MedicalResearch.com Interview with:
MedicalResearch.com: What is the background for this study?
Response: This project’s origin can be traced back to preliminary results obtained by Dr. John Asplin at Litholink Corporation revealing an organic acid, hydroxycitrate (HCA), was a promising inhibitor of calcium oxalate monohydrate (COM) crystallization. COM is a principle component of human kidney stones. Interestingly, HCA is a molecular analogue of citrate (CA), the current therapy for stone disease. My research group at the University of Houston began collaborating with Dr. Asplin to explore the effects of HCA in more detail. We conducted in vitro assays using two techniques: bulk crystallization studies to quantify HCA efficacy and more detailed in situ atomic force microscopy (AFM) studies to assess the growth of COM crystal surfaces in real time.
MedicalResearch.com: What are the main findings?
Response: Collectively, we found that hydroxycitrate was a more potent inhibitor than CA, and that HCA exhibited different specificity for binding to particular surfaces of COM crystals. Our AFM studies also revealed that HCA is capable of dissolving the crystal in highly supersaturated solutions under constant flow of solution and within a specific range of HCA concentration.
With this knowledge in hand, we began to collaborate with Prof. Yanni Mpourmpakis’ research group at the University of Pittsburgh to perform atomistic modeling (density functional theory, DFT). Combined experimental observations and modeling allowed us to propose a mechanism for HCA’s mode of action that differs from classical theories of crystal growth inhibition. In brief, HCA binding to step sites on crystal surfaces induces a strain that is relieved by the release of solute (calcium and oxalate), leading to crystal dissolution under specific conditions.
The final aspect of our project focused on investigating the potential use of HCA as a therapy for stone disease. In order for HCA to be used as a therapy, it must be excreted in urine with oral delivery.
As it turns out, hydroxycitrate is a natural extract of the fruit garcinia cambogia. This allowed us to perform human trial studies wherein non-kidney-stone-forming subjects were given a recommended oral dose of garcinia cambogia supplement, and our assays revealed appreciable HCA excretion in the collected urine samples.
MedicalResearch.com: What should readers take away from your report?
Response: In this Nature article we report that hydroxycitrate shows promise as a potential therapy to prevent kidney stones. HCA may prove in future studies to be preferred as a therapy over potassium citrate; however, better understanding of HCA metabolism in humans, optimal dosing regimens, and long term safety and tolerability are needed before HCA could be studied in a prospective clinical trial of kidney stone prevention.
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Jihae Chung, Ignacio Granja, Michael G. Taylor, Giannis Mpourmpakis, John R. Asplin, Jeffrey D. Rimer. Molecular modifiers reveal a mechanism of pathological crystal growth inhibition. Nature, 2016; 1 DOI: 10.1038/nature19062
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