The DOI matches its Crossref record; 14 of the 15 references it cites were found in a registry or an index; none of the 11 sources its claims cite is checked for support yet.
Detection of a Tadalafil Analogue as an Adulterant in a Dietary Supplement for Erectile Dysfunction
Open accessAbstract
Introduction: Several cases of adulteration of dietary supplements with tadalafil, sildenafil, and vardenafil, or their unapproved analogues have been reported worldwide. Mainly, the presence of the latter represents a serious health risk to consumers as their efficacy and toxic effects have not been assessed and may result in unpredictable adverse effects. Aim: To investigate the suspected adulteration with synthetic phosphodiesterase type 5 (PDE-5) inhibitors in a dietary supplement marketed in Argentina for the treatment of erectile dysfunction (ED). Methods: The content of the capsules of the dietary supplement (sample A) was analyzed by thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC) diode-array detection. From the organic extract of sample A, a major compound was purified by column chromatography (CC). The isolated compound was identified by proton nuclear magnetic resonance (1H NMR) and carbon NMR (13C NMR), heteronuclear single quantum coherence, distortionless enhancement by polarization transfer (DEPT 135), electrospray ionization mass spectrometry, and ultraviolet, and infrared (Fourier transform infrared spectroscopy) spectroscopy. Main Outcome Measure: Proof of adulteration of herbal products with synthetic PDE-5 inhibitors. Results: By TLC and HPLC analysis, a major compound was detected in sample A organic extract. The purification of this extract by CC led to the isolation of a pure compound which was identified according to its spectral data as (6R,12aR)-2-amino-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydropyrazino [1′,2′:1,6] pyrido [3,4-b] indole-1,4-dione or aminotadalafil. Conclusions: An unapproved PDE-5 inhibitor analogue, which was identified as aminotadalafil, has been detected in a dietary supplement. This study represents the first report in Latin America and one of the few independent studies of an adulteration with an unapproved PDE-5 inhibitor of an herbal product for ED treatment.
Overview
CoChat Summary
TL;DR
A dietary supplement marketed in Argentina for erectile dysfunction was found to be adulterated with the unapproved PDE-5 inhibitor analogue aminotadalafil. The identification was made by TLC/HPLC-DAD and confirmed by isolation and spectral analysis (NMR, MS, IR, UV).
Key findings
- TLC and HPLC-DAD detected one major compound in the supplement extract: Rf values 0.81 and 0.74 in two TLC systems, and an HPLC retention time of 11.79 minutes, eluting before tadalafil at 16.31 minutes; its UV spectrum (λmax 291.4, 284.3, and 220.6 nm) was similar to tadalafil.
- Purification by column chromatography yielded 97.5 mg of an amorphous yellowish powder; ESI-MS gave a molecular formula C21H18N4O4 with m/z 391.1 [M+H]+, indicating one more nitrogen but one less carbon and hydrogen than tadalafil.
- NMR showed replacement of tadalafil’s N-methyl group, evidenced by a two-proton signal at δH 5.11 and disappearance of the δH 2.93 methyl signal, leading to identification as (6R,12aR)-2-amino-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione, or aminotadalafil.
- The authors conclude this is the first report in Latin America and one of the few independent studies of adulteration with an unapproved PDE-5 inhibitor in an herbal product for ED treatment.
Methods
- The suspected dietary supplement (sample A) was submitted by the Urology Department at Hospital de Clínicas José de San Martín, University of Buenos Aires; three additional lots were purchased from the local market. The label claimed Panax ginseng, Astragalus membranaceus, Schizandra chinensis, Ginkgo biloba, and vitamins.
- The contents of four capsules (brown powder) were ground and extracted with dichloromethane (50 mL/g) by ultrasonic shaking at 25°C for 1 hour, filtered, and evaporated under vacuum at 40°C to yield the dried extract (DESA). Cialis (tadalafil 20 mg), Viagra (sildenafil 50 mg), and Levitra (vardenafil 20 mg) tablets were used as standards and treated similarly.
