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PubMed1988

Effect of local injection of cysteamine and cystamine on somatostatin and neuropeptide Y levels in the rat striatum.

Cysteamine and its dimeric form cystamine have been applied to the rat striatum by local injection. Both compounds resulted in a dose-dependent decrease of somatostatin levels. Maximal reduction of somatostatin (by about 50%) was obtained at a dose of 50 micrograms of cysteamine or cystamine after about 6 h. All three molecular weight forms of somatostatin--somatostatin-14, somatostatin-28, and the 13,000 molecular weight form of somatostatin--were reduced, as shown by size exclusion HPLC. Injection of radiolabeled cystamine revealed a fast conversion of the compound to cysteamine, suggesting it is active in the monomeric form. The levels of neuropeptide Y, which is colocalized with somatostatin in striatal neurons, failed to be changed by local or intraperitoneal injection of cysteamine, suggesting that this treatment does not affect vesicles of somatostatin/neuropeptide Y neurons.

Animals↗
PubMed1991

Effects of oral phosphocysteamine and rectal cysteamine in cystinosis.

Diurnal variation in leucocyte cystine and the effects of equimolar single doses of oral phosphocysteamine and rectal cysteamine were studied in eight patients with cystinosis, aged 1.8-16.5 years. No significant diurnal variation in leucocyte cystine was found. Absorption of cysteamine was reduced after rectal administration compared with the oral dose: mean (SD) peak concentration 17.2 (6.3) mumol/l v 36.4 (5.5) mumol/l at 40 min and mean (SD) area under the curve 22.3 (14.3) v 59.4 (33.1) mumol/h/l. Oral phosphocysteamine significantly reduced the mean (SD) leucocyte cystine from 8.09 (0.47) to 3.26 (1.48) nmol 1/2 cystine/mg protein at three hours. At 12 hours the mean leucocyte cystine was significantly lower than the pretreatment concentration. Rectal cysteamine did not significantly reduce the mean leucocyte cystine concentration. In conclusion, phosphocysteamine suspension may be administered every 12 hours. Rectal cysteamine administration is feasible but higher doses are required before efficacy can be judged.

Administration, Oral↗
PubMed1986

Cysteamine induces duodenal ulcer in the mouse.

A new model of duodenal ulcer disease has been developed in the mouse. The ulcers were produced after either oral or subcutaneous administration of cysteamine which has been shown to cause duodenal ulcer in the rat. Cysteamine induced duodenal ulcers in a time- and dose-dependent manner after oral administration. The new mouse model shares many similarities with both the rat model and human ulcer disease. Cysteamine caused a significant increase in gastric acidity and pepsin activity. The mouse can be protected against the cysteamine-induced duodenal ulcer by either the dopamine agonist lergotrile or histamine H2 receptor antagonist cimetidine. This new model of duodenal ulcer disease in the mouse may represent a simple and inexpensive way to screen for new antiulcerogenic drugs.

Administration, Oral↗
PubMed1984

Cysteamine depletes prolactin (PRL) but does not alter the structure of PRL-containing granules in the anterior pituitary.

Cysteamine causes a profound depletion of PRL in the anterior pituitary and in the systemic circulation, as measured by RIA and bioassay. However, electron microscopic study of PRL-containing cells in rat anterior pituitary does not reveal changes in secretory granule or cytoplasmic structure during the interval of depressed PRL content and of subsequent recovery to normal levels. In contrast to the results obtained by RIA, PRL-like immunoreactivity as detected by immunocyto-chemistry is present and similar to that of control preparations after cysteamine administration. We suggest that cysteamine alters PRL structure in secretory granules, probably by interacting with the disulfide bonds of PRL, thereby altering bioactivity and immunoreactivity. The presence of cysteamine-altered PRL in secretory granules does not seem to trigger degradation of granules by the lysosomal system.

Animals↗
PubMed1994

4-Methoxyphenyl 4-(3,4,5-trimethoxybenzyl)-1-piperazineacetate monofumarate monohydrate (KB-5492), a new anti-ulcer agent with a selective affinity for the sigma receptor, prevents cysteamine-induced duodenal ulcers in rats by a mechanism different from that of cimetidine.

