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Thursday, 17 May 2018

Principal component analysis of synthetic adulterants in herbal supplements advertised as weight loss drugs

Volume 31, May 2018, Pages 236-241 Complementary Therapies in Clinical Practice Author links open overlay panelAkram GhasemiDastjerdiaMaryamAkhgaribArtinKamalibZahraMousavia a Department of Toxicology & Pharmacology, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University (IAUPS), Tehran, Iran b Forensic Toxicology Department, Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran https://doi.org/10.1016/j.ctcp.2018.03.007 Get rights and content Highlights • Herbal slimming drugs were adulterated with active pharmaceutical ingredients. • Legitimate and controlled drugs were detected in herbal weight loss drugs. • Use of adulterated drugs is life threatening even though in low doses. Abstract Objective Obesity is one of the major problems in many countries. Herbal drugs are widely used to treat obesity. Unfortunately the majority of herbal weight loss drugs are adulterated with active pharmaceutical ingredients. The purpose of the present study was to analyse herbal weight loss drugs for the general search for pharmaceuticals. Methods sixty one herbal weight loss drugs that were collected from herb shops and internet in Kermanshah, Iran were analysed qualitatively using gas chromatography/mass spectrometry. Results Of the 61 weight loss products sampled, 72% were found to be adulterated with tramadol, caffeine, fluoxetine, rizatriptan, venlafaxine and methadone. Conclusion Herbal weight loss products were adulterated with controlled and legitimate drugs. Patients should be aware of the danger of using adulterated supplements. Previous article in issue Next article in issue Keywords Adulteration Herbal weight loss drugs Analytical toxicology GC/MS 1. Introduction Obesity is one of the most common problems that affects health and quality of life of many people. The World Health Organization (WHO) reports manifested that obesity is rising at alerting rate causing high prevalence of type 2 diabetes, cardiovascular diseases, hypertension and cancer [1,2]. Currently, more than one billion adults are overweight all over the world, of which 300 billion are obese [2]. Considering this situation, losing weight and preventing obesity comes into prominence. Therefore, there is a need for effective and safe methods for reducing weight [3]. Antiobesity medical management has failed to show satisfactory results due to some factors such as complexity of appetite regulation mechanisms, little drug effects, several side effects and lack of individualized treatment strategies [4]. Herbal foods and supplements as raw plant material or pharmaceutical dosage forms are used as effective drugs for the prevention and therapy of many health problems [5]. These drugs constitute an important component of traditional and complementary medicine in clinical practice [6]. Many patients are tempted to use herbal foods and supplements due to the idea that drugs with natural origin have fewer side effects in comparison to their synthetic congeners and therefore, are safe for self-medication [7,8]. Also, people trust herbal drug producers, supposed to sell natural products [1]. However, this belief may not always hold true. One of the strategies in weight loss program is appetite suppression. Herbal derived compounds control appetite, increase the activity of pancreatic lipase and stimulate lipid metabolism [9]. The popularity of natural products is increasing dramatically considering above points. Unfortunately herbal dietary supplements are the most adulterated preparations targeted by unscrupulous manufacturers. As getting rapid short-term antiobesity effects from herbal supplements is nearly impossible, they deliberately add active pharmaceutical ingredients (APIs) to food and herbal supplements to get desired pharmacologic effects in a short period of time [7,10,11]. For example, APIs are deliberately added to natural supplements advertised for erectile dysfunction, weight loss, addiction treatment and weight gain [[10], [11], [12], [13]]. There are some definitions for falsified medicinal products. According to the WHO explanation a product with false identity statement such as packaging or labeling, false composition and strength of active ingredients or false representation of manufacturer, origin or country of production is defined as falsified product [14]. Accordingly, excessive consumption of tainted food supplements gives birth to safety problems for the patients due to unknown amount of APIs in adulterated products [7]. Considering public health and legal regulations there is an urgent need for effective screening of APIs in herbal drugs [1]. Herbal weight loss supplements that are