- Analysis used TLC with two mobile phases, HPLC-DAD on a C18 column with gradient elution, purification by open column chromatography over silica gel, and structural identification by UV, FT-IR, ESI-MS, 1H NMR, 13C NMR, DEPT-135, and HSQC NMR.
Limitations
- Stated: the exact market penetration of such dietary supplements is difficult to assess because they are frequently sold informally and even online; the safety profiles and toxic effects of PDE-5 inhibitor analogues have not been fully established.
- Evident from the text: although three additional lots were purchased, the reported chromatographic and spectroscopic results focus on sample A/DESA, and no quantitative adulterant level or clinical adverse-event data are reported.
- Evident from the text: no formal method validation or confirmation against an authentic aminotadalafil reference standard is described; identification relies on spectral data compared with published data.
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Verification
Claims the paper makes
0 Valid · 0 Not valid · 6 Not checked · 14 Own results and interpretations
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The 2D HSQC spectrum shows correlations consistent with the chemical structure of the compound aminotadalafil (Figure 3).”
§ Detection of a Tadalafil Analogue as an Adulterant in a Dietary Supplement for Erectile Dysfunction > Results
plainstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notwithstanding, compound 1 showed a similar behavior to tadalafil as assessed by its Rf values and detection.”
§ Detection of a Tadalafil Analogue as an Adulterant in a Dietary Supplement for Erectile Dysfunction > Discussion
plainstates an associationSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“By comparing the results obtained with published data [3,10], it was concluded that the structure of compound 1 was (6R,12aR)-2-amino-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12ahexahydropyrazino [1′,2′:1,6] pyrido [3,4-b] indole-1,4-dione or aminotadalafil (Figure 4).”
- Also stated in: § Discussion · plain
“The structural elucidation of 1 was based on the analysis of its spectral data and identified as aminotadalafil, which has been previously reported as an adulterant in DS [3,10].”
§ Detection of a Tadalafil Analogue as an Adulterant in a Dietary Supplement for Erectile Dysfunction > Results
What the sources say
- Not matchedcites [3]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Discussion · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“An unapproved PDE-5 inhibitor analogue, which was identified as aminotadalafil, has been detected as an adulterant in a DS marketed in Argentina for the treatment of ED.”
§ Detection of a Tadalafil Analogue as an Adulterant in a Dietary Supplement for Erectile Dysfunction > Conclusions
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The purification of DESA, performed by CC, led to the isolation of a pure compound (1) that was obtained as an amorphous yellowish powder (97.5 mg).”
§ Detection of a Tadalafil Analogue as an Adulterant in a Dietary Supplement for Erectile Dysfunction > Results
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
1 more claim
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- Probably not a substantial claim. 6
Citations
Cites
Aytaç, Mckinlay, & Krane (1999) · BJU International · doi:10.1046/j.1464-410x.1999.00142.x · Cited by 1,340
ORIGINAL ARTICLES: Definitions/Epidemiology/Risk Factors for Sexual Dysfunction
Lewis, R. W., Fugl-Meyer, K. S., Corona, G., Hayes, R. D., Laumann, E. O., Moreira, E. D., Rellini, A. H., & Segraves, T. (2010) · The Journal of Sexual Medicine · doi:10.1111/j.1743-6109.2010.01778.x · Cited by 858
Singh, S. P., PRASAD, B., Savaliya, A. A., Shah, R. P., Gohil, V. M., & KAUR, A. (2008) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2008.09.004 · Cited by 170
