**2.5. Sibutramine (Meridia®, Reductil®)**

lumen of the stomach and small intestine through covalent binding with gastric and pancreatic lipase active serine residues [70]. Multiple randomized controlled trials have reported significant weight loss in patients taking orlistat compared to placebo controlled groups. One meta-analysis cites mean weight loss compared to control of -2.59 kg [95%CI, -3.46 to -1.74] or -2.9 kg [95%CI, -3.2 to -2.5] over 6 or 12 months, respectively, with a corresponding decrease

A large number of preclinical and clinical studies and case reports related to potential drug interactions with orlistat have been published. There have been several cases of orlistat interaction with cyclosporine [74-79]. In all cases, significant decreases in plasma cyclosporine levels were observed following adjunct treatment with orlistat for cyclosporine-associated weight gain. Although one proposed mechanism for the reduction in plasma cyclosporine is a decrease in drug absorption, decreased levels may be due to rapid gastrointestinal transit time resulting from contraindicated high fat diets rather than a true drug-drug interaction [80]. Because orlistat is designed to inhibit gastrointestinal lipases, theoretically absorption of lipophilic molecules would also be inhibited [81-83]. In one open-label, placebo-controlled randomized two-way crossover study, orlistat (120 mg) was administered to 12 healthy subjects three times daily for 9 days followed by administration of Vitamin A (25,000 IU) or Vitamin E (400 IU) [82]. Although no effect was seen on Vitamin A levels, a significant reduction in Cmax (approx. 43%) and AUC (approx. 60%) were observed for Vitamin E, suggesting impaired absorption of Vitamin E by orlistat. In another study, approximately a 30% reduction in beta-carotene levels was observed after administration of orlistat (120 mg) for four days followed by administration of 0 – 120 mg of beta-carotene three times a day for six days [83]. Absorption of lipophilic drugs such as the CNS agent lamotrigene can also be affected by orlistat. In one report, increased frequency of seizures was reported in an 18 year old female taking lamotrigene following initiation of an orlistat regimen [84]. One case of hypothyroidism in thyroid carcinoma was reported, presumably due to decreased absorption of thyroxine [85]. Although orlistat was not found to alter warfarin kinetics *per se*, but the drug may alter absorption of the fat soluble vitamin K which can have an effect warfarin levels and therefore these patients should be monitored for changes in coagulation parameters [86].

Rimonabant (Figure 1f) is a cannabanoid receptor antagonist that suppresses appetite by preventing activation of CB1 receptors by the endogenous cannabanoids anandamide and 2 arachidonoyl-glycerol [87]. In clinical trials the drug resulted in improvement of multiple endpoints associated with obesity and metabolic syndrome compared to control groups including significant weight loss, reduction in waist circumference, decreased triglycerides, blood glucose, fasting insulin, and leptin levels with increased HDL cholesterol and adipo‐ nectin levels [88-96]. Although rimonabant proved a potentially successful drug in the treatment of obesity, especially given lack of cardiovascular risks compared to other weight loss drugs (see *Sibutramine* below), the drug has not been approved by the U.S. Food and Drug Administration (FDA). Additionally, although the drug was initially approved in 2006 by the European Medicines Agency (EMEA), later studies indicating serious neuropsychiatric

in waist circumference, blood pressure, and blood glucose and lipid profiles [71-73].

**2.4. Rimonabant (Acomplia®, Zumulti®)**

112 Drug Discovery

Sibutramine hydrocholoride (Figure 1g), and its active primary (M1) and secondary (M2) metabolites, is a selective serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake inhibitor [106-110]. Clinical data supported the efficacy of sibutramine as a weight loss agent, reporting significant weight loss compared to placebo for patients taking at least 10 mg/day for up to one year [107, 110-114]. The drug was approved as an anti-obesity agent in 1997 by the U.S. FDA and in 2002 by the EMEA, despite evidence of increased risk of hypertension and tachycardia, with a requirement that additional post-marketing safety data be collected relative to cardiotoxicity. As a result, the SCOUT (Sibutramine Cardiovascular OUTcomes) trial was implemented, which enrolled 10,000 overweight or obese patients aged 55 and older with coexisting diabetes and/or heart disease in a randomized controlled trial with a 6-month lead in period [115-118]. At the end of the six year study period, data showed a significant decrease in body weight compared to placebo but increased cardiovascular morbidity in the randomized sibutramine group [115-118]. Following publication of the SCOUT trial results in 2010, the EMEA and most other major markets pulled sibutramine while the United States and Australia required stricter labeling. By 2011 sibutramine was pulled from all major markets globally. However, as with the case of rimonabant (see above), sibutramine is of note since it is the primary contaminant found in dietary weight loss supplements (see *Adulteration of Dietary Supplements* below).

