Administration Of Cystamine Research Articles

Cistinosis nefropática infantil

Nephropathy caused by cystinosis is a rare recessive disorder produced by a defect in the lysosomal transport of cysteine. This results in intracellular crystal deposits in the kidneys, cornea and other tissues. It constitutes the commonest congenital cause of Fanconi's syndrome and progresses during the first decade of life to chronic renal failure. The diagnosis is confirmed by the detection of cystine in circulating leucocytes and lymphoblasts. The treatment consists in replacing the losses caused by the tubular defect and the oral administration of cystamine which depletes cystine and favours its transport across the lysosomal membrane. The objective of this report is to present the first case of cystinosis diagnosed and treated in Chile. The patient was hospitalized at the age of 15 months with advanced disnutrition, clinical rickets, severe dehydration, hypokalaemia, hypophosphataemia, metabolic acidosis consistent with Fanconi's syndrome. An elevated concentration of cystine was found in the polymorphic leucocytes confirming the diagnosis. After 2 years of treatment with oral cystamine the patient demonstrates an excellent evolution with regards to stature and conservation of renal function, although the tubular defect persists.

Properties of phosphatidate phosphohydrolase in rat adipose tissue

Previously we have identified the presence of two different phosphatidate phosphohydrolase (PPH) activities in rat adipose tissue, based on Mg(2+)-dependency. In the present investigation, we have further characterized these isoenzymes, using both aqueous dispersed and membrane-bound phosphatidate as substrates and differentiated these activities on the basis of both Mg(2+)-dependency and N-ethylmaleimide (NEM)-sensitivity. These two distinguishing criteria gave identical estimates of PPH activities present in the different subcellular fractions. The microsomal and cytosol fractions contained mainly the Mg(2+)-dependent (NEM-sensitive) form, which was inhibited by various thiol reagents, was inactivated by heating at 55 degrees C for 20 min, and was decreased significantly within 2 h after intraperitoneal administration of cystamine (200 mg/kg). Such treatments had no effects on the Mg(2+)-independent (NEM-insensitive) form of PPH, which was mainly located in the plasma membranes, mitochondrial and microsomal fractions. Addition of Lipid A and guanosine 5'-[gamma-thio]triphosphate to the assay mixture had no effect on the PPH activities. The Mg(2+)-independent PPH form, which was thermostable in the intact subcellular fractions, became thermolabile when these fractions were disrupted in the presence of Triton X-100. The present studies demonstrate that: (1) the thermostability is not a satisfactory index to differentiate these isoenzymes; (2) the thiol/disulphide exchange may be involved in the regulation of Mg(2+)-dependent PPH activity; and (3) the PPH isoenzymes do not seem to be under G-protein control in adipose tissue, as reported previously in the mesangial cell line.

GROWTH RETARDATION AND URINARY LOSS OF GROWTH HORMONE IN CYSTINOSIS

Cystinosis is characterized by intracellular accumulation of cystine, which causes nephropathy and severe growth retardation. We report on two prepubertal patients, adequately treated with oral administration of cystamine. We performed a 24 hour growth hormone (GH) profile and measured serum IGF-1 and urinary GH. One patient (#1) was subsequently placed on GH therapy (2 IU/m2/day).We found very high levels of urinary GH and low values of IGF-1. The 24h GH profiles showed a normal number of peaks and values of mean concentration and AUCb which were low compared to those of normal prepubertal children. We suggest that the growth retardation seen in cystinosis could be partly due to the excessive loss of GH in the urinary, amounting to nearly 15% of the daily production and urinary filtration of GH. This loss may contribute to the low AUCb of the GH profiles. Treatment with GH increases growth velocity but the effect on final height is yet to be determined.

Induction of SOS functions in Escherichia coli and biosynthesis of nitrosamine in rabbits by nitrogen dioxide.

Nitrogen dioxide induced SOS functions in Salmonella typhimurium and Escherichia coli K-12 and was mutagenic in Escherichia coli WP2. When a rabbit was administered aminopyrine intravenously and administered nitrogen dioxide by inhalation, N-nitrosodimethylamine was detected in its blood. Analysis was conducted with 15N-nitrosodimethylamine as an internal standard by a combination of capillary gas chromatography and mass spectrometry. Accompanying administration of cystamine increased the blood concentration of N-nitrosodimethylamine in the rabbit, suggesting inhibition of its metabolism. Concurrent sulfur trioxide inhalation increased N-nitrosodimethylamine formation in the rabbit.

