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
Cysteamine bitartrate capsules (Cystagon) have been approved by the US Food and Drug Administration for use in patients with nephropathic cystinosis. Plasma cysteamine concentrations were virtually identical at various times following ingestion of either cysteamine hydrochloride or Cystagon capsules in 24 normal control subjects. A transfer study was done with eight cystinosis patients who had been receiving either cysteamine hydrochloride or phosphocysteamine for many years. The plasma cysteamine concentration was significantly higher 2h after Cystagon and the leukocyte cystine content was significantly lower at all times after Cystagon compared to older forms of the drug. These differences are probably the result of greater patient compliance in taking the capsules compared to the older, liquid forms of the drug. A new method for following the course of renal glomerular deterioration in diseases such as cystinosis has been published recently. This method was used to re-analyse data on the efficacy of cysteamine treatment and to re-analyse new data on treating cystinosis patients with either of two doses of cysteamine (1.30 g/m2 per day and 1.95 g/m2 per day). This new method agrees well with other methods and shows that both doses of drug are equally effective in maintaining glomerular function.
The cblE disorder is characterized by megaloblastic anemia of infancy associated with hmystinuria but no methylmalonic aciduria (N Eng J Med 310:688, 1984).Untreated, this disorder results in developnental delay. In cultured fibroblasts from the original proband, there was decreased synthesis of methyl-B12 and decreased methionine biosynthesis. Activity of the methyl-B12-dependent enzyme methionine synthase in cell extracts was decreased only when assayed in the presence of suboptimal reducing conditions (J Clin Invest 74:2149, 1984. We have studied cultured fibroblasts fran several additional patients with similar clinical findings. Methyl-Blq synthesis and methionine hiosynthesis were decreased. Methionine synthase activity in fibroblast extracts was decreased even under optimal reducing conditions. Canplementation studies were carried out using polyethylene glycol-induced fusion of cells fran these various patients. consecutive steps in the interconversion of tetrahydrofolate derivatives; tetrahydrofolates are the one-carbon units required for the synthesis of thymj.dylate, purines and methionine. We have recently described the isolation of a human liver cDNA of 250 bp, coding for this protein, from a Xgtll expression llbrary (Amer. J . Hum. Genet. 39: A204, 1986).In this communication, we report the chromosomal mapping of the gene in somatic cell hybrids. Southern blot analysis of BamHI-digested DNA reveals 2 prominent bands in humans ( -19 and 14 kb) and one major band in Chinese hamsters (-5 kb). In Chinese hamster X human hybrids, the 19 kb band is localized to human chromosome 14 (q21-qter) and the 14 kb band, to the X chromosome. The assignment of the gene to separate loci suggests the presence of 2 homologous genes, or, more likely, the existence of a pseudogene. Ongoing studies with longer cDNA probes will enable us to determine the exact number of homologous genes in this family. HE'IEROZYCME DE'IECTION IN CYSTINXIS USINC, EVLmR-l 724 Clark and Jerry A. Schneider, University ot California, San Diego, Department of Pediatrics, la Jolla. California.Heterozygotes for the autosomal recessive disease cystinosis are currently detected by measuring the cystine content of mixed leukocyte preparations. 'Ihis method offers about 90% accuracy. 'Ihe following sbidy was designed to determine if measuring the cystine content of purified preparations of polymrpkmuclear leukocytes ( m s ) would irprove the accuracy of heterozygote detection. Subjects included 29 obligate heterozygotes for nephropathic cystinosis and 18 individuals p r e s d to be normal. Mixed leukozytes were prepared from 10 m l of blood by dextran sedimentation; m s were prepared by centrifugation of 4.5 m l of blood on a discontinuous gradient of Ficoll-Hypaque. The cystine content of both leukocyte preparations was determined by a specific binding assay. All values are expressed as m l 112 cysfmg protein and are shown in the table below. Using mixed leukocyte preparations, 3 heterozygotes overlapped the normal range reconfirming a detection accu...
