; Wilkey,S.A.,; Appel,S.
and Davis,R.B. (2001). "Perceptions about complementary therapies relative to
conventional therapies among adults who use both: Results from a national
survey". Ann Intern Med 135: 344-351.
Ekins,S. and Wrighton,S.A. (2001). "Application of in silico approaches to predicting
drug -drug interactions". J Pharmacol Toxicol Method 45: 65-69.
Ellnain-Wojtaszek,M.; Kruczynski,Z. and Kasprzak,J. (2003). "Investigation of the free
radical scavenging activity of Ginkgo biloba L. leaves". Fitoterapia 74: 1-6.
Ernst,E. (2002). "The risk-benefit profile of commonly used herbal therapies: Ginkgo, St.
John's Wort, ginseng, echinacea, saw palmetto and Kava". Ann Intern Med 136:
42-53.
Evans,A.M. (2000). "Influence of dietary components on the gastrointestinal metabolism
and transport of drugs". Ther Drug Monit 22: 131-136.
Faber,K.N.; Muller,M. and Jansen,P.L. (2003). "Drug transport proteins in the liver".
Advanced Drug Delivery Reviews 55: 107-124.
Farnsworth,N.R.; Bingel,A.S.; Cordell,G.A.; Crane,F.A. and Song,H.H.S. (1975).
"Potential value of plants as sources of new antifertility agents II". J Pharm Sci
64:717-754.
FDM Market Sales Data for Herbal Supplements. (2005). Chicago, IL: Information
Resources Inc.
Fiebich,B.L.; Hollig,A. and Lieb,K. (2001). "Inhibition of substance P-induced cytokine
synthesis by St. John's Wort extracts". Pharmacopsychiatry 34: S26-S28.
Fleischauer,A.T. and Arab,L. (2001). "Garlic and cancer: a critical review of the
epidemiologic literature". J Nutr 131:1032S-1040S.
Fontana,R.J.; Lown,K.S. and Paine,M. (1999). "Effects of a char-grilled meat diet on
expression of CYP3A, CYP1A, and P- glycoprotein levels in healthy volunteers".
Gastroenterology 117: 89-98.
67
Foster,B.C.; Foster,M.S. and Vandenhoek,S. (2001). "An in vitro evaluation of human
cytochrome P450 3A4 and P-glycoprotein inhibition by garlic". J Pharm
Pharmaceut Sci 4: 176-184.
Frank,F. and Unger,M. (2004). "Simultaneous determination of the inhibitory potency of
herbal extracts on the activity of six major cytochrome P450 enzymes using liquid
chromatography/mass spectrometry and automated online extraction". Rapid
Communications in Mass Spectrometry 18: 2273-2281.
Fugh-Berman,A. (2000). "Herb-drug interactions". Lancet 355: 134-138.
Fugh-Berman,A. (2001). "Herb–drug interactions: review and assessment of report
reliability". Br J Gen Clin Pharmacol 52: 587-595.
Fuhr,U.; Doehmer,J.; Battula,N.; Wolfel,C.; Kudla,C.; Keita,Y. and Staib,A.H. (1992).
"Biotransformation of caffeine and theophylline in mammalian cell lines
genetically engineered for expression of single cytochrome-P450 isoforms".
Biochemical Pharmacology 43: 225-235.
Fukao,T.; Hosono,T.; Ariga,T.; Misawa,S. and Seki,T. (2004). "Chemoprotective effect
of diallyl trisulfide from garlic against carbon tetrachloride-induced acute liver
injury of rats". Bio Factors 21: 171-174.
Gail,M.H. and You,W.C. (2006). "Factorial trial including garlic supplements assesses
effect in reducing precancerous gastric lesions". J Nutr 136: 8135-8155.
Gallicano,K.D.; Foster,B. and Choudhri,S. (2003). "Effect of short-term administration of
garlic supplements on single dose ritonavir pharmacokinetics in healthy
volunteers". Br J Clin Pharmacol 55: 199-202.
Gerloff,T.; Stieger,B.; Hagenbuch,B.; Madon,J.; Landmann,L.; Roth,J.; Hofmann,A.F.
and Meier,P.J. (1998). The sister of P-glycoprotein represents the canalicular bile
salt export pump of mammalian liver". Journal of Biological Chemistry 273:
10046-10050.
Gibson,G. and Skett,P. (2001). Introduction to drug metabolism. Eds: Nelson Thornes.
