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PubMed1983

The effect of atropine, cimetidine and FPL 52694 on duodenal ulcers in mice.

Cysteamine-induced duodenal ulcers were compared in rats and mice. Mice were slightly less sensitive to cysteamine ulcerogenesis than rats, but the ulcers were similar in location, histopathology and responses to drugs. Cysteamine treated mice rather than rats are advocated for screening purposes since less test compound is required. Atropine, 3-30 mg/kg orally, reduced the incidence, number, size and severity of duodenal ulcers in both species. Cimetidine, 300-500 mg/kg orally, reduced the size and number of ulcers in rats but was less effective on the incidence and severity of ulcers. 300 mg/kg orally reduced only ulcer size significantly in mice. FPL 52694, 300 mg/kg orally, reduced the incidence, number, size and severity of cysteamine-induced duodenal ulcers in rats and mice. The anti-ulcer activities of atropine, FPL 52694 and cimetidine are discussed in relation to their gastric anti-secretory actions.

Animals↗
PubMed1990

Influences of glutathione and sulfhydryl containing compounds on aqueous humor outflow function.

Several sulfhydryl reactive compounds have previously been shown to influence aqueous humor outflow facility. The purpose of the current study was to investigate the effect of glutathione depletion on certain of these sulfhydryl actions. Enucleated calf, monkey, and human eyes were perfused via the anterior chamber by the constant pressure (15 mmHg) technique. In calf eyes, perfusion of 10 mM cysteamine produced a small (-23%, P = 0.03) decrease in outflow facility that was also observed after hyaluronidase pretreatment. In contrast, following pretreatment with 1 mM BCNU [1,3 bis(2 chlorethyl)-1-nitrosourea], an inhibitor of glutathione reductase, and 10 mM diamide, a glutathione oxidant, which did not by themselves significantly affect outflow facility, perfusion of cysteamine resulted in an opposite effect--a remarkably large (+90%, P less than 0.001) increase in outflow facility. Other reduced and oxidized sulfhydryl-containing compounds such as cysteine, beta-mercaptoethanol, and glutathione, itself, as well as the non-sulfhydryl reducing agent, ascorbic acid, were substituted for cysteamine in this protocol and found to produce similar effects of varying magnitudes. In general, the reduced sulfhydryl containing compounds and ascorbic acid were the most effective. Pretreatment with BCNU alone without diamide did not produce this effect. Treatment with BCNU and diamide resulted in a greater than 75% decrease in reduced glutathione levels and a concomitant tenfold increase in glutathione mixed disulfide levels (0.229 vs. 0.030 mumol g-1 wet weight) in the calf trabecular meshwork. The subsequent perfusion with cysteamine reversed this mixed disulfide formation.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Chloromercuribenzenesulfonate↗
PubMed1990

Scavengers of free radical oxygen affect the generation of low molecular weight DNA in stimulated lymphocytes from patients with systemic lupus erythematosus.

Factors that potentially affect the generation of excess low molecular weight DNA (LMW-DNA) in cultured phytohemagglutinin (PHA)-stimulated lymphocytes of patients with systemic lupus erythematosus (SLE) were studied because this species of DNA is consistently found and this DNA may play a role in the pathogenesis of the disease. Superoxide dismutase (SOD; 0.05 mg/mL), a scavenger of free radical oxygen, decrease LMW-DNA formation in lymphocytes by 22%. Co-cultivation with cysteamine, a second scavenger of free radical oxygen and a sulfhydryl radioprotective agent, resulted in a 32% decrease in the generation of excess LMW-DNA at a concentration of 0.5 x 10(-3) mol/L and largely prevented its formation at 1.0 x 10(-3) mol/L. Other free radical scavengers (catalase, mannitol, vitamins C and E), cyclooxygenase inhibitors (ibuprofen and aspirin), a xanthine oxidase inhibitor (allopurinol), and an iron chelator (desferoxamine) did not affect excess LMW-DNA formation. Glutathione (1 x 10(-3) mol/L) had no effect and cysteine was toxic. Because scavengers of free radicals might be useful in the therapy of lupus, a trial of cysteamine (30 to 60 mg/kg/d) was administered to six acutely ill patients with SLE. A therapeutic benefit was not demonstrated, and some patients had exacerbation of disease. Lymphocyte cell growth from control and lupus subjects was stimulated when cysteamine, 1 x 10(-5) to 1 x 10(-4) mol/L was added to the media, but inhibited at concentrations of 2 x 10(-4) mol/L or greater. These studies suggest that the autooxidation and toxicity of high-dose cysteamine preclude its therapeutic use as a free radical scavenger.