Amelioration of carbon tetrachloride-induced hepatic necrosis by post-toxicant treatment with cystamine

A quantitative animal model was developed to study amelioration of carbon tetrachloride-induced hepatic injury by post-toxicant administration of cystamine. Amelioration of CCl 4-induced injury by post-toxicant cystamine treatment was compared to prevention of injury by cystamine pretreatment and possible mechanisms of the post-toxicant cytoprotective effect were investigated. Pretreatment of rats with cystamine dihydrochloride (300 mg/kg, p.o.) 30 min prior to CCl 4 (0.25 ml/kg, i.p.) prevented CCl 4-induced hepatic necrosis, plasma enzyme elevations, and hepatic calcium accumulation. When administered up to 12 h after CCl 4, a single oral dose of cystamine inhibited necrosis in a dose-dependent manner, but did not reduce CCl 4-induced plasma enzyme elevation or hepatic calcium accumulation. Cystamine post-treatment, therefore, does not appear to inhibit toxicant-induced influx of extracellular calcium into toxicant-damaged cells. This also suggests that the influx of extracellular calcium does not necessarily constitute an irreversible event leading to cell death. The mild hypothermia induced by post-toxicant treatment with cystamine did not delay the apperance of the lesion. Evidence for a slightly earlier regeneration of hepatic tissue was noted when cystamine was administered 12 h after CCl 4. However, this effect was observed too long after exposure to the toxicant to account for the protection from necrosis observed 24 h after CCl 4.

The Early Effect of Sublethal X-irradiation of Phagocytic Cells in Mouse Blood and the Influence of Cystamine as Measured by Chemiluminescence

The metabolic burst accompanying phagocytosis of granulocytes (PMN) leads to the generation of activated oxygen species such as O-2, H2O2, 1O2 and OH; which give rise to chemiluminescence (CL) in the presence of luminol. Reliable CL-measurements of stimulated PMN can be carried out in freshly drawn mouse blood, when photon counts are related to the number of PMN. Effects of low dose total body X-irradiation were studied using C57B1/6 mice. It was found that 24 and 48 hours after irradiation (0.24-0.95 Gy) CL of whole blood was slightly decreased. If however CL-counts were related to the number of PMN, an enhanced CL per single granulocyte was recorded. The administration of cystamine leads to an immune stimulating effect of unirradiated animals. In animals, who received 0.95 Gy a distinct radioprotective effect of cystamine can be observed.

The Effect of γ Irradiation and Cystamine on Superoxide Dismutase Activity in the Bone Marrow and Erythrocytes of Rats

The effect of a single dose of cystamine (50 mg/kg body wt; ip) on superoxide dismutase activity (E.C. 1.15.1.1; SOD) was studied in the cytosol fraction of bone marrow cells and erythrocytes of peripheral blood. The experiments were carried out on irradiated (8.0 Gy /sup 60/Co) and nonirradiated male Wistar rats. Whole-body irradiation caused a decrease in the specific activity of superoxide dismutase in the bone marrow which persisted for more than 14 days, whereas an increased activity occurred in erythrocytes at the same intervals. Cystamine administration to rats prior to irradiation led to decreased SOD activity in the bone marrow that was less pronounced than in the nonprotected, irradiated animals. In erythrocytes, treatment with cystamine prior to irradiation considerably increased SOD activity (especially on Day 14); this increase was much more pronounced than that after either cystamine administration or irradiation. The administration of cystamine to nonirradiated animals led to a decrease in SOD activity in the bone marrow on the third day only; however, in erythrocytes the activity increased (mostly on Day 14). Irradiation of the bone marrow was reflected in a substantial decrease of its cellularity that was, to a certain extent, normalized after cystamine treatment. The SODmore » activity per bone marrow cell (expressed in U/10/sup 6/ cells) was increased in the protected rats on the third day after irradiation, but this increase was not as pronounced as in nonprotected, irradiated rats.« less

Radioprotection of lipogenesis from glucose (U-14C) and activities of pyridine nucleotide dehydrogenases in liver of gamma-irradiated female rats by cystamine.

