The Science of Crystallization: Macroscopic Phenomena and Defect Generation

Abstract

ligible role for these substances in the regulation of cystine stone formation. Collectively, the AFM and bulk crystalliza-tion behavior for L-cystine suggest that L-CDME is a viable therapeutic agent for the prevention of L-cystine kidney stones. This approach to stone prevention uses a potentially benign crystal growth inhibitor at low concentrations rather than drugs that rely on a chemical reaction with L-cystine (L-cystine-binding thiol drugs), increases in urine alkalinity (which are often accompanied by undesirable side effects), or dramatic increases in urine volume (which can be unreliable owing to patient nonadherance). The reduction in mass yield in the presence of inhibitors is a kinetic effect that maintains a metastable supersaturated L-cystine concentration, but from a pathological perspective this is a sufficient condition for preventing stone formation. L-cystine stone formers typically have urinary L-cystine concentrations ranging from 250 to 1000 mg/liter (equivalent to 1 to 4 mM), which is comparable with the concentrations we used for the AFM and bulk crystallization studies. Therefore, L-CDME concentrations near 2 mg/liter (<0.01 mM), at which inhibition of L-cystine growth was highly effective , may be adequate for therapeutic effect. Cell culture data, acquired for the purpose of evaluating cystine exodus from lysosomes, show loss of cell viability at approximately 1 mM L-CDME, and studies in rats, performed to measure oxi-dative stress in the brain cortex, demonstrated adverse effects at dosages of approximately 500 mg/kg (mass of rat) per day (33-35). Although the pharmacokinetics of L-CDME are not well known, on the basis of typical daily urine volumes a L-CDME dose of 10 to 50 mg per day-far below toxic levels but greater than the amount needed for crystal growth inhibition in vitro-may prove sufficient to achieve adequate L-CDME concentrations in urine for crystal growth inhibition in vivo.