Both KB-5492, a new anti-ulcer agent, and cimetidine, administered orally at 25-200 mg/kg, dose-dependently prevented cysteamine (400 mg/kg, s.c.)-induced duodenal ulcers in rats with ED50 values of 63 and 40 mg/kg, respectively. Anti-ulcer doses of cimetidine, but not KB-5492, inhibited gastric acid hypersecretion induced by cysteamine (400 mg/kg, s.c.). In contrast, anti-ulcer doses of KB-5492, but not cimetidine, increased duodenal HCO3- secretion in normal anesthetized rats. These findings suggest that KB-5492 prevents cysteamine-induced duodenal ulcers by stimulating duodenal HCO3- secretion, whereas cimetidine does so by inhibiting cysteamine-induced gastric acid hypersecretion.

Animals↗
PubMed2004

Pharmacological treatment of nephropathic cystinosis with cysteamine.

Cystinosis, clinically recognised since 1903, is an autosomal recessive lysosomal storage disease caused by mutations in CTNS. This gene codes for a lysosomal cystine transporter, whose absence leads to intracellular cystine crystals, widespread cellular destruction, renal Fanconi syndrome in infancy, renal glomerular failure in later childhood and other systemic complications. Before the availability of kidney transplantation, patients affected with cystinosis uniformly died during childhood. After solid organ transplantations became successful in the 1960s, cystinosis patients survived, but eventually developed life-threatening consequences of the disease (e.g., swallowing disorders). Since the introduction of cysteamine into the pharmacological management of cystinosis, well-treated adolescent and young adult patients have experienced normal growth and maintenance of renal glomerular function. Oral cysteamine therapy is given at doses of 60 - 90 mg/kg/day q.i.d. every 6 h, and generally achieves approximately 90% depletion of cellular cystine, as measured in circulating leucocytes. Cysteamine (and kidney transplantation) have commuted the death sentence of cystinosis into a nearly normal life with a chronic disease. Because treatment with oral cysteamine can prevent, or significantly delay, the complications of cystinosis, early and accurate diagnosis, as well as proper treatment, is critical.

Administration, Oral↗
PubMed1997

Male pronuclear formation and early embryonic development of hamster oocytes matured in vitro with gonadotrophins, amino acids and cysteamine.

Male pronuclear (MPN) formation in oocytes after in vitro maturation (IVM) was compared with that of matured follicular oocytes that had matured in vivo (controls). Cumulus-oocyte complexes were matured in vitro for 13 h in modified Tyrode's solution (TLP-PVA); cumulus-free oocytes were then incubated in 20% oviductal fluid for 3 h, and washed and capacitated spermatozoa were added. MPN formation was significantly lower (P < 0.05) in IVM oocytes 3 to 12 h after insemination (0 to 34%, respectively) than in control oocytes (range, 98-100%). Female pronuclear formation was 84-100% in controls and IVM oocytes, but spermatozoa incompletely decondensed in IVM oocytes. The addition of 10 mumol l-1 during IVM, significantly increased (P < 0.05) MPN formation (from 17% in the absence of cysteine to 47% in the presence of cysteine), but was lower than that in controls (88%). During IVM, the addition of 10% serum or gonadotrophins (FSH and LH) with or without amino acids did not support MPN formation without cysteamine, whereas the treatment with gonadotrophins and 11 amino acids plus 200 mumol cysteamine l-1 (82%) equalled controls (92%). Development of oocytes after IVM (in 0, 10, 20% serum) in TLP-PVA, gonadotrophins, 11 amino acids and 200 mumol cysteamine l-1 was compared with development in controls. Of the IVM treatments, 20% serum was inferior at fertilization, but yielded the highest percentage of fertilized oocytes developing to or beyond the four-cell stage (20% serum versus controls, respectively); fertilized oocytes, 75% versus 88%; > or = four-cell embryo, 40% versus 53%; blastocyst, 8% versus 14%. It was concluded that during IVM, gonadotrophins plus 11 amino acids interacted with cysteamine, enhancing the decondensation of spermatozoa and MPN formation; oocytes matured in this medium with 20% serum were fertilized and some developed to the blastocyst stage.

