**3.11. St. John's Wort (***Hypericum perforatum***)**

herbs are senna (*Cassia senna*), aloe latex (*Aloe vera*), and Cascara sagrada (*Frangula purshiana*). The leaves and pods from *Cassia senna* contain anthroquinone stimulant laxative compounds effective in the treatment of constipation and for bowel evacuation prior to medical procedures [27, 275-295]. The herb has been approved by the U.S. FDA as a non-prescription medication. Similarly, aloe latex, derived from the peripheral bundle sheath cells of the aloe leaf, contains anthracene compounds that are cleaved in the colon by bacterial enzymes into active anthrone compounds with stimulant laxative properties [296-299]. However, concerns over possible carcinogenic properties of certain anthraquinones in aloe latex, along with lack of safety evidence, prompted the U.S. FDA to ban aloe latex in 2002, although the herb is still used in other countries [178, 300, 301]. The bark of the deciduous buckthorn shrub Cascara sagrada is effective for the treatment of constipation due to the stimulant laxative properties of its anthraglycoside constituents [27, 302]. Like aloe latex, Cascara had previously been approved by the U.S. FDA as a non-prescription medication, but the designation was withdrawn into 2002 based on lack of safety and efficacy evidence, although the herb is still available as a

Stimulant laxatives share multiple common adverse effects and potential drug interactions. Because of decreased gastrointestinal transit time, absorption of some drugs, especially those with poor permeability, may be decreased [303, 304]. Experimental evidence in rats suggests absorption of carbohydrates may result in decreased blood glucose levels and therefore monitoring of patients receiving hypoglycemic agents or insulin is warranted [305-307]. Concomitant use of stimulant laxatives with diuretics, cardiac glycosides and licorice is contraindicated due to hypokalemic effects, especially with long term use of these laxatives [27, 178, 304, 308, 309]. Senna can potentially interfere with antiplatelet and anticoagulant activity by causing excessive bleeding [310]. There is one case report of a possible interaction of aloe and sevoflurane, in which a 35 year old female patient undergoing surgery for heman‐ gioma experienced perioperative bleeding [311]. Although the size and vascularization of the hemangioma were noted as partial root causes of the bleeding episodes, the authors felt that the combination of anesthetic and aloe administration (4 tablets daily for 2 weeks prior to

Licorice has historically been used both medicinally and as a food product and its relative safety at low doses has placed it on the U.S. FDA GRAS (generally recognized as safe) list, although at high doses licorice can cause severe adverse effects [27]. The main active components of licorice are glycyrrhizin and glycyrrhizic acid, although several other active constituents have been identified [312, 313]. One of the main adverse effects of high licorice consumption includes mineralocorticoid excess syndrome and resulting hypokalemia with associated increases in blood pressure, as well as secondary pseudohyperaldosteronism [314-338]. Licorice consumption may also alter blood glucose levels, potentially via binding to PPAR-γ [339, 340]. Although licorice is used in dietary supplements for weight loss, contradictory evidence reports weight gain with licorice consumption [341-343]. However, one study in which 3.5 grams daily licorice consumption was administered to 15 normal

supplement [300].

120 Drug Discovery

surgery) may have contributed to the adverse event.

**3.10. Licorice (***Glycyrrhiza glabra***)**

St. John's Wort (SJW) is a perennial herb native to Europe that is commonly used to treat depression, anxiety, post-menopausal symptoms, attention deficit hyperactivity disorder (ADHD), and other mood disorders [362-367]. The active constituents of SJW are hypericin and hyperforin, which are thought to act by inhibiting the synaptic uptake of serotonin (5-HT), GABA, noradrenaline, dopamine, and L-glutamate via a novel mechanism compared to synthetic antidepressants [362, 368-373]. Although there are no official studies regarding the use of SJW for weight loss, anecdotal reports suggest a positive effect on satiety, which may be attributable to the serotonergic uptake inhibition (see *Sibutramine* above). Following the removal of fenfluramine, an anorectic agent commonly used in the combination product "Phen-Fen" (phentermine – fenfluramine), from the market in 1997, SJW was combined with *Ephedra* or *Citrus aurantium* (see above) and marketed for weight loss as "Herbal Phen-Fen". Because of the expanding popularity of SJW in the 1990s – 2000s, a great deal of research on the mechanism of action and herb-drug interactions has been reported.