Chapman and Hall, London
Gillis,C.N. (1998). "Panax ginseng pharmacology: A nitric oxide link?" Biochem
Pharmacol 54: 1-8.
Goldman,P. (2001). "Herbal medicines today and the roots of modern pharmacology".
Ann Intern Med 135: 594-600.
Gorski,J.C.; Huang,S.M.; Pinto,A.; Hamman,M.A.; Hilligoss,J.K.; Zaheer,N.A.,
Desai,M.; Miller,M. and Hall,S.D. (2004). "The effect of echinacea (Echinacea
purpurea root) on cytochrome P450 activity in vivo". Clinical Pharmacology and
Therapeutics 75: 89-100.
68
Grimm,W. and Müller,H.H. (1999). "A randomized controlled trial of the effect of fluid
extract of Echinacea purpurea on the incidence and severity of colds and
respiratory infections". Am J Med 106: 138-143.
Haber,D.; Siess,M.H.; De Waziers,I.; Beaune,P. and Suschetet,M. (1994). "Modification
of hepatic drug-metabolizing enzymes in rat fed naturally occurring allyl
sulphides". Xenobiotica 24: 169-182.
Hadley,S.K. and Petry,J.J. (1999). "Medicinal herbs: A primer for primary care". Hosp
Pract 34: 105.
Hall,S.D.; Wanf,Z. and Shiew-Mei,H. (2003). "The interaction between St. John's Wort
and an oral contraceptive". Clin Pharmacol Ther 74: 525-535.
Harris,J.C.; Cottrell,S.; Plummer,S. and Lloyd,LD. (2001). "Antimicrobial properties of
Allium sativum (garlic)". Applied Microbiology and Biotechnology, 57: 282-286.
Haster,A. (2000). Medicinal and Aromatic Plants-Industrial Profiles. Eds: Van Beek,T.A.
Amsterdam: Harwood.
Hennessy,M.; Feely,J.; Kelleher,D.; Spiers,J.P.; Barry,M.; Kavanagh,P. and Back,D.
(2002). "St Johns Wort increases expression of P-glycoprotein: implications for
drug interactions". Br J Clin Pharmacol 53: 75-82.
Hsu,A.; Granneman,G.R. and Bertz,R.J. (2007). "Ritonavir: clinical pharmacokinetics
and interactions with other anti-HIV agents". Clin Pharmacokinet 35: 275-291.
http: www.fda.gov/cder/drug/advisory/stjwort.htm
Hu,Z. (2005). "Herb-drug interactions: a literature review". Drugs 65: 1239-1282.
Ioannides,C. (2002). "Pharmacokinetic interactions between herbal remedies and
medicinal drugs". Xenobiotica 32: 451-478.
Izzo,A.A. (2004). "Herb-drug interactions: an overview of the clinical evidence.
Fundamental and clinical pharmacology" 19: 1-16.
Izzo,A.A.; Di Carloa,G.; Borrellia,F. and Ernst,E. (2005). "Cardiovascular
pharmacotherapy and herbal medicines: the risk of drug interaction". International
journal of Cardiolog 98: 1-14.
Izzo,A.A. and Ernst,E. (2001). "Interactions between herbal medicines and prescribed
drugs: A systematic review". Drugs 61: 2175.
Jiang,X.; Williams,K.M. and Liauw,W.S. (2004). "Effect of St John's Wort and ginseng
on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects".
Br J Clin Pharmacol 57: 592-599.
69
Johne,A.; Brockmolller,J.; Bauer,S.; Maurer,A.; Langheinrich,M. and Roots,I. (1999).
"Pharmacokinetic interaction of digoxin with an herbal extract from
St John's Wort (Hypericum perforatum)". Clin Pharmacol Ther 66: 338-345.
Kaminsky,L.S. and Zhang,Z.Y. (1997). "Human P450 metabolism of warfarin".
Pharmacol Ther 73: 67-74.
Kanowski,S.; Herrmann,W.M.; Stephan,K.; Wierich,W. and Ho¨rr,R. (1996). "Proof of
efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering
from mild to moderate primary degenerative dementia of the Alzheimer type or
multi-infarct dementia". Pharmacopsychiatry 29: 47-56.
Kaur,C. and Kapoor,H. (2001). "Antioxidants in fruits and vegetables the millennium's
health". Int J Food Science Technol 36: 703-725.
Kensler,T.W.;
Curphey,T.J.;
Maxiutenko,Y.
and
Roebuck,B.D.