Sibutramine is known to be metabolized by CYP 3A4 into two active metabolites (M1 and M2). Data reported by the manufacturer in limited clinical trials (n = 12 – 27 patients) suggest potential pharmacokinetic changes in AUC and Cmax for sibutramine when taken in combina‐ tion with CYP 3A4 inhibitors such as cimetidine, ketoconazole, erythromycin, simvastatin, and omeprazole; while sibutramine does not generally have a significant impact on the levels of these drugs in return [106]. Because of the role of CYP 3A4 in sibutramine elimination, use of the drug with other CYP 3A4 substrates, including coadministration with grapefruit juice, is contraindicated [111]. One case report describes a possible interaction between sibutramine and citalopram in a 43 year old female patient who experienced hypomanic symptoms shortly after adding 10 mg sibutramine to her current citalopram and fluoxetine regimen [119]. Symptoms ceased within one day of discontinuing sibutramine. Although the exact mecha‐ nism of the interaction is unknown, the author hypothesized a possible amphetamine-like hypomania or serotonin syndrome due to increased brain serotonin levels via the combination of a serotonin reuptake inhibitor and serotonin-norepinephrine reuptake inhibitor. Another case report notes a possible interaction between sibutramine and cyclosporine in a 26 year old transplant patient resulting in significant increases in cyclosporine trough plasma levels, likely due to inhibition of CYP 3A4 metabolism [120]. Coadministration of α<sup>2</sup> adrenergic blockers, such as the herb yohimbine, with sibutramine has been recognized as potentially life threat‐ ening due to potential sympathetic side effects resulting in hypertension and tachycardia [121]. Due to the potential risk of bleeding caused by sibutramine, the drug should be used with caution in patients taking warfarin and other anticoagulants [106].

Interactions with bitter orange are varied. Synephrine, like ephedrine, is known to cause adverse cardiovascular effects at high doses, the risk of which are heightened when combina‐ tion products also including caffeine are ingested and therefore patients taking cardiac medications should be cautioned on its use [135, 136]. Some evidence demonstrates that bitter orange can inhibit cytochrome P450 3A4, although to a lesser extent than with grapefruit [137-140]. A 76% increase in AUC was observed following administration of 10 mg extended release felodipine administered with 240 mL Seville orange juice compared to control [139]; while a significant increase in indinavir tmax was observed with administration of 8 ounces of Seville orange juice compared to control [140]. Because synephrine and octopamine, both endogenous substances, can interact with monoamine oxidase there is a theoretical interaction

Interactions with Drugs and Dietary Supplements Used For Weight Loss

http://dx.doi.org/10.5772/51145

115

Caffeine is a methylxanthine that is commonly found in food, beverages, and dietary supple‐ ments. It is used as an additive in beverages and dietary supplements for its energy enhancing properties. Many dietary supplements marketed for weight loss contain high levels of caffeine, often from multiple sources, for increased thermogenesis and lipid metabolism [143, 144]. Most studies investigating the anti-obesity effects of caffeine have been done using combination products that include ephedra, or have looked at enhancement of athletic endurance [145-151]. Therefore, it is difficult to assess the effect of caffeine alone on weight loss. One study dem‐ onstrated an increase in thermogenic metabolic rate in subjects drinking coffee along with food,

Adverse effects associated with caffeine consumption include restlessness, jitteriness, anxiety, insomnia, and cardiovascular effects [152-156]. Most drug and herb interactions with caffeine are mild to moderate and are related to increased adverse effects resulting from decreased caffeine elimination or additive effects with other methylxanthine containing products [157]. For example, estrogen drugs (e.g. oral contraceptives and estrogen replacement therapy) have been shown to decrease clearance of caffeine up to 50 – 65% [158, 159]. The most significant caffeine interaction occurs with coadministration of *Ephedra* or ephedrine containing products (see *Ephedra* below). The ban on ephedra in the United States has resulted in marketing of "ephedra-free" dietary supplements using ephedra alternatives, including caffeine containing herbs and bitter orange (see *Bitter Orange* above). In one randomized controlled trial study, subjects were administered products containing *Citrus aurantium* standardized to either a high dose of synephrine (46.9 mg) or a product containing caffeine and a low synephrine dose (5.5 mg) [136]. A significant increase on blood pressure was observed in patients taking the product containing both caffeine and synephrine, but not high dose synephrine alone, suggesting an

Green tea has gained in popularity for the treatment of a wide variety of diseases and for promotion of general wellbeing. The addition of green tea to weight loss supplements is due in part to the caffeine content of *Camellia sinensis*. However, in addition to alkaloid content

of bitter orange with MAOIs [141, 142].

compared to ingestion of decaffeinated coffee [144].

**3.3. Caffeine-containing herbs**

interaction between the two herbs.

*3.3.1. Green tea (Camellia sinensis; EGCG)*