Adult↗
PubMed1992

Differential effects of octreotide on motor responses to nicotine in rats.

We tested the hypothesis that brain somatostatin levels modify two motor behaviors evoked by ICV infusions of nicotine. Unrestrained, awake rats were given fixed-concentration infusions of nicotine until the prostration/immobility (PI) syndrome and convulsions were produced. Infusion duration ranged from 0.9 to 1.2 min for the PI syndrome and 2.5 to 4.9 min for the convulsions. Octreotide, a stable somatostatin analog (4.5 micrograms, ICV), significantly raised the threshold for nicotine convulsions 1.0 and 5.5 h after pretreatment but not at 24 or 48 h. Cysteamine, a somatostatin releaser and depletor (0.35-0.75 mg/rat, ICV), also caused a dose-dependent increase in seizure threshold. Similarities in the response to octreotide and cysteamine suggest that depression of nicotine convulsions by cysteamine may be mediated by release of endogenous somatostatin. Neither octreotide nor cysteamine altered the threshold for the PI syndrome. These results support the view that one motor behavior evoked by nicotine is subject to control by somatostatin whereas another is not.

Animals↗
PubMed1994

Thiol-bearing compounds selectively inhibit protein kinase C-dependent oxidative events and proliferation in human T cells.

The aminothiol cysteamine at 10(-5) to 10(-4) M concentrations inhibited both the proliferation of mitogenically stimulated human peripheral mononuclear cells and the phorbol myristate acetate-mediated oxidation of 2',7'-dichlorofluorescein within these cells. Both 2',7'-dichlorofluorescein oxidation and the proliferative response were maximally sensitive to cysteamine-induced inhibition during the first 2 h of mitogenic stimulation. This period of sensitivity indicates that cysteamine preferentially arrests cells transiting from G0 to G1 and is the first such demonstration, of an early cell cycle site of arrest for this compound. 2,3-Dimercapto-1-propane-sulfonic acid and WR 1065 were found to be more effective than cysteamine in attenuating T cell replication but not N-acetylcysteine. Aminothiols preferentially inhibited the intracellular oxidation of 2',7'-dichlorofluorescein, rather than the activity of protein kinase C, which initiates the oxidation, indicating that oxidative events are one of a number of crucial and independent events required for the successful transition through G0-G1. Since aminothiols affect both lectin and PMA/ionomycin-directed proliferation, these aminothiol-sensitive events may serve to integrate and regulate common pathways in T cell activation.

Alkaloids↗
PubMed2005

Biomimetics with a self-assembled monolayer of catalytically active tethered isoalloxazine on Au.

A new biomimetic nanostructured electrocatalyst comprised of a self-assembled monolayer (SAM) of flavin covalently attached to Au by reaction of methylformylisoalloxazine with chemisorbed cysteamine is introduced. Examinations by Fourier transform infrared spectroscopy and scanning tunneling microscopy (STM) show that the flavin molecules are oriented perpendicular to the surface with a 2 nm separation between flavin molecules. As a result of the contrast observed in the STM profiles between areas only covered by unreacted cysteamine and those covered by flavin-cysteamine moieties, it can be seen that the flavin molecules rise 0.7 nm above the chemisorbed cysteamines. The SAM flavin electrocatalyst undergoes fast electron transfer with the underlying Au and shows activity toward the oxidation of enzymatically active beta-NADH at pH 7 and very low potential (-0.2 V vs Ag/AgCl), a requirement for use in an enzymatic biofuel cell, and a 100-fold increase in activity with respect to the collisional reaction in solution.