Cystine exodus from partially purified granular fractions of normal leucocytes is stimulated by MgATP. N-Ethylmaleimide, an inhibitor of the lysosomal H+-translocating ATPase, eliminated the stimulated exodus, but had no effect on basal exodus. As the initial content of cystine was increased, the initial velocity of both the basal and ATP-stimulated egress increased. However, as saturation with substrate was approached, the ATP stimulation disappeared leaving only the N-ethylmaleimide-insensitive basal exodus. The increased initial velocity in the presence of ATP may represent improved binding of cystine to the partially saturated inner transporter as a result of conformational or charge optimization brought about by the action of the H+-translocating ATPase.
M ,R e n n e r t .Univ. O k l a . , D e p t . P e d i a t r . , O k l a . C i t y .T h e X -l i n k e d mouse m u t a n t b r i n d l e d is a m o d e l f o r Menkes s y n d r o m e . I n y o u n g h e m i z y g o t e s , r e d u c e d l i v e r a n d b r a i n c o p p e r c o n c e n t r a - t i o n s are a s s o c i a t e d w i t h n e u r o l o g i c d y s f u n c t i o n .I n f e t u s e s c o p p e r c o n c e n t r a t i o n s i n p l a c e n t a a n d k i d n e y a r e h i g h e r i n b r i n d l e d t h a n c o n t r o l s w h i l e t h o s e i n l i v e r a n d c a r c a s s are lower.To t r e a t t h e c o p p e r d e f i c i e n c y i n b r i n d l e d y o u n g , h e t e r o z y g o t e s w e r e i n j e c t e d a t 1 6 o r 1 8 d a y s g e s t a t i o n w i t h c o p p e r , 6 m c g / g / d o s e , a s c u p r i c c h l o r i d e , 1 8 a n d 6 h o u r s b e f o r e s a c r i f i c e .P l a c e n t a l , c a r c a s s , a n d h e p a t i c c o p p e r c o n c e n t r a t i o n s i n b r i n d l e d f e t u s e s i n c r e a s e d ( p > 0 . 0 0 6 ) .I n j e c t i o n o f m e t h y l p r e d n i s o l o n e , 5 mcg/g, 2 0 h o u r s b e f o r e t h e c o p p e r , t o i n c r e a s e f e t a l h e p a t l c copper s t o r a g e t h r o u g h m e t a l l o t h i o n e i n i n d u c t i o n , r e s u l t e d o n l y i n f u r t h e r i n c r e a s e i n t h e c a r c a s s c o p p e r c o n c e n t r a t i o n s .T h e s e d a t a s u g g e s t : p l a c e n t a l c o p p e r t r a n s p o r t i n b r i n d l e d f e t u s e s i s i m p a i r e d ; h e p a t i c c o p p e r b i n d i n g c a p a c i t y o f c o n t r o l a n d b r i n d l e d f e t u s e s is l i m i t e d a n d c a n n o t b e a u g m e n t e d b y p r e t r e a t m e n t w i t h m e t h y l p r e d n i s o l o n e ; e x t r a -h e p a t i c W e have been using chromosome heteromorphisms and r e s t r i ct i o n fragment length polymorphisms (RFLPs) t o i n v e s t i g a t e t h e mechanism of o r i g i n of trisorny 13, and t h e possible association between e r r o r s of recombination and t h e non-disjunctional event leading t o trisomy. To date, we have studied 33 liveborn o r spontaneously aborted trisomy 13 conceptions. By combining analysis of chromosome heteromorphisms with analysis'of seven probes detecting chromosome 1 3 RFLPs, we have been able t o determine t h e parental o r i g i n of 23 cases, with 20 being maternal and 3 paternal i n o r i g i n .I n eight cases i n which we have both cytogenetic and molecular information, we can make inferences regarding recombination i n t h e two non-disjoined chromosomes. We have evidence f o r recombination i n two of t h r e e cases i n which the e x t r a 13 originated i n maternal meiosis I and i n both instances t h i s observation i s based on r e s u l t s from s e v e r a l probes. This suggests t h a t absence of recombination due t o p a i r i n g f a i l u r e is unlikely t o be an important mechanism i n t h e genesis of human trisomy. Furthermore, analysis of recombinatio...
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