(2000).
"Chemoprotection by organosulfur inducers of phase 2 enzymes:dithiolethiones
and dithiins". Drug Metabol Drug Interact 17: 3-22.
Kim,L.S.; Walters,R.F. and Burkholder,P.M. (2002). "Immunological activity of larch
arabinogalctan and echinacea: A preliminary. randomized, double-blind, placebocontrolled trial". Altern Med Rev 7: 138.
Kligler,B. (2003). "Echinacea". Am Fam Phys 67: 77-80.
Koscielny,J.; Klubendorf,D. and Latza,R. (1999). The antiatherosclerotic effect of Allium
sativum. Atherosclerosis 144: 237-249.
Kuiper,G.G.; Lemmen,J.G.; Carlsson,B.; Safe,S.H. and Van derSaag,P.T. (1998).
"Interactions of estrogenic chemicals and phytoestrogens with estrogen receptor
". Endocrinology 139:4252-4263.
Lantz,M.S. (1999). "St. John's Wort and antidepressant drug interactions in the elderly".
J Geriatr Psychiatr Neurol 12: 7-10.
Lawson,L. (1998). Garlic powder for hyperlipidemia-analysis of recent negative results.
Q Rev Nat Med 1: 187-189.
Lehmann,J.M. (1998). "The human orphan nuclear receptor PXR is activated by
compounds that regulate CYP3A4 gene expression and cause drug interactions". J
Clin Invest 102: 1016-1023.
Li,T.S. and Harries,D. (1996). "Medicinal values of ginseng". The Herb, Spice and
Medicinal Plant Digest 14: 1-5.
Lieberman,H.R. (2001). "The effects of ginseng, ephedrine, and caffeine on cognitive
performance, mood and energy". Nutrition Reviews 59: 91-102.
70
Linde,K.; Ramirez,G.; Mulrow,C.D.; Weidenhammer,W.; Melchart,D. and Pauls,A.
(1996). "St John's Wort for depression—an overview and meta-analysis of
randomised clinical trials". BMJ 313: 253-258.
Liu,Y.; Zhang,J.; Li,W.; Ma,H.; Sun,J.; ;Ling,M and Yang,L. (2006): “Ginsenoside
metabolites, rather than naturally occurring ginsenosides, lead to Inhibition of human
cytochrome P450 enzymes”. Toxicological Sciences 91: 356-364
Lui,J. and Staba,E.J. (1989). "The ginsenosides of various ginseng plants and selected
products". J Nat Prod 43: 34-36.
MacGregor,C.A.; Canney,P.A.; Patterson,G.; McDonald,R. and Paul,J. (2005). "A
randomised double-blind controlled trial of oral soy supplements versus placebo
for treatment of menopausal symptoms in patients with early breast cancer". Eur J
Cancer 41:708-714.
Mandlekar,S.; Hong,J. and Ah-Ng,T. (2006). "Modulation of metabolic enzymes by
dietary phytochemicals: A review of mechanisms underlying beneficial versus
unfavorable effects". Current drug metabolism 7: 661-675.
Mar,C. and Bent,S. (1999). An evidence-based review of the 10 most commonly used
herbs. W M J 171: 168-171.
Mary,L.C.; Melanie,A.; Jordan,B. and Pedro,I. (2005). "Evidence-based drug-herbal
interactions". Life science 78:2146-2157.
Mathewson,K.M. (1998). "Pharmacotherpeutics: a nursing process approach.: Davis,F.A.
eds: Mathewson. 21 Philadelphia, U.S.
Matic,M. (2007). "Pregnane X receptor promiscuous regulator of detoxification
pathways". Int J Biochem Cell Biol 39: 478-483.
McMahon,F.G. and Vargas,R. (1993). "Can garlic lower blood pressure? A pilot study".
Pharmacotherapy 13: 406-407.
McRae,S. (1996). "Elevated serum digoxin levels in a patient taking digoxin and Siberian
ginseng". Can Med Assoc J 155: 293.
Meech,R. and Mackenzie,P.I. (1997). "Structure and function of uridine diphosphate
glucuronosyltransferases". Clinical and Experimental Pharmacology and
Physiology 24: 907-915.
Meisel,C.; Johne,A. and Roots,I. (2003). "Fatal intracerebral mass bleeding associated
with Ginkgo biloba and ibuprofen". Atherosclerosis 167: 367.