Amino Acids↗
PubMed1983

Cysteamine blocks somatostatin secretion without altering the course of insulin or glucagon release. A new model for the study of islet function.

Cysteamine (300 mg/kg) administered subcutaneously depletes pancreatic somatostatin to 36% of control levels, but does not alter pancreatic insulin or glucagon content. Although perfusion of pancreata from normal animals with glucose (300 mg/dl) markedly stimulated somatostatin release, pancreata from cysteamine-treated animals failed to secrete somatostatin in response to glucose. Cysteamine treatment was without effect on insulin and glucagon release under the conditions tested. The isolated perfused pancreas from the cysteamine-treated rat provides a model for further investigations into regulation of islet hormone release in the absence of stimulated somatostatin release.

Animals↗
PubMed1982

The mechanism of gastrin release in cysteamine-induced duodenal ulcer.

Duodenal ulcer can be induced in rats by a single dose of cysteamine. The ulcer formation is accompanied by acid hypersecretion and elevated serum gastrin levels. This study was performed to elucidate the mechanisms of gastrin release after an ulcerogenic dose of cysteamine. Cysteamine induced a rise in serum gastrin from 29 +/- 5 pg/ml to a maximum of 203 +/- 62 pg/ml after 3 h in unoperated rats, whereas no rise was seen in vagotomized or antrectomized rats. The beta-adrenergic blocking agent propranolol strongly inhibited cysteamine-induced gastrin release, whereas atropine dependent on an intact vagus and may be mediated by beta-adrenergic receptors.

Animals↗
PubMed1988

Metabolism of a new radioprotector; S-acetyl-N-glycyl cysteamine. I. Absorption, distribution and excretion metabolites in mice bearing EMT6 tumours.

1. The disposition of S-acetyl-N-glycyl cysteamine (I) labelled with 14C on the cysteamine group (label 1), the glycyl group (label 2) and the acetyl group (label 3) has been studied in mice bearing EMT6 tumours. 2. Label 1 was mainly excreted in urine (63.1% dose in 24 h). Label 2 elimination was both in urine (36.0% dose in 24 h) and in expired air as 14CO2 (12.1% dose in 24 h). Label 3 was essentially eliminated in expired air as 14CO2 (55.4% dose in 24 h). 3. Tissue distribution studies of label 1 and label 2 showed that concentrations in tissues were higher than blood concentration as early as 10 min after administration. Whichever label was used, only little radio-activity was found in EMT6 tumour and brain. 4. Analysis of the urinary elimination products showed the presence of unchanged I and of cystamine, N-acetylcystamine, N-acetyl-S-methyl cysteamine sulphoxide and taurine. I is a prodrug of cysteamine which is released after deacetylation and hydrolysis of the amide bond. A metabolic pathway is proposed for this new radioprotective agent.

Animals↗
PubMed1996

Detection of Auger enhancement induced in HeLa cells labeled with iododeoxyuridine and irradiated with 150 kV x-rays--Effects of cysteamine and dimethylsulfoxide.

We examined the effects of cysteamine and dimethylsulfoxide on the lethality of iododeoxyuridine-labeled HeLa cells irradiated with 150 kV x-rays (effective energy was 48 keV) and compared with those irradiated with 60Co gamma-rays. The protectable fraction was estimated from the regression lines for the reciprocal plots of the concentration of protectors, versus the degree of protection. The protectable fraction by cysteamine was 9.4% lower in iododeoxyuridine-labeled cells than in control cells when they were irradiated with x-rays, whereas no such difference was observed with dimethylsulfoxide. The slopes of the regression lines were steeper (i.e., more difficult to protect) for both protectors in iododeoxyuridine-labeled cells irradiated with x-rays. No such differences were observed in gamma-irradiated cells. The cause for these differences are attributable to Auger enhancement. The results suggest that at least a portion of Auger enhancement is not protectable by cysteamine and is hard to be protected by both protectors cysteamine and dimethylsulfoxide.