Drug interactions with SJW are primarily related to binding of active constituents to the pregnane X receptor leading to induction of cytochrome P450 metabolizing or induction of pglycoprotein efflux mechanisms via the MDR-1 drug transporter [374-388]. As a result, pharmacokinetics of many cytochrome P450 drug substrates is altered, often leading to decreased plasma concentrations and reduced efficacy [27]. There have been numerous studies that have demonstrated potential metabolism-related drug interactions with CYP 3A4, 1A2, 2C9 and 2C19 [389]. Kinetics of antiplatelet and anticoagulant agents may be altered in the presence of SJW [390, 391]. In one open-label, three-way crossover randomized study, 12 healthy male subjects were given 1 gram of SJW (standardized to hypericin 0.825 mg/g and hyperforin 12.5 mg/g) for 21 days, with administration of a single 25 mg dose of warfarin on day 14 [390]. A significant increase in warfarin (Cl/F) was observed compared to warfarin alone, with a corresponding decrease in AUC and half-life. However, there was no significant impact on INR or platelet aggregation. The interaction is likely caused not only by alteration of drug metabolism via CYP 450 induction, but also binding of warfarin to the SJW constituents hypericin and pseudohypericin, leading to decreased absorption of the drug [392]. In another study, patients not responding to clopidogrel therapy alone experienced an increase in therapeutic activity when clopidogrel and SJW were coadministered; therefore it is possible that patients responding to stand alone clopidogrel treatment may be at increased risk of bleeding [391]. There has been one case report of a possible interaction between theophylline and SJW in which theophylline levels significantly increased following discontinuation of SJW in a smoker also taking 11 other drugs [393]. However, another study in healthy subjects showed no impact of SJW on theophylline kinetics [394]. Plasma concentrations of protease inhibitors such as indinavir may be reduced in the presence of SJW due to induction of pglycoprotein efflux in the gastrointestinal tract [395-398]. Decreased plasma levels of the "statins" simvastatin and atorvastatin have been reported in controlled, randomized, cross‐ over studies [399, 400]. Reports of pharmacokinetic interactions have also been reported for digoxin, gliclazide, imatinib, irinotecan, methadone, omeprazole, verapamil, and voriconazole have also been published [401-412]. In general, coadministration of SJW with drugs signifi‐ cantly eliminated via these enzymes should be avoided.

requiring dosage adjustments during and for up to two weeks following discontinuation of

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SJW may interact with selective serotonin reuptake inhibitors (SSRIs), monoamines, and other antidepressant and psychiatric medications due to the serotonin uptake inhibitory properties of hypericin and hyperforin, although metabolic induction plays a role for some drugs [368, 370-373, 432-446]. In one case report, a patient who had been taking paroxetine 40 mg daily for treatment of depression discontinued her medication and began taking SJW 600 mg daily [434]. No adverse events were reported with the switch, but upon coadministration of a 20 mg dose of paroxetine to aid in sleep the patient experience extreme grogginess, weakness, fatigue, and incoherency. The author cited the potential for additive serotonin uptake inhibition resulting in "serotonin syndrome". One case of a male adult patient stabilized on methylphenidate for attention deficit hyperactivity disorder (ADHD) is reported in which the patient experienced increased ADHD symptoms after taking SJW 600 mg daily for four months [438]. The mech‐ anism of the interaction is unknown. Interactions have also been reported for amitriptyline, clozapine, fexofenadine, and sertraline; therefore administration of SJW in patients taking

An interaction between SJW and drugs known to cause phototoxic adverse reactions is also possible, due to the photosensitizing nature of hypericin [448-450]. In one study, 11 subjects were exposed to UVA1 radiation at baseline and following 10 days treatment with 1020 mg (3000 mcg hypericin) extract [449]. Minimum erythemal dose (MED) as measured 8, 24 and 48 hours after exposure to radiation and was found to be significantly lower at 8 and 48, but not 24 hours, after exposure compared to control. There is one case report of a patient experiencing severe phototoxicity upon exposure to laser light (532 nm) and pulsed dye laser light (585 nm), presumably due to ingestion of SJW [451]. SJW may also increase the sensitivity and skin toxicity of radiation treatment in patients undergoing radiation therapy, possibly through photosensitizing effects although the exact underlying mechanism is not

Willow bark from the *Salix alba* tree is often contained in weight loss supplements, presumably due to earlier studies that noted enhanced thermogenic properties of ephedra in combination products also including aspirin (see *Ephedra* above). The active constituents of white willow are predominantly the salicylates (acetylsalicylic acid) and, therefore, the bark has traditionally been used in the treatment of pain [27, 453, 454]. The analgesic and anti-inflammatory activity of willow bark is due to inhibition of cyclooxygenase-2 (COX-2) mediated prostaglandin E2 release [455, 456]. Although there are few case reports dealing with willow bark extract specifically, drug and herb interactions seen with other salicylates are possible [455, 457]. Generally, caution should be used in concomitant administration of drugs contraindicated for aspirin, such as beta-blockers, NSAIDs, carbonic anhydrase inhibitors (e.g. acetazolamide), probenecid, alcohol, and salicylates, while the kinetics of protein bound drugs can also be modified [27]. Salicin may also have an effect on platelet aggregation, and therefore interac‐ tions with anticoagulants and antiplatelet drugs are possible [458, 459]. In one randomized

these and similar drugs should be avoided [440, 443, 444, 446, 447].