71
Melchart,D.; Linde,K.; Worku,F.; Sarkady,L.; Holzmann,M. and Wagner,H. (1995).
"Results of five randomized studies on the immunomodulatory activity of
preparations of Echinacea". J Alt Comp Med 1: 145-160.
Messina,B.M. (2006). "Herbal supplements: Facts and myths—talking to your patients
about herbal supplements". J PeriAnesthesia Nursing 21: 268-278.
Miron,T.; Rabinkov,A.; Mirelman,D.; Wilchek,M. and Weiner,L. (2000). "The mode of
action of allicin: its ready permeability through phospholipid membranes may
contribute to its biological activity". Biochim Biophys Acta 1463: 20-30.
Moore,L.B.; Goodwin,B.; Jones,S.A.; Wisely,G.B.; Serabjit-Singh,C.J.; Willson,T.M.;
Collins,J.L. and Kliewer,S.A. (2000). "St. John's Wort induces hepatic drug
metabolism through activation of the pregnane X receptor". Proc Natl Acad Sci U
S A 97: 7500-7502.
Mullin,R.J. and Heddle,R. (2002). "Adverse reactions associated with Echinacea: The
Australian experience". Ann Allergy Asthma Immunol 88: 42-51.
Murphy,P.A.; Kernb,S.E.; Stanczykc,F.Z. and Westhoff,A.L. (2005). "Interaction of St.
John's Wort with oral contraceptives: effects on the pharmacokinetics of
norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding".
Contraception 71: 402-408.
Nathan,P. (1999). "The experimental and clinical pharmacology of St John's Wort
(Hypericum perforatum L.)". Molecular Psychiatry 3: 333-338.
Nelson,L. and Perrone,J. (2000). "Herbal and alternative medicine". Clinics of North
America 18: 709-722.
Noonan,C. and Noonan,P.W. (2006). "Marketing dietary supplements in the United
States: A review of the requirements for new dietary ingredients". Toxicology
221: 4-8.
Nu,H. and Timi,E. (2004). "The inhibitory effects of herbal components on CYP2C9 and
CYP3A4 catalytic activities in human liver microsomes". Am J Ther 11: 206-212.
Obach,R.S. (2000). "Inhibition of human cytochrome P450 enzymes by constituents of
St. John's Wort, an herbal preparation used in the treatment of depression". J
Pharmacol Exp Ther 294: 88-95.
Pal,D. and Mitra,A.K. (2006). "MDR and CYP3A4-mediated drug-herbal interactions".
Life science 78: 2131-2145.
Patel,J.; Buddha,B.; Dey,S.; Pal,D. and Mitra,A.K. (2004). "In vitro interaction of the
HIV protease inhibitor ritonavir with herbal constituents: changes in Pgp and
CYP3A4 activity". Am J Ther 11: 262-277.
72
PDR for Herbal Medicines. (1998). Montvale, NJ, Medical Economics Co.
Percival,S.S. (2000). "Use of Echinacea in Medicine". Biochemical Pharmacology, 60:
155-158.
Philip,R.P. (2004). "Herbal remedies: The good, the bad, and the ugly". Journal of
Complementary and Integrative Medicine: 1:4.
Piscitelli,S.C. (2002). "Indinavir concentrations and St John's Wort". Lancet 355: 547548.
Piscitelli,S.C.; Burstein,A.H.; Welden,N.; Gallicano,K.D. and Falloon,J. (2002). "The
effect of garlic supplements on the pharmacokinetics of saquinavir". Clin Infect
Dis 34: 234-238.
Pizzagalli,F.; Fattinger,K.; Meier,P.J. and Hagenbuch,B. (2001). "Organic aniontransporting polypeptide B (OATP-B) and its functional comparison with three
other OATPs of human liver". Gastroenterology 120: 525-533.
Predy,G.N.; Goel,V.; Lovlin,R.; Allan Donner,A.; Stitt,L. and Basu,T.K. (2005).
"Efficacy of an extract of north American ginseng containing poly-furanosylpyranosyl-saccharides for preventing upper respiratory tract infections: a
randomized controlled trial". CMAJ 173: 1043-1048.
Price,K.R. and Fenwick,G.R. (1985). "Naturally occurring estrogens in foods-A review".
Food Addit Contam 2: 73-106.
Radominska-Pandya,A.; Czernik,P.J.; Little,J.M.; Battaglia,E. and Mackenzie,P.I. (1999).