Cell Survival↗
PubMed1987

Cysteamine oxygenase: possible involvement of superoxide ion in the catalytic mechanism.

The reaction catalyzed by cysteamine oxygenase on cysteamine in the presence of phenazine methosulphate as cofactor like compound is inhibited by nitroblue tetrazolium, a scavenger of superoxide ions. The reaction is not inhibited by superoxide dismutase and allyl alcohol and it is not activated by superoxide ions produced in solution. Nitroblue tetrazolium is reduced by cysteamine or mercaptoethanol and phenazine methosulphate. This reaction is completely inhibited by superoxide dismutase. In the presence of cysteamine oxygenase the reduction with mercaptoethanol is greatly enhanced and it is only partially inhibited by superoxide dismutase. According to these data a reaction mechanism is proposed in which superoxide ions and thiyl radicals are produced at the active site during catalysis.

1-Propanol↗
PubMed1992

[An experimental study of adrenalin-stimulated gastric acid secretion and gastrin secretion in rats of cysteamine-induced duodenal ulcer].

It is known that cysteamine-induced duodenal ulcers in rats are similar to the human duodenal ulcers in some aspects. We investigated their similarities in view of adrenalin-stimulated gastric acid secretion and gastrin secretion in these rats. Acid outputs decreased in the control group by the administration of adrenaline, but in the cysteamine-administered group acid outputs increased dose dependently. Serum gastrin levels and plasma noradrenaline levels increased by cysteamine administration. The abnormal gastric acid secretion by the adrenalin infusion in the process of cysteamine-induced duodenal ulcers in rats, which was resembled to that of duodenal ulcer patients, was recognized.

Animals↗
PubMed2004

[Cysteamine attenuates suppression of peripheral IL-2 and lymphocytic proliferation induced by ruminal and duodenal operations in goats].

Sixteen castrated male goats were randomly allocated into two groups (Control n=8; Experiment n=8) to investigate the effects of cysteamine on surgery-induced cellular immune suppression. The experiment commenced with 13 d of pre-operation (pre-Op), which contained 3 d of roughage-fed period (RP) and 10 d of roughage + concentrate-fed period (RCP), followed by first operation (Op-1) and then the second operation (Op-2). The goats were allowed to have 14 d of recovery between two operations. The fistulas were fixed to rumen walls in Op-1 and to duodenal walls in Op-2. Cysteamine (15 mg x kg(-1) x BW x d(-1)) was added to diet and fed to goats in Exp. group since RCP of pre-Op through whole experimental period. Blood was sampled through jugular vein from goats of both groups at pre-feeding of the last day of RP and RCP, 8 d after Op-1, 4 d and 13 d after Op-2, respectively to determine serum concentration of interlukin-2 (IL-2), cortisol, as well as PHA-stimulated lymphocytic proliferation rate (SI). In pre-operative periods there were no significant differences in concentration of IL-2 (0.82+/-0.1 vs 1.03+/-0.22 microg l(-1)) and cortisol (20.48+/-4.52 vs 20.80+/-9.93 microg l(-1)), as well as lymphocytic SI (90.72+/-7.25 vs 129.22+/-18.59) between Control and Exp. groups. The concentrations of IL-2 (0.82+/-0.1 vs 0.73+/-0.08 vs 0.55+/-0.12 microg l(-1)) and lymphocytic SI (90.72+/-7.25 vs 49.31+/-6.4 vs 7.09+/-1.66) in Control were depressed acutely (P<0.05), but cortisol concentration elevated (20.48+/-4.52 vs 26.67+/-10.51 vs 32.33+/-3.29 microg l(-1)) in post-operative periods (8 d after Op-1 and 4 d after Op-2), compared with those in RCP. While they remained unaltered in Exp. group except a slight decrease of lymphocytic SI at 4 d after Op-2. The different responses of Control and Exp. groups to surgery stress led to a 80-90% higher of IL-2 and about 3 times greater of SI in Exp. than those in Control, which was contributed by cysteamine administration. Our data show that in operated goats the cellular immune was suppressed by surgery stress, cysteamine administration prevented decreases of IL-2 and lymphocytic SI and increase of cortisol induced by surgery stress, consequently attenuates surgery-induced suppression of cellular immune activity.

