A Comparison of the Effectiveness of Cysteamine and Phosphocysteamine in Elevating Plasma Cysteamine Concentration and Decreasing Leukocyte Free Cystine in Nephropathic Cystinosis

Abstract

ABSTRACT. Cysteamine (B-mercaptoethylamine, MEA) is currently used to treat children with nephropathic cystinosis. In this study MEA was compared to phosphocysteamine (MEAP), a phosphorothioester that tastes and smells better than MEA, with respect to its ability to elevate plasma MEA and deplete leukocytes of cystine. Studies were performed in six children with nephropathic cystinosis ranging in age from 2 to 10 yr. After equimolar oral doses of either MEA or MEAP plasma cysteamine was determined at various times for 6 h. MEA was determined by sodium borohydride reduction followed by highperformance liquid chromatography separation and el&-trochemical detection. Leukocyte cystine was measured before and 1 and 6 h after drug administration. Peak plasma MEA was obtained 30 min to 1 h after a dose and was not significantly different when MEA (48.6 f 10.7, mean + SD) or MEAP (54.1 f 20.2) was given. Significant plasma MEA concentrations were seen as early as 15 min after an oral dose, indicating rapid absorption. Analysis of vomitus indicated that hydrolysis of the phosphate group of MEAP occurs in the stomach. The percent decrease in leukocyte cystine content obtained with MEA administration (61.9%) was not significantly different from the decrease observed when MEAP was administered (65.3%). MEA and MEAP appear to be equally effective in their cystine-depleting properties. (Pediatr Res 23: 616-620, 1988) Abbreviations MEA, cysteamine MEAP, phosphocysteamine MEA (P-mercaptoethylamine) has been used since 1979 as a part of a national collaborative study to treat children with

Strict cysteamine dose regimen is required to prevent nocturnal cystine accumulation in cystinosis

“…Despite the evident pharmacokinetic data [10,11], many patients and even many physicians do not realize that 2-3 h extra night pause may cause a significant cystine accumulation. Our study demonstrates that the administration of the same daily cysteamine dose distributed equally during 24 h results in significantly lower morning PMN cystine content, compared to the "only wake-time" regimen, applied by the majority of the patients.…”

“…Because intracellular leukocytes' cystine content decreases to the minimal levels about 2 h after cysteamine ingestion and than returns to pre-dose levels 6 h after the drug intake, the adequate cysteamine dose regimen implies the administration of the drug every 6 h [10,11]. This dose regimen, however, is extremely difficult to follow, especially at night.…”

Cysteamine enhances the procoagulant activity of Factor VIII-East Hartford, a dysfunctional protein due to a light chain thrombin cleavage site mutation (arginine-1689 to cysteine).

“…This is above the peak plasma cysteamine concentrations (48.6±10. 7 [SD] ,tM) obtained in the treatment ofcystinosis (27). However, in patients with frequent recurrent hemarthroses, e.g., ARC-10 and the patient reported by O'Brien and Tuddenham (28) and Gitschier et al (29), even a very small VIII:C increase might have a significant clinical benefit, and clinical trials will be necessary to evaluate the potential role of cysteamine in the management of FVIII-EH patients.…”

Intravenous Cysteamine Therapy for Nephropathic Cystinosis

“…For example, we noted a 62% leukocyte cystine depletion 90 min after an i.v. cysteamine dose of 10 mglkg; Smolin et al (18) found 62% depletion 1 h after a dose of 18 mglkg. With our patient serving as his own control, leukocyte cystine concentrations at their nadir (approximately 6 h after a dose) were virtually identical whether the dose was received i.v.…”

“…The therapy of nephropathic cystinosis, besides replacement of renal losses, involves treatment with the cystine-depleting agent, cysteamine (16), or its more palatable bioequivalent, phosphocysteamine (17,18). Cysteamine, given orally every 6 h at a dosage of 1.3-1.95 g/m2/day (60-90 mg of free base/ kglday), has proven remarkably efficacious in preventing renal glomerular deterioration (19), permitting improvement of renal function in children under age 3 (20), and enhancing somatic growth in preadolescent cystinosis patients (19,20).…”