sold in some retail stores, beauty salons and over internet have not been assessed and approved by the Iran's Food and Drug Administration (IFDA). As there is no control or registration mechanism for hand-made herbal products and their poorly regulated market in many countries, many stakeholders have reported numerous cases of adulteration of herbal weight loss drugs [7,8,15]. Hachem et al. in a study conducted on 160 herbal food weight loss supplements found that more than 50% of these supplements were tainted with six APIs together. Sibutramine, sildenafil, phenolphthalein, fluoxetine and lorcaserin were detected as undeclared APIs in herbal drugs [16]. Evidence from Korean market confirms that chlorosibutramine (sibutramine analogue) was isolated as adulterant in slimming dietary supplements [7]. Neves et al. investigated dietary weight loss supplements in Brazil for the detection of undeclared APIs. Results of their study showed that dietary supplements contained sibutramine, phenolphethalein, amphepramone and fenproporex [17]. According to Wang et al. herbal weight reducing dietary supplements were adulterated with phenolphthalein, N-mono-desmethyl sibutramine and sibutramine [18]. Previous studies have shown that the prevalence of overweight is about 32% in Iranian population [2]. Therefore, there is a need for effective antiobesity drugs especially natural ones in obesity treatment protocols in Iran. The present study is crucial in determining undeclared APIs in herbal supplements claiming to aid in weight reduction in Kermanshah province, Iran for the first time. Up to now, a very limited number of studies have investigated the presence of undeclared APIs in herbal slimming drugs in Iran [[19], [20], [21]]. Obtained results will be beneficial in mirroring the most frequent composition of weight loss products in herb shops, using gas chromatography/mass spectrometry instrumentation (GC/MS) in a bigger sample size and also discuss about component analysis and adulteration issue in more detail. 2. Materials & methods 2.1. Reagents and solutions Analytical grade methanol, chloroform, borate buffer, hydrochloric acid (37%) and potassium hydroxide were purchased from the Merck Chemical Co. (Darmstadt, Germany). Water for chromatography (Merck Millipore) was used to prepare solid samples. Helium gas (99.99% purity) was supplied by Roham Co. (Tehran, Iran). All chemicals and solvents used were of analytical reagent grade and high purity. 2.2. Methods 2.2.1. Herbal drugs collection Herbal drugs advertised as weight reducing agents sold as raw herbal powders or pharmaceutical dosage forms (tablets, handmade capsules, herbal teas, herbal jells and herbal resins) were acquired from herb shops, retail stores or internet all over the Kermanshah province, Iran over one year study period, 1st of March 2016 till 30th February 2017. It should be taken into account that none of the herb shops were registered by the IFDA or the Ministry of Health and Medical Education, Iran. 2.2.2. Toxicological analysis procedures Suspicious drug categories in herbal slimming products are anorectics, antidepressants, anxiolytics, diuretics and laxatives. All products were screened for these drug classes. Systematic toxicological analysis was performed for the detection of probable active pharmaceutical ingredients in samples using GC/MS instrumentation. Reference standards of presumptive analytes were used to ensure the detection of drugs. 2.2.2.1. Physical characteristics of herbal drugs The first step in analytical toxicology operations is the visual inspection of pharmaceutical dosage forms. Shape, color, odor and weight of all dosage forms and raw herbal powders were enrolled. 2.2.2.2. Analytical procedures All of the screening and confirmatory methods were well prevalidated in the laboratory. Different and decreasing concentrations of analytes were spiked in non-biological and biological samples. Linearity, limit of detection (LOD), limit of quantitation (LOQ), accuracy, precision and repeatability were evaluated [[22], [23], [24], [25], [26], [27]]. 2.2.2.2.1. Extraction and isolation of unknown active pharmaceutical ingredients All of the collected dosage forms were prepared prior to toxicological analysis. Tablets and solid dosage forms such as herbal resins were crushed to fine and uniform powder using a mortar. The contents of hard gelatin capsules were emptied to be prepared for the extraction of pharmaceutical analytes. Liquid dosage forms were analysed without any dilution. Cleanup procedure for the extraction of pharmaceutical ingredients was performed with dispersive liquid microextraction (DLLME) method. One mg of each prepared sample (powder or liquid) and one mL of deionized water were blended and transferred into a 10 mL centrifuge tube. The mixture was mixed