Biomimetics↗
PubMed1997

The protective effect of zinc sulphate pretreatment against duodenal ulcers in the rat.

Exogenously administered zinc compounds have been shown to possess antiulcer activity in the development of gastric lesions. The aim of this study was to investigate the effects of zinc sulphate pretreatment of rats on cysteamine-induced duodenal ulcers and to correlate them with changes in zinc serum and tissue levels. Atomic absorption spectrophotometry was used to determine zinc serum and tissue concentrations in all animal groups. Cysteamine produced marked duodenal ulceration in control animals 24 h after application, with an increase in endogenous zinc tissue concentrations and a marked decrease in serum concentrations. Zinc sulphate (20, 40 or 80 mg kg-1) applied per os one hour prior to cysteamine application inhibited the development of duodenal lesions in a dose-related manner. The application of zinc sulphate in a single intraperitoneal (i.p.) application (80 mg kg-1) did not, however, prevent the formation of duodenal lesions. In order to assess zinc absorption from the gastrointestinal tract, one group of rats received a single oral dose of zinc sulphate (80 mg kg-1) without cysteamine application. The observations of this study seem to indicate that zinc plays an important cytoprotective role in duodenal ulcer disease.

Administration, Oral↗
PubMed2001

Endogenous glutathione and platelet function in platelet concentrates stored in plasma or platelet additive solution.

Platelet function was studied in platelet concentrates by assay of the thrombin-induced release of endogenous serotonin and presence of the swirling phenomenon in relation to endogenous glutathione (GSH) and cysteine. In platelets stored in plasma, addition of cysteamine resulted in only a moderate fall in GSH after 5 days of storage, from an average of 14.91 to 11.46 nmol per 109 platelets. Exogenously added GSH had no effect, and addition of buthionine sulfoximine (BSO) resulted in almost complete depletion of GSH, to an average of 0.65 nmol per 109 platelets. Addition of cysteamine or GSH resulted in increased endogenous cysteine whereas BSO had no effect. In platelets stored in a platelet additive solution (T-sol), complete depletion of GSH was found in the presence of cysteamine, GSH and BSO. Endogenous serotonin was unchanged during storage both in plasma and in additive solution (2.8 nmol per 109 platelets). Despite almost total depletion of endogenous GSH, the thrombin-induced release of serotonin after 5 days' storage was significantly affected only in the presence of BSO in platelets stored in additive solution (mean values 72.3% vs. 63.3% of endogeneous serotonin, P < 0.05). Similarly, addition of cysteamine or GSH had no significant effect on swirling but BSO reduced the swirling score after 5 days' storage in platelet additive solution compared with plasma. After 10 days' storage, there was a significant reduction in swirling in the concentrates where BSO was added (P < 0.05).

Blood Platelets↗
PubMed1993

UV-radiation protecting efficacy of thiols, studied with UVA-induced binding of 8-MOP and CPZ to rat epidermal biomacromolecules in vivo.

The following topically-applied thiols were investigated with regard to their possible UV-radiation protective properties: captopril, cysteamine, ergothioneine, mesna, mercaptopropionylglycine, N-acetyl-cysteine and penicillamine. As a measure for protection the inhibition of in vivo irreversible photobinding of the labelled phototoxic drugs chlorpromazine (CPZ) and 8-methoxypsoralen (8-MOP) to rat epidermal biomacromolecules was used. Ergothioneine, mesna and penicillamine did not show any effect; probably, as a result of their charge they are not able to enter the stratum corneum. Captopril, cysteamine, mercaptopropionylglycine and N-acetylcysteine showed a considerable inhibition of CPZ and 8-MOP photobinding. Captopril and N-acetylcysteine were clearly the most potent whereas cysteamine was the least effective. Captopril, mercaptopropionylglycine and N-acetylcysteine appeared to have a wider action range and to be a more effective protector than dl-alpha-tocopherol and di-butyl-hydroxytoluene. Cysteamine and mercaptopropionylglycine were only capable of protecting the stratum corneum. Captopril and N-acetylcysteine on the other hand showed an additional dose-dependent inhibition of photobinding to the viable epidermis. Gradually with increasing time after application, the protecting efficacy with regard to the viable layer of the epidermis decreased; the duration of protection depending on the dose.