Venhuis, B. J., & de Kaste, D. (2012) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2012.02.014 · Cited by 164
Manallack, D. T., Hughes, R. A., & Thompson, P. E. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm040217u · Cited by 132
Structure elucidation of sildenafil analogues in herbal products
Blok‐Tip, L., Zomer, B., Bakker, F., Hartog, K. D., Hamzink, M., ten Hove, J., Vredenbregt, M. J., & de Kaste, D. (2004) · Food Additives & Contaminants · doi:10.1080/02652030412331272467 · Cited by 117
Campbell, N., Clark, J., Stecher, V. J., Thomas, J. W., Callanan, A. C., Donnelly, B. F., Goldstein, I., & Kaminetsky, J. C. (2013) · The Journal of Sexual Medicine · doi:10.1111/jsm.12172 · Cited by 83
Fleshner, N. E., Harvey, M., Adomat, H. H., Wood, C. A., Eberding, A., Hersey, K. M., & Guns, E. T. (2005) · The Journal of Urology · doi:10.1097/01.ju.0000165187.31941.cd · Cited by 71
Structural elucidation of a tadalafil analogue found as an adulterant of a herbal product
Zou, P., Hou, P., Low, M., & Koh, H. (2006) · Food Additives & Contaminants · doi:10.1080/02652030500479690 · Cited by 69
Development of a liquid chromatographic method for bioanalytical applications with sildenafil
Sheu, M., Wu, A., Yeh, G., Hsia, A., & Ho, H. (2003) · Journal of Chromatography B · doi:10.1016/s1570-0232(03)00223-x · Cited by 50
Cited by
Schisterman, E. F., Sjaarda, L. A., Clemons, T., Carrell, D. T., Perkins, N. J., Johnstone, E., Lamb, D., Chaney, K., Van Voorhis, B. J., Ryan, G., et al. (2020) · JAMA · doi:10.1001/jama.2019.18714 · Cited by 179
Avigan, M., Mozersky, R. P., & Seeff, L. B. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17030331 · Cited by 123
Skalicka‐Woźniak, K., Georgiev, M. I., & Orhan, İ. E. (2016) · Food and Chemical Toxicology · doi:10.1016/j.fct.2016.06.018 · Cited by 86
Common risks of adulterated and mislabeled herbal preparations
Ekar, T., & Kreft, S. (2018) · Food and Chemical Toxicology · doi:10.1016/j.fct.2018.10.043 · Cited by 82
Adulterants in selected dietary supplements and their detection methods
Muschietti, L., Redko, F. C., & Ulloa, J. L. (2020) · Drug Testing and Analysis · doi:10.1002/dta.2806 · Cited by 52
Self-citation
Metadata
- Authors
- Ulloa, J., Sambrotta, L., Redko, F., Mazza, O. N., Garrido, G., Becher, E. F., & Muschietti, L.
- Affiliations
- Cátedra de Farmacognosia , Buenos Aires , Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- Hospital de Clínicas "José de San Martín" (AR)
- Corresponding author
- Becher, Edgardo F.
- Venue
- The Journal of Sexual Medicine
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-01-01
- Volume
- 12
- Issue
- 1
- Pages
- 152-157
- ISSN
- 1743-6095 (ISSN-L)
- 1743-6109
- OpenAlex
- W1571624993
- Semantic Scholar
- 12286a7116e54306e0f60431e5cd16ed8f1ab84b
- Cited by
- 28
- References
- 15
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 4 · 2019: 5 · 2018: 2 · 2017: 2 · 2016: 5 · 2015: 2
- FWCI
- 3.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Journal of Sexual Medicine (publishedVersion)
- PubMed (publishedVersion)
- CONICET Digital (CONICET) (submittedVersion, cc-by-nc-sa)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pharmaceutical Quality and Counterfeiting
- Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
- Keywords
- supplement adulteration, phosphodiesterase-5 inhibitors, herbal supplements, consumer health risk
- MeSH terms
- Tadalafil, Argentina, Carbolines, Chromatography, High Pressure Liquid, Drug Contamination, Pharmaceutical Preparations, Humans, Erectile Dysfunction, Male, Dietary Supplements, Spectrometry, Mass, Electrospray Ionization, Plant Preparations, Benzodioxoles, Phosphodiesterase 5 Inhibitors
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