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LETTER TO THE EDITOR |
Analytical Unit, St George's-University of London, London, United Kingdom
Analytical Unit, St George's-University of London, London, United Kingdom
St George's-University of London, London, United Kingdom
Analytical Unit, St George's-University of London, London, United Kingdom
Analytical Unit, St George's-University of London, London, United Kingdom
Address for reprints: Susannah L. Kenyon, Analytical Unit, St George's-University of London, Cranmer Terrace, London SW17 0RE, United Kingdom; e-mail: skenyon{at}sgul.ac.uk.
Herbal medicines are widely available and are often used because of the belief that they are a safe alternative to conventional medication.1 An increasing number of Internet sites promote "safe, herbal alternatives" and "100% natural" products for the treatment of impotence.2 In the United Kingdom, there are 3 phosphodiesterase type 5 inhibitor drugs available on prescription to treat impotence: sildenafil, tadalafil, and vardenafil.3 Numerous Internet sites claim to sell these drugs, as many with an e-mail account can testify.4 The case described here involves the use of capsules containing an herbal preparation that was sold as a treatment for erectile dysfunction and that listed no prescription drugs among its ingredients.
A 50-year-old man was receiving 
- and ß-adrenoceptor blocking drugs for the treatment of hypertension and was using sildenafil (50 mg) at least weekly. He was introduced by a friend to the herbal remedy on the basis that it was a natural remedy to improve sexual health and libido. The patient also continued to take his prescribed sildenafil in addition to the herbal capsules. The listed ingredients in these capsules were Eurycoma longifolia (100 mg), Cordyceps sinensis (50 mg), Ginsenosides-Panx ginseng root (50 mg), Alpiniae oxyphyllae fruit (50 mg), Cistanche deserticola stem (45 mg), Epimedium sagittatum leaves (45 mg), Ganoderma lucidum mycelium (45 mg), Cinnamomum cassia bark (25 mg), Morus alba leaves (25 mg), and Poria cocos mycelium (15 mg). He sought reassurance on the safety of the product by reference to the manufacturer's Web site,5 which stated that "Our products are natural herbal powder made in a more convenient-to-use form capsules" and that "Each therapeutic product should be raw, unaltered and as close to their nature state as possible."
The patient reported good clinical efficacy, including a generous improvement in his libido and his ability to sustain an erection, so much so that he became suspicious about the contents of the product. Capsules taken from boxes he had purchased were sent to the Analytical Unit for toxicological analysis.
METHODS AND RESULTS
Pure reference standards of sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) were generous gifts from Pfizer (New York, NY), Lilly (Indianapolis, Ind), and Bayer (West Haven, Conn), respectively. High-performance liquid chromatography (HPLC)-grade methanol was purchased from Rathburn chemicals Limited (Walkerburn, Scotland). AnalaR-grade ammonium formate was purchased from BDH (Leicestershire, England). Deionised water was prepared on site (ELGA Limited). Two separate boxes of "Tongkat Ali Power Plus" (Etumax), containing a total of 15 capsules, were analyzed. The contents of each capsule were weighed, extracted into methanol, and screened by scanning UV spectrophotometry, thin layer chromatography (TLC), and gas chromatography-mass spectrometry (GC/MS). Results were then confirmed, and the contents quantitated using liquid chromatography with tandem mass-spectrometric detection (LC/MS/MS).
All 15 capsules contained sildenafil; mean measured concentration, 59 mg/capsule, (range, 50-71 mg). Ten of the capsules also contained tadalafil; mean measured concentration, 1.4 mg/capsule (range, 0.4-2.4 mg). The maximum recommended daily doses of sildenafil and tadalafil are 100 mg and 20 mg, respectively.3
Screening Methods
The reference standards and capsule extracts were analyzed using a PerkinElmer Lambda 35 UV/VIS spectrometer (Wellesley, Mass), scanning across a UV wavelength range of 190 to 400 nm. The absorption spectra recorded for all 15 capsules matched that of sildenafil. Thin layer chromatography was carried out using a silica Gel F 254 stationary phase and a methanol:ammonia (100:0.5 volume/volume [v/v]) mobile phase. Pure reference standards were run alongside the extracts of the capsule extracts to act as controls. The separation achieved was visualized using UV light and idoplatinate reagent. The TLC results gave a tentative identification that both sildenafil and tadalafil were present in all capsules. The extracts were then analyzed on an Agilent GC/MS using electron impact ionization (Agilent Technologies Inc, Palo Alto, Calif). Sildenafil was identified in all of the capsules. The results from the screening methods used supported the suspicion that the herbal capsules contained more than just herbal material.
Liquid Chromatography With Tandem Mass-Spectrometric Detection
The LC system consisted of a PerkinElmer Series 200 pump, autosampler, and column oven. Chromatography was achieved on an Alltech Alltima C18 (150 x 2.1 mm, 5 µm) column (Columbia, Md) maintained at 50°C. The mobile phase contained methanol: deionised water (80:20 v/v), with ammonium formate added to achieve a final concentration of 2 mM. Mass-spectrometric detection was performed on a Sciex API2000 triple quadrupole instrument equipped with a turbo-ion spray interface (Applied Biosystems, Foster City, Calif) held at 400°C. Nitrogen was used as the collision gas. Positive ionization was used, and the extracts were analyzed using both product ion scan and multiple reaction monitoring (MRM) mode.