"Structural and functional studies of UDP-glucuronosyltransferases". Drug
Metabolism Reviews 31: 817-899.
Ratna,W.N. (2002). "Inhibition of estrogenic stimulation of gene expression by
genistein". Life Sci 71: 865-877.
Rendic,S. (2002). "Summary of information on human CYP enzymes; human P450
metabolism data". Drug Metab Rev 34: 83-448.
Roby,C.A.; Anderson,G.D.; Kantor,E.; Dryer,D.A. and Burstein,A.H. (2000). "St. John's
Wort: effect on CYP3A4 activity". Clin Pharmacol Ther 67: 451-457.
Rodrigues,A.D. (1994). "Use of in vitro human metabolism studies in drug
development". Biochem Pharmacol 48: 2147-2156.
Rodriguez-Landa,J.F. and Contreras,C.M. (2003). "A review of clinical and experimental
observations about antidepressant actions and side effects produced by Hypericum
perforatum extracts". Phytomedicine 10: 688-699.
73
Rose,D.P.; Boyar,A.P. and Wynder,E.L. (1986). "International comparison of mortality
rates for cancer of the breast, ovary, prostate and colon and per capita food
consumption". Cancer 58: 2363-2371.
Rosenblatt,M. and Mindel,J. (1997). "Spontaneous hyphema associated with ingestion of
Ginkgo biloba extract". New England Journal of Medicine 336:1108.
Rout,G.R., Das,P., and Samantaray,S. (2000). "In vitro manipulation and propagation of
medicinal plants". Biotechnology Advances 18: 91-120.
Rowland,I.; Faughnan,M.; Hoey,L.; Wahala,K.; Williamson,G. and Cassidy,A. (2003).
"Bioavailability of phyto-oestrogens". Br J Nutr 89: 45-58.
Rude,R. (1997). Predicting health effects of exposure to compounds with estrogenic
activity: Methodological issues. Environ Health Perspect 105: 655-663.
Sabine,E.K.; Leane,L. and Manfred,M. (2002). "Oxidative metabolism and genotoxic
potential of major isoflavone phytoestrogens". J Chromatogr B 777: 211-218.
Sava,D.T.; Dolbaum,C.M. and Blen,M. (1998). "Estrogen and progestin bioactivity of
foods, herbs, and spices". Proc Soc Exp Biol 217: 369-378.
Schulz,V.; Hänsel,R. and Tyler,V.E. (2003). "Rational phytotherapy: A physicians guide
to herbal medicine". Springer-Verlag. New York, NY.
Schwabe,W. (2005). "Influence of the Ginkgo extract EGb 761 on rat liver cytochrome
P450 and steroid metabolism and excretion in rats and man". Journal of Pharmacy
and Pharmacology 57: 641-650.
Seth,S.D. and Sharma,B. (2004). "Medicinal plants in India". Indian J Med Res 120: 911.
Shader,R.I. and Greenblatt,D.J. (2002). "More on oral contraceptives, drug interactions,
herbal medicines and hormone replacement therapy". Journal of Clinical
Psychopharmacology 20: 397-398.
Sievenpiper,J.L.; Arnason,J.T.; Leiter,L.A. and Vuksan,V. (2003). "Variable effects of
American ginseng: a batch of American ginseng (Panax quinquefolius L.) with a
depressed ginsenoside profile does not affect postprandial glycemia". European
Journal of Clinical Nutrition 57: 243-248.
Soller,R.W. (2000). "Regulation in the herb market: The myth of the 'unregulated
industry". Herbal Gram 49: 64-67.
Staba,E.J.; lash,L. and Staba,J.E. (2001). "A commentary on the effects of garlic
extraction and formulation on product composition". Journal of Nutrition 131:
1118-1119.
74
Stevinson,C.;
Pittler,M.H.
and
Ernst,E.
(2000).
"Garlic
hypercholesterolemia". Ann Intern Med 133: 420-429.
for
treating
Sugimoto,K.; Ohmori,M.; Tsuruoka,S.; Nishiki,K.; Kawaguchi,A. and Harada,K. (2001).
"Different effects of St John's Wort on the pharmacokinetics of simvastatin and
pravastatin". Clin Pharmacol Ther 70: 518-524.
Synoid,T.W. (2001). "The orphan nuclear receptor SXR coordinately regulates drug
metabolism and efflux". Nat Med 7: 584-590.