SJW [431].

known [452].

**3.12. Willow bark (***Salix alba***)**

Several studies and case reports describe interactions between SJW and oral contraceptives, resulting in breakthrough or irregular bleeding and unplanned pregnancy [413-416]. In one case report, an unwanted pregnancy occurred in a 36-year old patient while taking an ethinyl estradiol/dinogesterol oral contraceptive (Valette®). The patient had previously been taking fluvastatin (20 mg/day) for 2 years, but had discontinued the drug and started 1700 mg SJW extract daily for 3 months prior to conception [414]. One randomized controlled trial in 18 female subjects taking low dose oral contraceptives (0.02 mg ethinyl estradiol / 0.150 mg desogestrel) in combination with 300 mg SJW twice daily reported a significant increase in breakthrough bleeding compared to subjects taking oral contraceptive alone [417]. Progestins and estrogens contained in oral contraceptives are known to be metabolized by various CYP enzymes and therefore induction of these enzymes by SJW results in decreased plasma concentrations and therapeutic failure [417-420].

Interactions between SJW and with drugs used in the prevention of organ transplant rejection such as tacrolimus and cyclosporine have been reported [421-431]. Several transplant patients have experienced transplant rejection potentially related to coadministration of SJW. In one case report a patient treated with 75 mg cyclosporine daily for several years following kidney transplant experienced a drop in cyclosporin plasma levels attributed to SJW administration [427]. Levels returned to normal when SJW was discontinued and dropped upon rechallenge with SJW extract. Similarly, tacrolimus plasma levels markedly decreased in a study involving 10 stabilized renal transplant patients administered 600 mg SJW extract for two weeks, requiring dosage adjustments during and for up to two weeks following discontinuation of SJW [431].

SJW may interact with selective serotonin reuptake inhibitors (SSRIs), monoamines, and other antidepressant and psychiatric medications due to the serotonin uptake inhibitory properties of hypericin and hyperforin, although metabolic induction plays a role for some drugs [368, 370-373, 432-446]. In one case report, a patient who had been taking paroxetine 40 mg daily for treatment of depression discontinued her medication and began taking SJW 600 mg daily [434]. No adverse events were reported with the switch, but upon coadministration of a 20 mg dose of paroxetine to aid in sleep the patient experience extreme grogginess, weakness, fatigue, and incoherency. The author cited the potential for additive serotonin uptake inhibition resulting in "serotonin syndrome". One case of a male adult patient stabilized on methylphenidate for attention deficit hyperactivity disorder (ADHD) is reported in which the patient experienced increased ADHD symptoms after taking SJW 600 mg daily for four months [438]. The mech‐ anism of the interaction is unknown. Interactions have also been reported for amitriptyline, clozapine, fexofenadine, and sertraline; therefore administration of SJW in patients taking these and similar drugs should be avoided [440, 443, 444, 446, 447].

An interaction between SJW and drugs known to cause phototoxic adverse reactions is also possible, due to the photosensitizing nature of hypericin [448-450]. In one study, 11 subjects were exposed to UVA1 radiation at baseline and following 10 days treatment with 1020 mg (3000 mcg hypericin) extract [449]. Minimum erythemal dose (MED) as measured 8, 24 and 48 hours after exposure to radiation and was found to be significantly lower at 8 and 48, but not 24 hours, after exposure compared to control. There is one case report of a patient experiencing severe phototoxicity upon exposure to laser light (532 nm) and pulsed dye laser light (585 nm), presumably due to ingestion of SJW [451]. SJW may also increase the sensitivity and skin toxicity of radiation treatment in patients undergoing radiation therapy, possibly through photosensitizing effects although the exact underlying mechanism is not known [452].

