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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: 38105mol/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. 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