A MRM method was set to simultaneously monitor the precursor ion and 2 product ions for each of the 3 drugs. The precursor ions [M+H]+ for sildenafil, tadalafil, and vardenafil were mass-to-charge ratio (m/z) 475, 390, and 489, respectively. The 2 most abundant product ions were selected for each drug; sildenafil (m/z 58 and 283), tadalafil (m/z 268 and 204), and vardenafil (m/z 151 and 312). Methanolic stock solutions of the reference material were diluted with methanol:deionised water (50:50 v/v) to prepare a combined standard. The extracts from the capsules were also diluted with methanol:deionised water (50:50 v/v). An aliquot of the combined standard and the capsule solutions was transferred to autosampler vials and analyzed using the MRM method. The results indicated that all capsules contained sildenafil and 10 contained tadalafil. Vardenafil was not detected in any of the capsules.
Many scientists regard LC/MS/MS as having absolute specificity; although this technique is very powerful, it can still suffer from interference. This is important to consider when working with complex matrices such as herbal material, which contain many ingredients. For further confirmation of the MRM results, a product ion scan (Figure 1) for each of the 3 drugs was carried out for all 15 capsules. The fragmentation patterns recorded for sildenafil, tadalafil, and vardenafil were similar to those seen in the literature.6 Product ion spectra for the reference standards were compared to those collected for the capsules. These results confirmed those found using MRM. The quantity of sildenafil and tadalafil in the capsules was determined using the MRM method.
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COMMENT
Our findings add to a growing concern about the safety of herbal products and illustrate the potential dangers for patients taking "natural" or "herbal" remedies that are not under the control of a regulatory agency. Others have found herbal products for the treatment of erectile dysfunction to contain sildenafil and tadalafil, but sildenafil was found at only half the concentration found in the case reported here.7
The patient described was at risk of a double dose of sildenafil (possibly exceeding the single recommended dose of 100 mg in 24 hours) and interaction with his prescribed antihypertensive medication.3 This could have potentially led to a profound drop in his blood pressure. Interactions involving other herbal products and prescription medication have previously been documented.8
Anyone seeking information on this herbal remedy might have been reassured as to its safety. The manufacturer claims rigorous standards of manufacture, in compliance with Good Manufacturing Practice, and approval by the Malaysian Ministry of Health.
Legislation introduced in the United Kingdom in October 2005 is designed to ensure that herbal products sold in the United Kingdom are registered with the Medicines and Healthcare Products Regulatory Agency. However, for those products already legally on the market before April 30, 2004, the manufacturers have until 2011 to register their products.
Although the new legislation is aimed at protecting consumers from the dangers of unlicensed herbal products, it is unlikely to have a marked effect on Internet sales of herbal preparations. Therefore, it is important to educate consumers, health professionals, and retailers of these products about their potential for pharmacodynamic and pharmacokinetic interactions with prescribed medication.8 In the case of these herbal capsules, they contained not only clinically active doses of synthetic drugs but also a combination of 2 drugs that would not have been prescribed together because of their additive effects.
ACKNOWLEDGEMENTS
Financial disclosure: None declared.
REFERENCES
1. Thurairaja R, Barrass B, Persad R. Internet websites selling herbal treatments for erectile dysfunction. Int J Impot Res. 2005;17: 196-200.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
2. Dennehy CE, Tsourounis C, Miller AE. Evaluation of herbal dietary supplements marketed on the internet for recreational use. Ann Pharmacother. 2005;39: 1634-1639.
3. British National Formulary (BNF). Vol 47. Gurnee, Ill: Pharmaceutical Press; 2004: 405.
4. Smith KM, Romanelli F. Recreational use and misuse of phosphodiesterase 5 inhibitors. J Am Pharm Assoc (Wash DC). 2005;45: 63-72; quiz 73-75.
5. Etumax Web site. Available at: www.etumax.com. Accessed February 21, 2006.
6. Xiaolan Zhu, Song Xiao, Bo Chen, et al. Simultaneous determination of sildenafil, vardenafil and tadalafil as forbidden components in natural dietary supplements for male sexual potency by high-performance liquid chromatography-electrospray ionization mass spectrometry. J Chromatography A. 2005;1066: 89-95.[CrossRef]
7. Fleshner N, Harvey M, Adomat H, et al. Evidence for contamination of herbal erectile dysfunction products with phosphodiesterase type 5 inhibitors. J Urol. 2005;174: 636-641.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8. Mills E, Wu P, Johnston BC, Gallicano K, Clarke M, Guyatt G. Natural health product-drug interactions: a systematic review of clinical trials. Ther Drug Monit. 2005;27: 549-557.[CrossRef][Medline]
[Order article via Infotrieve]
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