Acetylcysteine↗
PubMed1993

Effect of thiol compounds on in vitro development and intracellular glutathione content of bovine embryos.

The purpose of this investigation was to determine the effect of beta-mercaptoethanol (beta-ME) and cysteamine, low-molecular-weight thiol compounds, on the development and intracellular glutathione content of bovine embryos obtained by in vitro fertilization of in vitro-matured oocytes. Embryos developed to the 6-8-cell stage after in vitro fertilization were cultured without feeder cells in TCM-199 containing 10% fetal calf serum with or without beta-ME or cysteamine. The percentage of embryos that developed to the blastocyst and hatched blastocyst stages were significantly higher in medium containing beta-ME or cysteamine. Also, total intracellular glutathione levels were higher for embryos cultured in the medium with beta-ME or cysteamine than for those cultured in medium without thiol compounds. Moreover, when buthionine sulfoximine, a specific inhibitor of glutathione synthesis, was added to medium containing thiol compounds, there was a reduction both in the development of embryos to the blastocyst stage and in intracellular glutathione content. These results indicate that the inclusion of low-molecular-weight thiol compounds aids the in vitro development of bovine embryos without feeder cells and that the effect of thiol compounds is mediated through the increase of intracellular glutathione levels.

Animals↗
PubMed2005

Treatment of YAC128 mice and their wild-type littermates with cystamine does not lead to its accumulation in plasma or brain: implications for the treatment of Huntington disease.

Cystamine is beneficial to Huntington disease (HD) transgenic mice. To elucidate the mechanism, cystamine metabolites were determined in brain and plasma of cystamine-treated mice. A major route for cystamine metabolism is thought to be: cystamine --> cysteamine --> hypotaurine --> taurine. Here we describe an HPLC system with coulometric detection that can rapidly measure underivatized cystamine, cysteamine and hypotaurine, as well as cysteine and glutathione in the same deproteinized tissue sample. A method is also described for the coulometric estimation of taurine as its isoindole-sulfonate derivative. Using this new methodology we showed that cystamine and cysteamine are undetectable (< or = 0.2 nmol/100 mg protein) in the brains of 3-month-old HD transgenic (YAC128) mice (or their wild-type littermates) treated daily for 2 weeks with cystamine (225 mg/kg) in their drinking water. No significant changes were observed in brain glutathione and taurine but significant increases were observed in brain cysteine. Cystamine and cysteamine were not detected in the plasma of YAC128 mice treated daily with cystamine between the ages of 4 and 12 or 7 and 12 months. These findings suggest that cystamine is not directly involved in mitigating HD but that increased brain cysteine or uncharacterized sulfur metabolites may be responsible.

Animals↗
PubMed1984

Direct measurement of duodenal acid-pepsin exposure at site of ulceration in rats.

A new technique for the preparation of a chronic duodenal fistula in the rat is described. The effect of cysteamine and propionitrile on the acidity of duodenal contents was studied, and the degree of acidity correlated with the respective duodenal ulcerogenicity of these two compounds. After subcutaneous administration of cysteamine, reduced duodenal acid was seen for 2-4 h, followed by large increases continuing up to 12 h and declining thereafter. Oral cysteamine administration produced acid increases of rapid onset and shorter duration, accompanied by increased pepsin activity. The weak duodenal ulcerogen propionitrile did not affect duodenal acidity. Cimetidine markedly reduced the duodenal acidification induced by cysteamine, whereas the dopamine agonist bromocriptine did not affect acid delivery to the duodenum but reduced the pepsin activity in the duodenal contents by 50%. The duodenal fistula rat provides a new model system for studies on the pathogenesis of experimental duodenal ulcer.

Animals↗
PubMed1988

Cimetidine and mucosal cell renewal in the duodenum.