Takanaga,H.; Ohnishi,A. and Yamada,S. (2000). "Polymethoxylated flavones in orange
juice are inhibitors of P- glycoprotein but not cytochrome P450 3A4". J
Pharmacol Exp Ther 293: 230-236.
Tesch,B.J. (2003). "Herbs commonly used by women: an evidence-based review". Am J
Obstet Gynecol 188: 44-54.
Thompson,J. and Edzard,E. (2002). "Panax ginseng: A systematic review of adverse
effects and drug interactions". Drug Safety 25: 323-344.
The Complete German Commission E Monographs, Therapeutic Guide to Herbal
Medicines. (1998) Austin: American Botanical Council.
Turner,R.B.; Bauer,R. and Woelkart,K. (2005). "An evaluation of Echinacea angustifolia
in experimental rhinovirus infections". N Engl J Med 353: 341-348.
Valli,G. and Giardina,E.V. (2002). "Benefits, adverse effects and drug interactions of
herbal therapies with cardiovascular effects". Journal of the American College of
Cardiology 39: 1083-1095.
Venkatakrishnan,K.; Von Moltke,L.L. and Greenblatt,D.J. (1999). "Nortriptyline E-10hydroxylation in vitro is mediated by human CYP2D6 (high affinity) and
CYP3A4 (low affinity): implications for interactions with enzyme-inducing
drugs". Journal of Clinical Pharmacology, 39:567-577.
Venkataramanan,A.; Komoroski,A.B. and Strom,S. (2003). "In vitro and in vivo
assessment of herb drug interactions". Life science 78:1105-1115.
Vogler,B.K.; Pittler,M.H. and Ernst,E. (1999). "The efficacy of ginseng. A systematic
review of randomised clinical trials". Eur J Clin Pharmacol 55: 567-575.
Vuksan,V.; Sievenpiper,J.L. and Koo,V.Y. (2000). "American ginseng (Panax
quinquefolius L.) reduces postprandial glycemia in nondiabetic subjects and
subjects with type 2 diabetes mellitus". Arch Intern Med 160:1009-1013.
Wentworth,J.M. (2000). "St John's Wort, a herbal antidepressant, activates the steroid X
receptor". J Endocrinol 166: R11-R16.
75
Wong,J.M.; Harper,P.A. and Meyer,U.A. (1991). "Ethnic variability in the allelic
distribution of human aryl hydrocarbon receptor codon 554 and assessment of
variant receptor function in vitro". Pharmacogenetics 1:66-67.
Woolf,T.F. (1999). Handbook of Drug Metabolism. Informa health care ed. Woolf Tf.
Marcel Dekker, New York, 131-151.
Yamasaki,T.; Li,L.; Benjamin,H.S. and Lau,B.H.S. (2006). "Garlic compounds protect
vascular endothelial cells from hydrogen peroxide-induced oxidant injury".
Phytotherapy Research 8: 408-412.
Yin,O.Q.; Tomlinson,B.; Waye,M.M.; Chow,A.H. and Chow,M.S. (2004).
"Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba
and omeprazole". Pharmacogenetics 14: 841-850.
You,L. (2004). "Phytoestrogen genistein and Its pharmacological interactions with
synthetic endocrine-active compounds. current pharmaceutical design". 10: 27492757.
Yuan,C.S.; Wei,G.; Dey,L.; Karrison,T.; Nahlik,L.; Maleckar,S.; Kasza,K.; Ang-Lee,M.
and Moss,J. (2004). "American ginseng reduces warfarin's effect in healthy
patients: a randomized, controlled Trial". Ann Intern Med 141: 23-27.
Yue,Q.Y.; Bergquist,C. and Gerden,B. (2000). "Safety of St. John's Wort (Hypericum
perforatum)". Lancet 355: 576-577.
Zhou,S. (2003). "Interactions of herbs with cytochrome P450". Drug Metab Rev 35: 3598.
Zhou,S. (2004). "Herbal modulation of P-glycoprotein". Drug Metab Rev 36: 57-104.
Zhou,S.; Chan,E.; Pan,S.Q.; Huang,M. and Lee,E.J. (2004). "Pharmacokinetic
interactions of drugs with St. John's Wort". J Psychopharmacol 18: 262-276.
Zhou,S.F.; Zhou,Z.W.; Li,C.G.; Chen,X.; Yu,X.; Xue,C.C. and Herington,A. (2007).
"Identification of drugs that interact with herbs in drug development". Drug
Discovery Today 12: 664-673.
76