with 2 mL of borate buffer (0.1 M, pH = 9.2). For efficient extraction of alkaline drugs the pH of the medium was adjusted to pH = 12. Acidic drugs and opium alkaloids were extracted in pH = 2–3 and pH = 8–9 respectively. The resulting solution was extracted by DLLME technique using triple solvent system (aqueous phase, extracting and dispersing solvents) for the extraction of analytes from herbal supplements. The method was prevalidated in the laboratory [11]. A mixture of dispersing (2.5 mL methanol) and extracting (30 μL chloroform) solvents was pushed by force to the prepared samples in borate buffer. The mixture was well stirred and ultrasonicated for 5 min. Chloroform was collected from the end of test tube after centrifugation at 3000 rpm for 5 min and evaporated to dryness under gentle stream of nitrogen gas. The residue was reconstituted with 30 μL of methanol. Suspected analytes were concentrated in the final 30 μL methanol and analysed using GC/MS instrumentation. 2.2.2.2.2. Instrumentation and apparatus An Agilent model 7890 A gas chromatograph (Agilent Technologies, Sdn Bhd, Selangor, Malaysia) equipped with split/splitless injector was used. The column was a HP5-MS capillary column (cross-linked 5% methyl phenyl silicone, 30 m length × 0.25 mm ID × 0.25 μm film thickness). The capillary column was connected to a mass analyser (MS 5975C) (Agilent Technologies) operated by electron impact (70 eV) in full scan mode (50–550 m/z). The following parameters were adjusted to perform analysis: injector temperature, 250 °C; and interface temperature, 280 °C. The oven temperature was programmed as follows: initial temperature, 60 °C; initial hold, 1 min; temperature program rate, 2 °C/min; final temperature, 280 °C; final hold, 15 min. Helium carrier gas was maintained at a constant flow of 1.5 mL/min. NIST, Wiley and MPW 2011 libraries were used for the identification of suspected pharmaceuticals. 3. Results In the current study, 61 herbal weight loss supplements that were gathered from herb shops, retail stores, door-to-door delivery and over internet in Kermanshah province, Iran were analysed to detect undeclared APIs using GC/MS instrumentation. As it is shown in Table 1 most frequent products analysed in this study were hard gelatin capsules in different colors. All of the samples had herbal odor. The mean weight of capsules was 0.63 ± 0.13 (mean ± SD) grams. None of the samples had standard labels with defined logo or even the name of herbs or active pharmaceutical ingredients. The labels had no descriptive and/or image of the medication. Just a brief description of the drug such as “apple cider vinegar, slimming tea, sour lemon extract, …” were inserted on drug packets. Composition of the products were not stated on the labels or in package leaflets. The labels of all herb products indicated to have the property of weight loss, fat burning, metabolic acceleration and appetite suppression. The analysis of drugs with the same packaging obtained from different herb shops showed a chromatographic profile fully different from the other. It is not uncommon to find multiple APIs in a single dosage form. The analysis of suspected products revealed that 44 (72%) of samples contained at least one or more potentially harmful pharmaceutical ingredients. Among detected drugs, tramadol, as well as caffeine were the most identified drugs in herbal weight reducing supplements. Table 1. Pharmaceutical dosage forms, their brand names and also, active pharmaceutical ingredients detected in each dosage form obtained from herbal weight loss drugs, Kermanshah province, Iran. Product name Pharmaceutical dosage form Detected active pharmaceutical ingredients Sigol Bustan Brown powder Fluoxetine, Tramadol Ginseng Green hard gelatin capsules Fluoxetine, Tramadol, Rizatriptan Super Power 007 White powder Fluoxetine, Caffeine Super Power 007 Red hard gelatin capsule Tramadol Mohazzel Blue hard gelatin capsule Fluoxetine, Tramadol Traditional capsule Hard gelatin capsules in different colors Fluoxetine, Tramadol, Rizatriptan, Venlafaxine Red Slimming Red hard gelatin capsule Tramadol, Rizatriptan Apple Cider Vinegar White tablet Fluoxetine, Methadone Locke Mghsul (Anacardiacea) Brown resin Tramadol, Caffeine Senna Maki Brown powder Tramadol Herbal Slimming Beige powder Tramadol, Rizatriptan, Caffeine, Venlafaxine Herbal Slimming Hard gelatin capsules in different colors Tramadol, Rizatriptan, Caffeine, Venlafaxine Herbal Slimming Blue Jelly None SlimMax White capsule Rizatriptan, Caffeine, Venlafaxine SlimQuick White capsule Caffeine Celery tea bag Sachet Caffeine, Ritodrine Laxative Green capsule Caffeine Lime (Citrus aurantifolia) Yellow soft gelatin capsule None Cumin (Cuminum cyminum) Green soft gelatin capsule None Fig. 1 shows one of the dosage forms in hard