Animals↗
PubMed1990

[Treatment of cystinosis using cysteamine].

Eighteen pediatric patients with cystinosis were treated with cysteamine. Treatment was started at a variable age, between 10 months and 7 years, and was continued for 6 months to eight years. Results were evaluated on renal function changes and growth. Whereas 65% of patients with cystinosis develop terminal renal failure before the age of ten years, three (16%) of our 18 patients given cysteamine started dialysis before the age of ten and all three had first received cysteamine only after 4 1/2 years of age. The plasma creatinine level was also lower in treated patients as compared with a control multicenter group. Growth was also significantly improved by treatment, especially in those children treated before the age of 26 months who were taller by 2 SD at age five and 2.5 SD at age eight than untreated controls. Some children who complied strictly with the treatment regimen had an normal stature (- 1 SD) at ten years of age. In conclusion, the effectiveness of cysteamine seems obvious in this group of patients if rigorous compliance with the drug dosing schedule is achieved.

Child↗
PubMedDate not supplied

Effects of pantethine, cysteamine and pantothenic acid on open-field behavior and brain catecholamines in rats.

Cysteamine (1.95 mM/kg) markedly decreased the locomotor, rearing and grooming activities, as well as the number of defecation boluses in an open-field test. An equimolar dose of pantethine reduced the locomotor activity to a lesser extent, but has the same potency in decreasing the number of defecation boluses, whereas pantothenic acid did not affect the behavior of the rats. Cysteamine, and to a lesser extent pantethine, reduced the noradrenaline and increased the dopamine and DOPAC concentrations in the hypothalamus. Pantothenic acid itself did not influence the hypothalamic catecholamine concentrations. These results suggest that the lower efficacy of pantethine compared to cysteamine on both behavioral and neurochemical parameters is probably due to a rate-limiting activity of the enzyme pantetheinase in the conversion of pantetheine to cysteamine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Effect of pretreatment with cysteamine on gamma-radiation-induced sister chromatid exchanges in mouse bone marrow cells in vivo.

The effect of pretreatment with cysteamine on gamma-radiation-induced sister chromatid exchanges (SCEs) and on the mitotic index and average generation time was determined. Groups of mice were treated in one of the following regimens: (1) irradiated, (2) treated with cysteamine and irradiated, (3) treated with cysteamine only, or (4) left untreated. Intraperitoneal administration of cysteamine preceding gamma-radiation exposure protected against SCE induction. However, radioprotection was not reflected by change in the mitotic index or in the average generation time. The results suggest that, under the experimental conditions of this study, the SCEs are caused by free radicals produced by gamma radiation, but not the additional damage indices measured.

Animals↗
PubMed1989

The molecular nature of mutants induced by X rays is altered by the presence of the radioprotector cysteamine.

The molecular structure of mutants induced in human lymphoblast cells by 500 cGy X rays in the presence of the radioprotector cysteamine (25 mM) has been compared with that induced by an equally mutagenic treatment of 150 cGy X rays alone. Sets of mutants at the hypoxanthine-guanine phosphoribosyl transferase locus were analyzed by Southern blot. Of 24 mutants induced by X rays in the presence of cysteamine, 67% exhibited no change in the restriction fragment pattern and thus were defined as point mutations; 8% appeared to be total gene deletions and 25% were partial deletions or rearrangements. In contrast, among 28 mutants induced by X rays alone (Liber et al., Mutat. Res. 178, 143-153 (1987)), 46% were point mutations, while 50% were total gene deletions and only 1 mutant (4%) was a partial deletion or rearrangement. Thus mutants isolated in the presence of cysteamine consisted of more point mutations and partial deletions/rearrangements, and considerably fewer total gene deletions. These results suggest that cysteamine may protect selectively against processes which lead to large-scale molecular changes.

Blotting, Southern↗