#### **3.12. Willow bark (***Salix alba***)**

presence of SJW [390, 391]. In one open-label, three-way crossover randomized study, 12 healthy male subjects were given 1 gram of SJW (standardized to hypericin 0.825 mg/g and hyperforin 12.5 mg/g) for 21 days, with administration of a single 25 mg dose of warfarin on day 14 [390]. A significant increase in warfarin (Cl/F) was observed compared to warfarin alone, with a corresponding decrease in AUC and half-life. However, there was no significant impact on INR or platelet aggregation. The interaction is likely caused not only by alteration of drug metabolism via CYP 450 induction, but also binding of warfarin to the SJW constituents hypericin and pseudohypericin, leading to decreased absorption of the drug [392]. In another study, patients not responding to clopidogrel therapy alone experienced an increase in therapeutic activity when clopidogrel and SJW were coadministered; therefore it is possible that patients responding to stand alone clopidogrel treatment may be at increased risk of bleeding [391]. There has been one case report of a possible interaction between theophylline and SJW in which theophylline levels significantly increased following discontinuation of SJW in a smoker also taking 11 other drugs [393]. However, another study in healthy subjects showed no impact of SJW on theophylline kinetics [394]. Plasma concentrations of protease inhibitors such as indinavir may be reduced in the presence of SJW due to induction of pglycoprotein efflux in the gastrointestinal tract [395-398]. Decreased plasma levels of the "statins" simvastatin and atorvastatin have been reported in controlled, randomized, cross‐ over studies [399, 400]. Reports of pharmacokinetic interactions have also been reported for digoxin, gliclazide, imatinib, irinotecan, methadone, omeprazole, verapamil, and voriconazole have also been published [401-412]. In general, coadministration of SJW with drugs signifi‐

Several studies and case reports describe interactions between SJW and oral contraceptives, resulting in breakthrough or irregular bleeding and unplanned pregnancy [413-416]. In one case report, an unwanted pregnancy occurred in a 36-year old patient while taking an ethinyl estradiol/dinogesterol oral contraceptive (Valette®). The patient had previously been taking fluvastatin (20 mg/day) for 2 years, but had discontinued the drug and started 1700 mg SJW extract daily for 3 months prior to conception [414]. One randomized controlled trial in 18 female subjects taking low dose oral contraceptives (0.02 mg ethinyl estradiol / 0.150 mg desogestrel) in combination with 300 mg SJW twice daily reported a significant increase in breakthrough bleeding compared to subjects taking oral contraceptive alone [417]. Progestins and estrogens contained in oral contraceptives are known to be metabolized by various CYP enzymes and therefore induction of these enzymes by SJW results in decreased plasma

Interactions between SJW and with drugs used in the prevention of organ transplant rejection such as tacrolimus and cyclosporine have been reported [421-431]. Several transplant patients have experienced transplant rejection potentially related to coadministration of SJW. In one case report a patient treated with 75 mg cyclosporine daily for several years following kidney transplant experienced a drop in cyclosporin plasma levels attributed to SJW administration [427]. Levels returned to normal when SJW was discontinued and dropped upon rechallenge with SJW extract. Similarly, tacrolimus plasma levels markedly decreased in a study involving 10 stabilized renal transplant patients administered 600 mg SJW extract for two weeks,

cantly eliminated via these enzymes should be avoided.

122 Drug Discovery

concentrations and therapeutic failure [417-420].

Willow bark from the *Salix alba* tree is often contained in weight loss supplements, presumably due to earlier studies that noted enhanced thermogenic properties of ephedra in combination products also including aspirin (see *Ephedra* above). The active constituents of white willow are predominantly the salicylates (acetylsalicylic acid) and, therefore, the bark has traditionally been used in the treatment of pain [27, 453, 454]. The analgesic and anti-inflammatory activity of willow bark is due to inhibition of cyclooxygenase-2 (COX-2) mediated prostaglandin E2 release [455, 456]. Although there are few case reports dealing with willow bark extract specifically, drug and herb interactions seen with other salicylates are possible [455, 457]. Generally, caution should be used in concomitant administration of drugs contraindicated for aspirin, such as beta-blockers, NSAIDs, carbonic anhydrase inhibitors (e.g. acetazolamide), probenecid, alcohol, and salicylates, while the kinetics of protein bound drugs can also be modified [27]. Salicin may also have an effect on platelet aggregation, and therefore interac‐ tions with anticoagulants and antiplatelet drugs are possible [458, 459]. In one randomized double-blind study involving 16 patients administered standardized extracts of *Salicis cortex* (240 mg salicin/day), mean arachidonic induced platelet aggregation was reduced (61% compared to 78% in placebo group), but not as significantly as in the acetylsalicylic acid group (13% reduction) [458]. One randomized placebo-controlled trial investigating the efficacy of willow bark extract in osteoarthritis reported an increase in triglyceride levels, suggesting a potential interaction between willow bark and antihyperlipidemics [460]. Some patients in another randomized controlled trial, who were given 240 mg salicin daily for four weeks, suffered blood pressure instability and edema; use of willow bark in patients taking antihy‐ pertensives should be cautioned [461].

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