Whole-body gamma-irradiation (1200 R) of female rats significantly increased liver glycogen and incorporation of glucose (U-14C) into liver fatty acids. Administration of cystamine before irradiation protected the enhanced lipogenesis from glucose (U-14C), but afforded only a partial protection of liver glycogen levels. Irradiation significantly decreased the activities of liver pyruvate kinase and isocitrate dehydrogenase, and this decrease was not prevented by the administration of cystamine before irradiation. A significant increase in the activity of liver malate dehydrogenase (dehydrogenating) was noted in irradiated rats, which was not prevented by the administration of cystamine before irradiation. Irradiation did not affect the activities of combined hexose monophosphate pathway dehydrogenases and of malate dehydrogenase (decarboxylating).

Prevention by cystamine of liver necrosis and early biochemical alterations induced by carbon tetrachloride

The effect of the previous administration of cystamine on the hepatotoxicity of orally and intraperitoneally administered carbon tetrachloride (CCl 4) was investigated. Cystamine significantly prevented the necrosis and fatty infiltration, as well as the depression of glucose 6-phosphatase and ethylmorphine N-demethylase activities caused by oral CCl 4 administration. These results are due to a delay in the gastrointestinal absorption of CCl 4 caused by cystamine. However, cystamine also prevented necrosis and fatty infiltration when CCl 4 was given intraperitoneally. Moreover, it also significantly blocked the irreversible binding of 14C from 14CCl 4 to liver microsomal lipids and the depression of glucose 6-phosphatase in spite of the fact that the microsomal lipid peroxidation process was not inhibited and that CCl 4 levels in the livers of cystamine-treated and untreated rats were similar. The destruction of ethylmorphine N-demethylase could not be prevented by cystamine when CCl 4 was given intraperitoneally. The results are discussed in relation to the postulated mechanistical similarity between CCl 4 liver injury and damage from ionizing radiation.

The Effect of the Interval between Intraperitoneal Administration of Cystamine and Exposure on the Dose-Reduction Factor for Hematopoietic Stem Cells

The effect of radioprotective substances on hematopoiesis has been described in a number of papers (1-6). It is necessary to study the protective effect of these agents not only on hematopoiesis as a whole, but, above all, on the radiosensitivity of the individual cell types. We considered it useful to investigate the effect of radioprotective substances on stem cells for two reasons. Firstly, stem cells form the progenitor compartment for the mature elements of the blood. Secondly, we can determine quantitatively the reproductive capacity of stem cells after irradiation by using the spleen colony method of Till and McCulloch (7). We have already demonstrated that by a comparison of the number of colonies of hematopoietic tissue in the spleens of control and experimental mice (protected by cystamine) it is possible to derive a dose-reduction factor (DRF) for a given protective agent for the hematopoietic stem cells (8). We now wish to report that the observed DRFs are dependent on the interval between the injection of the protective agent and irradiation.

The effect of cystamine on oxidative phosphorylation in the spleen of irradiated albino rats

In this work, performed on albino rats, the author demonstrated that x-irradiation in a dose of 600 r.leads to the change of the oxidative phosphorylation level in the spleen. In these conditions there occurs a drop of the phosphorylation level and its dissociation from the tissue respiration. Administration of cystamine (in prophylactic effective doses) to the animals prior to the irradiation with ionizing radiation decreases the changes of the oxidative phosphorylation in the spleen, without eliminating them completely.

PLASMA CATECHOL AMINE LEVELS AND ADRENAL ASCORBIC ACID CONTENT FOLLOWINGβ-MERCAPTOETHYLAMINE (MEA) ADMINISTRATION

The effect of β-mercaptoethylamine (MEA) on the peripheral plasma catechol amine level and the adrenal ascorbic acid content of rats was studied. Peripheral plasma catechol amine concentrations were determined at 10, 30 and 60 minutes following intraperitoneal injections of 125 mg./kg. of MEA. An increase of plasma epinephrine concentration occurred 10 minutes after the administration of MEA and this elevation persisted throughout the one hour observation period. Similar results were obtained after the administration of cystamine, the dimer form of MEA. The I.P. administration of 125 mg./kg. of MEA to intact rats caused a significant decrease in adrenal ascorbic acid content at the end of one hour as compared to saline control rats. However, MEA did not have any effect on the concentration of adrenal ascorbic acid of hypophysectomized rats. These results indicate that the decrease of adrenal ascorbic acid of intact rats following MEA treatment is not due to a direct action of the chemical on the adrenal g...