**3.5. Ephedra (***Ephedra sinica***, ma huang)**

(caffeine, theobromine, theophylline) green tea also contains polyphenols, most notably the catechin epigallocatechin-3-gallate (EGCG) [160-164]. EGCG, in concert with caffeine, is proposed to elicit anti-obesity effects via inhibition of catechol O-methyl transferase and phosphodiesterase [164]. A meta-analysis of clinical trials involving green tea in weight loss concluded that weight loss is decreased, relative to placebo, in treatment involving both green

As expected, the majority of drug interactions associated with green tea are related to caffeine content. However, a few interactions described in the literature are due to other constituents of green tea. Green tea may be contraindicated, especially at high doses, in patients taking anticoagulants such as warfarin due to the high Vitamin K content of the herb. There is one case report of a patient taking warfarin who experienced a significant reduction in INR following initiation of daily consumption of one-half to one gallon of green tea [166]. Once green tea consumption was stopped INR normalized. Green tea is also thought to cause decreased estrogen levels and combination products containing the herb have been used to improve fertility and relieve menopausal symptoms [167-170]. Therefore, use of high doses of green tea in patients taking oral contraceptives or estrogen replacement therapy may be

Guarana (*Paullinia cupana*) is a plant native to South America that is used traditionally and in anti-obesity supplements for its high caffeine content, although other minor constituents including theophylline, theobromine, catechin and epicatechin are found in these extracts [171-176]. There are no studies investigating the effects of Guarana alone on weight loss so it is difficult to determine the anti-obesity properties of the herb. In one double-blind, parallel, placebo controlled trial 47 subjects were administered three capsules containing yerba mate (*Ilex paraguayensis*, 112 mg), guarana (95 mg) and damiana (*Turnera diffusa*, 36 mg) daily for 45 days, resulting in significant weight loss (-5.1 ± 0.5 kg) compared to placebo (-0.3 ± 0.08 kg) [145]. One of the few interactions reported with guarana not related to caffeine content suggests possible interference with anticoagulants since platelet aggregation was observed *in vitro* and

Dandelion is a perennial herb of multiple global varieties that has traditionally been used for liver, spleen, kidney, and gastrointestinal disorders, although there have been no clinical trials investigatingtheeffectsofdandelioninweightloss [27,178].Itiscommonlyaddedtoweightloss supplements,mainlyforitsdiureticproperties,althoughtheherbdoespossesssomemildlaxative properties [179-181].Therearenoknowndrugs interactionsbetween*Taraxacum*andotherherbs or drugs, although one study in rats suggests a probable interaction with quinolone antibiotics due to the high mineral content of *Taraxacum* [182]. In the study, ciprofloxacin (20 mg/kg) Cmax significantly decreased while Vd and t½ significantly increased when administered with crude dandelion extract (2 g/kg) compared to control. There is one case report of hypoglycemia in a 58 year old diabetic patient following a 2-week period of dandelion consumption in salads [183].

tea ECGC and caffeine but not with decaffeinated green tea products [165].

cautioned.

116 Drug Discovery

*3.3.2. Guarana (Paullinia cupana)*

in animal studies [177].

**3.4. Dandelion (***Taraxacum officinale***)**

Ephedra, derived from the evergreen shrub *Ephedra sinica*, contains multiple plant alkaloids including ephedrine and pseudoephedrine that are chemically related to amphetamines. These compounds act by increasing availability and activity of endogenous neurotransmitters such as epinephrine and norepinephrine, resulting in brain and cardiovascular catecholamine receptor stimulation [184]. The herb has traditionally been used for bronchodilation in the treatment of respiratory ailments such as asthma, as an athletic performance enhancer, and for its thermogenic properties in weight loss [148, 185-189]. Ephedra as a weight loss dietary supplement is commonly found in combination products also containing caffeine or caffeinecontaining herbs. In one study a product containing 90 mg and 192 mg of ephedra alkaloids and caffeine, respectively, administered daily over six months in a randomized, double-blind placebo controlled trial resulted in significant decreases in body weight, body fat and LDLcholesterol with an increase in HDL-cholesterol [148]. The addition of aspirin to ephedrine containing products can potentiate the thermogenic properties of ephedra, improving weight loss compared to products containing ephedra alone [190-201]. Due to high risk of cardiovas‐ cular toxicities and cardiomyopathies, ephedra has been banned in the United States [202-211]. However, the herb is still available in other countries [212].

Because of the controversial nature of ephedra related to cardiac toxicity and its eventual ban via the U.S. FDA, there are a significant number of clinical studies and case reports related to toxicities and interactions with ephedra and ephedrine. Ephedra can potentially interact with anesthetics since it is known that administration of ephedrine can reverse anesthesia induced hypotension and regression of analgesia following epidural blockade [213, 214]. Ephedrine has both chrontropic and inotropic effects, and therefore interactions with cardiovascular agents may be possible [184, 211, 215, 216]. However, no effects on heart rate or blood pressure were seen in clinical trials investigating the efficacy of ephedra in weight loss [192, 217, 218]. Theoretically interactions with antiadrenergic agents and MAOIs can occur due to sympatho‐ mimetic effects of ephedrine, potentially increasing risk of hypertensive crisis. There is a case report of a patient taking a product containing caffeine, ephedrine, and theophylline who experienced multiple adverse effects including encephalopathy, hypotension, tachycardia, and hypothermia 24 hours following discontinuation of phenelzine [219]. Interactions with ephedrine and tricyclic antidepressants are also possible [220]. Some evidence from clinical trials suggests that ephedra in combination with caffeine can cause hyperglycemia, and therefore interactions with antidiabetic agents is possible [147, 148, 221]. A lowering of seizure threshold has been observed in patients taking ephedrine, and therefore use of ephedra in this patient population is cautioned [222]. A major interaction between ephedra and methylxan‐ thines (e.g. caffeine, theophylline) is possible due to increased risk of cardiovascular, neuro‐ logic and psychiatric adverse effects due to additive sympathomimetic and CNS stimulant activity [184, 223, 224]. One case study reports a 21 year old male patient admitted to the hospital emergency room with a blood pressure of 220/110 mmHg and ventricular arrhythmia following ingestion of a caffeine/ephedra containing product ("Herbal Ecstasy") [225].