resin shape named “Locke Maghsul” obtained from the plants of the family of Anacardiacea that contained tramadol and caffeine as contaminant. Fig. 1 Download high-res image (379KB)Download full-size image Fig. 1. “Locke Maghsul” advertised as weight loss drug that was adulterated with caffeine and tramadol. Fig. 2 shows the Chromatogram of caffeine and tramadol detected in Locke Maghsul resin. The pharmaceutical dosage forms, their brand names and also, active pharmaceutical ingredients detected in each dosage form are shown in Table 1. All of the producers and sellers claimed that herbal products were plant extracts and vitamins with no additives. Frequency of undeclared active pharmaceutical ingredients detected in different herbal dosage forms is shown in Table 2. Fig. 2 Download high-res image (124KB)Download full-size image Fig. 2. Chromatogram of extracted drugs from Locke Maghsul resin using GC/MS instrumentation. Table 2. Undeclared active pharmaceutical ingredients detected in different herbal dosage forms advertised as slimming agents obtained from herb shops, Kermanshah province, Iran. Drug name Percent (%) Tramadol 21.3 Caffeine 21.3 Rizatriptan 11.5 Fluoxetine 8.2 Venlafaxine 6.6 Methadone 1.6 Ritodrine 1.6 Without drug 27.9 Total 100 4. Discussion In the present study we investigated the adulteration of herbal weight reducing drugs to detect undeclared APIs. Results indicated that herbal weight loss drugs were adulterated with controlled and legitimate drugs. Herbal medicinal products are among the most growing sectors in the world. The annual sale of natural products reaches several billion euros. These herbal products, known as botanicals, can be obtained easily from internet or retail outlets as over-the-counter drugs without any prescription. Discrimination between high-quality herbal drugs from low-quality ones is not easy [28]. In many countries they are sold on the market without the need of a medicines product license or registration [29]. Adulteration practice violates the laws of many countries due to potential and unpredictable side effects in patients [30]. A survey conducted by FDA in the United States of America (USA), demonstrated that between 2007 and 2014, a total of 572 dietary supplements were adulterated with undeclared APIs of which 228 samples were advertised as slimming products [28]. One of the problems, to be addressed in the promotion of herbal medicine quality is adulteration with pharmaceutical active ingredients. Incorrect formulation process reduces the effectiveness, quality and purity of herbal medicines [31]. Phytochemical standards are generally used for the identity, purity and strength evaluation of drugs and their genuine or adulterated nature [32]. As the presence of APIs is not predictable, it could be omitted in routine screening if more sensitive and specific methods were not used. Furthermore, analytical toxicology is one of the methods for the detection of APIs deliberately added to herbal supplements to change their pharmacologic properties [10,11]. The pharmacologic basis of using APIs in herbal slimming drugs involves the use of different drug classes that reduce appetite, decrease anxiety and increase urinary flow [33]. In the present study most of the APIs were added to final products for apparent reasons. Nevertheless, the motive for using other APIs that were irrelevant to the claimed therapeutic purposes is not clearly understood. Previous studies confirmed that several types of illegal adulterants such as prohibited substances, legal and under control pharmaceuticals have been reported to be found in herbal drugs without notification of their amount and even chemical names [[10], [11], [12]]. To the best of our knowledge, this research comprehensively detected for the first time tramadol, methadone, rizatriptan and ritodrine in slimming products. More than 21% of analysed drugs were adulterated with tramadol. Tramadol is a regulated drug that should be taken under medical supervision and follow up due the high incidence of abuse potential and adverse effects such as seizure [25]. Few studies discussed the role of tramadol on palatable food intake and body weight. Since this effect is not characteristic for opioid receptor agonists, other neurochemical pathways such as inhibitory effect on the reuptake of noradrenaline and serotonin may be involved in the anorectic effect of this drug [34]. The other possible explanation for adding tramadol to herbal supplements is that the patient would be dependent to the drug and use it continuously. Another assumption is that opioids, used as narcotics, are disguised as slimming aids in order to pass the control authorities. Adulteration of herbal remedies is common due to the loose regulations and enforcement required to validate herbal products [35]. There are reports that adulterants can be concealed in complex matrices such as gelatin capsule shells. Therefore, criminological investigations should be performed to analyse suspected products in addition to routine drug screening tests [32]. It is well recognized that serotonin (5-HT) has an important role in appetite control. Serotonin drugs reduce calorie intake via reduced hunger and increased satiety [36]. Rizatriptan is a 5-HT1B and 5-HT1D agonist with antimigraine effect. 