Cimetidine may protect gastric and duodenal mucosa by increasing cell turnover. Mucosal cell turnover in the duodenum of 7 control rats receiving intraperitoneal injections of normal saline for 6 days was compared with 8 rats receiving cimetidine for 6 days (500 mg/kg/24 h). Cell proliferation was assessed by autoradiography after injection of tritiated thymidine. The 'leading edge' was defined as the highest tritium-labelled nucleus in the crypt-villus (D/V) column expressed as a percentage of the complete C/V column. Ten C/V columns were measured in each rat. The number of tritium-labelled nuclei in 10 complete C/V columns was also counted in each rat. In the controls the median leading edge was 74.8% (25% quartile 70.6%, 75% quartile 76.2%) and in the rats receiving cimetidine 73.4% (25% quartile 72.1%, 75% quartile 75.9%). The median labelled cell counts were 2,052 (25% quartile 2,008, 75% quartile 2,173) and 1,999 (25% quartile 1,822, 75% quartile 2,041), respectively. These differences were not significant (p greater than 0.1; Mann-Whitney U test). Duodenal mucosal proliferation was assessed in 19 rats 48 h after two subcutaneous injections of 20 mg cysteamine and in another 9 after the same dose of cysteamine plus cimetidine (500 mg/kg/24 h). The median leading edge was 90.1% (25% quartile 84.4%, 75% quartile 92.8%) in cysteamine-treated rats and 76.7% (25% quartile 71%, 75% quartile 79.9%) in rats receiving cysteamine plus cimetidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Secretory changes associated with chemically-induced duodenal ulceration: simultaneous measurements of acid, pepsin, base and pancreatic enzymes in rats with chronic gastric fistula.

Rats with chronic gastric fistula were used to study gastric and duodenal/pancreatic secretory changes evoked by chemical duodenal ulcerogens. Although the data demonstrate stimulation of gastric output of acid and pepsin by certain doses of cysteamine or propionitrile, cysteamine produced dose-response increases in acid secretion only during the 1st hour following administration. The base output was also elevated at most of the time intervals after cysteamine. Decreased alkaline secretion was only seen following propionitrile injection. Although hyperacidity at the ulcer site may occur during duodenal ulcerogenesis, these results suggest that direct stimulation of acid-pepsin secretion or depression of pancreatic alkaline output are not the primary mechanisms explaining the ulcerogenic action of cysteamine and propionitrile.

Amylases↗
PubMed1990

The depletion of plasma prolactin by pantethine in oestrogen-primed hyperprolactinaemic rats.

Pantethine was investigated for its potential to deplete prolactin in the plasma and pituitary cells of oestrogen-primed hyperprolactinaemic rats. This compound has been used in the past to deliver cysteamine systemically, through its congener pantetheine, a metabolic precursor for cysteamine. Cysteamine itself, specifically reduces plasma and pituitary prolactin. The addition of pantethine (2-10 mmol/l) to the media of isolated pituitary cells over 4 h did not appreciably alter the intracellular content of immunoreactive prolactin. Moreover, oral administration of pantethine at 0.5 and 1.0 g/kg body weight did not influence the concentration of immunoreactive plasma prolactin. However, the concentration of plasma prolactin fell by 48 and 67%, when pantethine was injected i.p. at 0.5 and 1.0 g/kg body weight, after 4 h. Intravenous administration of pantethine resulted in even greater losses of prolactin, in the order of 50 and 81% depletion for 0.5 and 1.0 g/kg body weight respectively and within 2 h of administration. However, cysteamine was found to be more efficacious than pantethine on a molar basis with regard to depleting the plasma concentration of prolactin in hyperprolactinaemic rats.

Administration, Oral↗
PubMed1990

Homologous and heterologous regulation of somatostatin-binding sites on chicken adenohypophysial membranes.

