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We are writing to express my interest in your recent article titled "Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant Candida auris[1]." The study is of great importance, particularly in addressing the challenge of antifungal resistance, which has significant implications for public health. However, after carefully reviewing the article, we have some concerns regarding the potential toxicity of the high dose of lansoprazole used in your study. We would like to share my thoughts and propose some suggestions for further improving the article.
In your study, lansoprazole was administered at concentrations ranging from 16 μM to 300 mg/kg, which is significantly higher than the typical therapeutic dose range. While this approach demonstrated promising results in enhancing the antifungal activity of amphotericin B, it also raises concerns about potential toxicity, which could confound the interpretation of the results.
Based on the FDA Adverse Event Reporting System (FAERS) database, we conducted a disproportionality analysis to identify adverse events that occur more frequently with Lansoprazole compared to other placebos. This involved calculating reporting odds ratios, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker to determine if any adverse events are significantly associated with Lansoprazole. As a result, lansoprazole has been associated with various adverse effects, including kidney disease, excessive stomach acid production, diarrhea, diabetes, hypertension, liver and gallbladder diseases, reproductive system disorders, and immune system disorders (Table1). The high dose of lansoprazole used in your study may lead to increased toxicity, potentially affecting the health of the animal models and influencing the outcome of the experiments. To address these concerns, we would like to suggest several measures to improve the study's rigor and enhance the reliability of the results:
Incorporating a control group: Consider adding a control group with a lower dose of lansoprazole or a placebo to compare the toxicity and efficacy of different lansoprazole concentrations. This would help to ensure that the observed effects are not solely due to lansoprazole's toxicity.
Monitoring toxicity indicators: During the experiment, it would be beneficial to monitor toxicity indicators, such as renal and liver function, reproductive system function, and immune system parameters. This would provide insights into the potential toxic effects of lansoprazole at different doses. Utilize statistical methods to analyze the differences in toxicity between different lansoprazole dose groups. This would enable a quantitative assessment of the relationship between lansoprazole dose and toxicity.
Performing pathological examinations: Post-experiment pathological examinations of the animal models' organs could reveal any pathological changes caused by lansoprazole. This would help to assess the potential organ-specific toxicity of lansoprazole.
Cellular assays to evaluate the cytotoxic effects of lansoprazole at various concentrations, which will help in understanding its impact on cellular health and viability.
As to other aspects, firstly, the study does not provide sufficient evidence to confirm that the inhibition of mitochondrial complex III by lansoprazole is the sole or primary mechanism of its antifungal activity. It would be beneficial to investigate and rule out other potential mechanisms that may contribute to its efficacy[2]. Additionally, the study lacks investigation into the long-term effects of lansoprazole on amphotericin B resistance. Assessing the durability of the synergistic effect over an extended period would provide valuable insights into its clinical potential[3]. Furthermore, the exact mechanisms by which lansoprazole enhances the activity of amphotericin B are not fully explained. Exploring and elucidating these mechanisms would strengthen the scientific foundation of the study[4]. Moreover, the potential drug-drug interactions between lansoprazole and amphotericin B have not been studied. Investigating possible interactions is essential for understanding the safety and efficacy of their combined use. The pharmacokinetic properties of lansoprazole, including its metabolism in the human body, have not been thoroughly examined. Further investigations are required to develop a detailed treatment plan and assess the long-term antifungal efficacy of the combination therapy.
Table 1. Signal detection for lansoprazole -associated adverse events.
In conclusion, while your study has made significant contributions to the field of antifungal resistance, it is essential to address the potential toxicity of the high dose of lansoprazole used. By incorporating the suggested measures, you could enhance the rigor of your study and provide more reliable data to support the clinical translation of lansoprazole as an adjuvant to amphotericin B.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
Supported by Sanming Project of Medicine in Shenzhen Municipality (SZZYSM202311011).
Supported by the key project of Zhejiang Provincial Natural Science Foundation (LZ22H270001).
References
- 1. Salama EA, Elgammal Y, Wijeratne A, Lanman NA, Utturkar SM, Farhangian A, Li J, Meunier B, Hazbun TR, Seleem MN. Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant Candida auris. Emerg Microbes Infect. 2024;13(1):2322649. doi:10.1080/22221751.2024.2322649
- 2. Gao L, Xia X, Gong X, Zhang H, Sun Y. In vitro interactions of proton pump inhibitors and azoles against pathogenic fungi. Front Cell Infect Microbiol. 2024;14:1296151. doi:10.3389/fcimb.2024.1296151
- 3. Yi M, Niu M, Zhang J, Li S, Zhu S, Yan Y, Li N, Zhou P, Chu Q, Wu K. Combine and conquer: manganese synergizing anti-TGF-β/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers. J Hematol Oncol. 2021;14(1):146. doi:10.1186/s13045-021-01155-6
- 4. Dong Y, Zan J, Lin H. Bioleaching of heavy metals from metal tailings utilizing bacteria and fungi: Mechanisms, strengthen measures, and development prospect. J Environ Manage. 2023;344:118511. doi:10.1016/j.jenvman.2023.118511