An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis
- Cho Ray Hospital, Viet Nam
- Oxford University Clinical Research Unit
- Hospital for Tropical Diseases, Viet Nam
- Liverpool School of Tropical Medicine, United Kingdom
- Liverpool University, United Kingdom
- University of Sydney, Australia
- Mahidol Oxford Tropical Medicine Research Unit, Thailand
- University of Iowa, United States
Abstract
Background: Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anti-cancer agent tamoxifen has synergistic anti-cryptococcal activity with amphotericin in vitro. It is off-patent, cheap, and widely available. We performed a trial to determine its therapeutic potential.
Methods:Open label randomized controlled trial. Participants received standard care - amphotericin combined with fluconazole for the first two weeks - or standard care plus tamoxifen 300mg/day. The primary end point was Early Fungicidal Activity (EFA) - the rate of yeast clearance from cerebrospinal fluid (CSF). Trial registration https://clinicaltrials.gov/ct2/show/NCT03112031 .
Results: 50 patients were enrolled, (median age 34 years, 35 male). Tamoxifen had no effect on EFA (- 0.48log10 colony-forming units/mL/CSF control arm versus -0.49 tamoxifen arm, difference - 0.005log10CFU/ml/day, 95%CI: -0.16, 0.15, P=0.95). Tamoxifen caused QTc prolongation.
Conclusion: High dose tamoxifen does not increase the clearance rate of Cryptococcus from CSF. Novel, affordable therapies are needed.
Funding:The trial was funded through the Wellcome Trust Asia Programme Vietnam Core Grant 106680 and a Wellcome Trust Intermediate Fellowship to JND grant number WT097147MA.
Data availability
The clinical trial has been conducted in Vietnam under the Ministry of Health and local Ethical Committee approvals. Requests to share the clinical data underlying the trial have to be acknowledged by the local Ethical Committee (and therefore we cannot hand over the data repository or management to an external party). The original de-identified clinical data underlying the study are available by emailing the OUCRU Data Access Committee at DAC@oucru.org or ekestelyn@oucru.org (Head of the Clinical Trials Unit and Data Access Committee Chair). The review procedures (the data sharing policy and the data request form) are available on the OUCRU website at http://www.oucru.org/data-sharing/The code for the study analysis is freely available at https://doi.org/10.5287/bodleian:XmeOzdR8z
Article and author information
Author details
Funding
Wellcome Trust (Wellcome Trust Asia Programme Vietnam Core Grant 106680)
- Guy E Thwaites
Wellcome Trust (WT097147MA)
- Jeremy N Day
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The study protocol was approved by the Ethical Review Committees of the Hospital for Tropical Diseases, Cho Ray Hospital, and the Vietnamese Ministry of Health, and by the Oxford University Tropical Research Ethics Committee. A trial steering committee with 2 independent members oversaw the running of the trial, and an independent data and safety monitoring committee oversaw trial safety. The first safety analysis was performed after the first 20 patients had reached the primary endpoint. The funding bodies and drug manufacturers played no role in the study design, implementation, analysis, or manuscript preparation. All the authors made the decision to submit the manuscript for publication and vouch for the accuracy and completeness of the data and analyses presented. The trial was registered at https://clinicaltrials.gov/ct2/show/NCT03112031.
Copyright
© 2021, Ngan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis
eLife 10:e68929.
https://doi.org/10.7554/eLife.68929
Further reading
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- Medicine
Background:
Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is a severe and deadly adverse event following ERCP. The ideal method for predicting PEP risk before ERCP has yet to be identified. We aimed to establish a simple PEP risk score model (SuPER model: Support for PEP Reduction) that can be applied before ERCP.
Methods:
This multicenter study enrolled 2074 patients who underwent ERCP. Among them, 1037 patients each were randomly assigned to the development and validation cohorts. In the development cohort, the risk score model for predicting PEP was established via logistic regression analysis. In the validation cohort, the performance of the model was assessed.
Results:
In the development cohort, five PEP risk factors that could be identified before ERCP were extracted and assigned weights according to their respective regression coefficients: –2 points for pancreatic calcification, 1 point for female sex, and 2 points for intraductal papillary mucinous neoplasm, a native papilla of Vater, or the pancreatic duct procedures (treated as ‘planned pancreatic duct procedures’ for calculating the score before ERCP). The PEP occurrence rate was 0% among low-risk patients (≤0 points), 5.5% among moderate-risk patients (1–3 points), and 20.2% among high-risk patients (4–7 points). In the validation cohort, the C statistic of the risk score model was 0.71 (95% CI 0.64–0.78), which was considered acceptable. The PEP risk classification (low, moderate, and high) was a significant predictive factor for PEP that was independent of intraprocedural PEP risk factors (precut sphincterotomy and inadvertent pancreatic duct cannulation) (OR 4.2, 95% CI 2.8–6.3; p<0.01).
Conclusions:
The PEP risk score allows an estimation of the risk of PEP prior to ERCP, regardless of whether the patient has undergone pancreatic duct procedures. This simple risk model, consisting of only five items, may aid in predicting and explaining the risk of PEP before ERCP and in preventing PEP by allowing selection of the appropriate expert endoscopist and useful PEP prophylaxes.
Funding:
No external funding was received for this work.
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- Medicine
Estrogen significantly impacts women’s health, and postmenopausal hypertension is a common issue characterized by blood pressure fluctuations. Current control strategies for this condition are limited in efficacy, necessitating further research into the underlying mechanisms. Although metabolomics has been applied to study various diseases, its use in understanding postmenopausal hypertension is scarce. Therefore, an ovariectomized rat model was used to simulate postmenopausal conditions. Estrogen levels, blood pressure, and aortic tissue metabolomics were analyzed. Animal models were divided into Sham, OVX, and OVX +E groups. Serum estrogen levels, blood pressure measurements, and aortic tissue metabolomics analyses were performed using radioimmunoassay, UHPLC-Q-TOF, and bioinformatics techniques. Based on the above research content, we successfully established a correlation between low estrogen levels and postmenopausal hypertension in rats. Notable differences in blood pressure parameters and aortic tissue metabolites were observed across the experimental groups. Specifically, metabolites that were differentially expressed, particularly L-alpha-aminobutyric acid (L-AABA), showed potential as a biomarker for postmenopausal hypertension, potentially exerting a protective function through macrophage activation and vascular remodeling. Enrichment analysis revealed alterations in sugar metabolism pathways, such as the Warburg effect and glycolysis, indicating their involvement in postmenopausal hypertension. Overall, this current research provides insights into the metabolic changes associated with postmenopausal hypertension, highlighting the role of L-AABA and sugar metabolism reprogramming in aortic tissue. The findings suggest a potential link between low estrogen levels, macrophage function, and vascular remodeling in the pathogenesis of postmenopausal hypertension. Further investigations are needed to validate these findings and explore their clinical implications for postmenopausal women.