5-HT is a powerful anorectic agent. Rizatriptan is deliberately added to herbal weight loss supplements to induce anorexia [37]. Ritodrine is a β2 agonist drug with tocolytic activity. β2 agonists inhibit the contraction of smooth muscles in gastrointestinal tract and small intestinal transit of liquid meal, leading to gastric stasis, loss of appetite, nausea and vomiting. Nausea, gastritis and loss of appetite were among the main adverse effects reported by Basilisco et al. [38]. Weight loss was reported during short-term treatment with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and sertraline [39]. Therefore, it would be one of the reasons that fluoxetine was added to herbal weight loss supplements. Some adulterants such as caffeine may be added to herbal supplements mainly used as weight loss, athletic performance enhancers and energetics secretly. Ozdemir et al. in their survey on herbal weight loss products found that six of nine samples were adulterated with undeclared caffeine [40]. Methylxanthines such as caffeine are used due to their stimulating and thermogenic effects. Besides, many food supplements with ergogenic and aesthetic properties have abusive potential. Methadone is one of the synthetic opioids with agonist effects on opioid receptors. Methadone is used as an alternative for opioids in addiction treatment and methadone maintenance program [24]. There are reports that methadone use may be accompanied by some side effects such as loss of appetite [41]. However, the reason for adding methadone to weight loss products is not clear. In contrast to the results of the present study, sibutramine was the most adulterant detected in herbal supplements in the study of Ching et al. in Hong Kong [42]. Also, hydrochlorothiazide and furosemide were detected in herbal slimming drugs using capillary electrophoresis (CE) in the study of Moreira et al. [33]. Deconinck et al. conducted a study on 125 food supplements using infrared (IR) spectrometry. They detected sibutramine in their analysed samples [43]. Previous scholars indicated that herbal weight loss products were adulterated with sibutramine, phenolphthalein, orlistat with Chinese and Southeast Asian countries sources [19,43]. FDA withdrew sibutramine from the market due to its cardiovascular side effects and risk of cardiac stroke [44]. However, in spite of the search for all suspicious drugs, none of the analysed herbal supplements in the present study contained abovementioned APIs. The difference may be due to the fact that the sources of drugs are different. Also, drug availability is different at different time points in one geographic area. Those patients taking adulterated herbal drugs may suffer from several unpredictable implications [45]. Adulteration of herbal supplements with undeclared APIs and their health consequences have recently came to light. Adverse effects and the potential toxicity of adulterated herbal drugs should be considered even though their concentrations are low and less than prescription strength [3]. Continuous use of adulterated drugs even in low doses and without proper medical supervision may be dangerous and could lead to potentially toxic outcomes and even fatal consequences. This situation will be compounded if the patient is taking other prescription drugs as well [12,42]. Adverse effects may be due to the pharmacologic action of pharmaceutical adulterants or drug-drug and also, drug-herb interactions [5,30]. 5. Conclusion Our data, in a way, reflect a more complete picture of adulteration of herbal slimming products sold in Kermanshah province, Iran with many undeclared active pharmaceutical ingredients. Therefore, there is an urgent need for effective systems to detect and divulge the adulteration of herbal supplements to the public. Also, these results necessitate periodical inspections of natural herbal products by governmental organizations to ban and restrict production, distribution and use of falsified herbal products in medical therapy protocols. Limitations It is important to mention some limitations concerning sample collection. As many herbal supplements producers were afraid of controlling authorities, they sold only products that were less likely to be adulterated to circumvent the regulations. 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