Binding of 125I-labelled [Tyr1]-somatostatin (125I-[Tyr1]-SRIF) to pituitary caudal lobe membranes was suppressed in immature chickens 1 and 2 h after i.v. administration of unlabelled SRIF at concentrations of 1-100 micrograms/kg. In-vitro preincubation of chicken pituitary glands for 0.5-4.0 h with 0.1 mumol SRIF/l similarly reduced the binding of 125I-[Tyr1]-SRIF to caudal lobe membrane preparations. After a 4-h incubation in 0.1 mmol SRIF/l, the withdrawal of SRIF from the incubation media was accompanied 4 h later by a partial recovery in the binding of 125I-[Tyr1]-SRIF to pituitary membranes. Passive immunoneutralization of endogenous SRIF resulted in a prompt (within 1 h) and sustained (for at least 24 h) suppression of 125I-[Tyr1]-SRIF binding to pituitary membranes. The i.m. administration of cysteamine (300 mg/kg) to 12-week-old birds depleted hypothalamic SRIF stores and decreased the density of 125I-[Tyr1]-SRIF-binding sites in the caudal and cephalic lobes of the chicken pituitary gland. The reduction in SRIF content and in SRIF-binding sites occurred within 1 h of cysteamine administration and was maintained for at least 24 h. In 6-week-old birds, cysteamine (300 mg/kg) administration suppressed pituitary binding of 125I-[Tyr1]-SRIF for at least 5 days. Circulating concentrations of GH were markedly decreased 1 and 4 h after cysteamine injection, but not after 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

[Characteristics of the effect of 16,16-dimethyl prostaglandin E2 on the alkaline secretion of the proximal duodenal mucosa in rats--a comparison with the effect of secretin].

Effect of intravenous infusion of 16,16-dimethyl prostaglandin E2 (16,16-dmPGE2) on the alkaline secretion of the proximal duodenal mucosa was investigated using a lumen perfusion system of the duodenal loop in rats. The following results were obtained: 1) 0.001 to 1 microgram/kg/hr of 16,16-dmPGE2 increased the alkaline secretion significantly and dose-dependently. 2) Indomethacin (5 mg/kg) inhibited the alkaline secretion and 16,16-dmPGE2 (0.1 microgram/kg/hr) completely repaired this inhibition. 3) In cysteamine-treated rats, 16,16-dmPGE2 (1 microgram/kg/hr) completely repaired the inhibition of the alkaline secretion induced by cysteamine. 4) Prostaglandin was a potent stimulator of alkaline secretion of the proximal duodenal mucosa not only in cysteamine-treated rats but also in normal rats. This is in contrast to our previous report which showed that secretin repaired the alkaline secretion in cysteamine-treated rats without affecting it in normal rats. We have concluded that prostaglandin and secretin may be involved differently in the mechanism of alkaline secretion of the proximal duodenal mucosa. Further investigation is required to elucidate the mechanism.

16,16-Dimethylprostaglandin E2↗
PubMed1975

Tumor rejection in experimental animals treated with radioprotective thiols.

In experimental animals, a systemic treatment with thiols of the mercaptoalkylamine type has affected all of five solid tumors so far investigated. (Three of the tumors were transplanted into the strain of origin.) There was either inhibition of growth or "oncodieresis," i.e., a necrosis and sloughing of tumors conducive to full recovery and repair. Mercaptoalkylamines and derivatives of the type used in our experiments are known to bind to cellular sites by a two-point attachment involving both thiol and amino groups. One of these compounds, cysteamine, was active in its native, unsubstituted form, but did not bring about oncodieresis when either the amino or thiol group, or both, were alkylated. Mercaptopropylamine, the 3-carbon homolog of cysteamine, was less active. Cystamine, a disulfide dimer of cysteamine that has no free reactive sulfhydryl, did not induce any reaction. Thioglycerol, lacking a terminal amino group, had only negligible activity. Rejection was much more striking when treatment was started on the day of inoculation than when started 7 days later. Male mice rejected better than females. Results were inferior when tow of the agents were given simultaneously or together with other radioprotectants, such as L-cysteine, glutathione, dimethyl sulfoxide, or reserpine. Tumor rejection was enhanced when the phosphorylated thioyls, S-2-(3-aminopropylamino)ethylphosphorothioic acid or S-(2-ethylguanidine)phosphorothioci acid, were given simultaneously with the radioprotective serotonin, but there was no synergy of serotonin with the nonphosphorylated compounds S-2-aminoethylisothiouronium bromide or cysteamine. Serotonin alone did not affect the tumors.

Animals↗