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PubMed1997

Effect of quinacrine, a phospholipase A2 inhibitor on stress and chemically induced gastroduodenal ulcers.

Quinacrine, a phospholipase A2 inhibitor, has been studied for its ability to inhibit gastric secretion and to protect the gastric and duodenal mucosa against chemically and stress-induced ulcers. Acid secretion studies were undertaken in pylorus-ligated rats with and without quinacrine treatment. Experimental gastric lesions were induced by water-immersion restraint stress, indomethacin and 80% ethanol in rats; whereas duodenal ulcers were produced by treatment of rats with cysteamine. The level of nonprotein sulfhydryl compounds and gastric wall mucus were also measured in the glandular stomach of the rats following ethanol-induced gastric lesions. The results of this study demonstrate that quinacrine produces a dose-dependent inhibition of gastric acid secretion in rats. Pretreatment with quinacrine significantly attenuated the formation of stress-, indomethacin- and ethanol-induced gastric lesions. Quinacrine also protected intestinal mucosa against cysteamine-induced duodenal ulcers. The antiulcer activity of quinacrine was associated with appreciable inhibition of ethanol-induced depletion of nonprotein sulfhydryls and gastric wall mucus. These findings point towards the mediation of sulfhydryls in quinacrine-induced gastrointestinal cytoprotection. In conclusion, this study demonstrates that quinacrine possesses significant antiulcer and cytoprotective activity against various experimentally induced gastroduodenal lesions. Although the mechanism of action of quinacrine requires further evaluation, the experimental observations derived from this study may have future clinical relevance and therefore deserve to be investigated thoroughly.

Animals↗
PubMed1977

Therapeutic comparison of thiol compounds in severe paracetamol poisoning.

Twelve patients with toxic blood concentrations of paracetamol were treated with either cysteamine or amino-acid solution. None of the patients developed severe liver damage, although transient mild biochemical abnormalities developed in three. None of the patients treated with amino-acid solution had side effects due to therapy, whereas all those treated with cysteamine did. It is recommended that amino-acid solutions be used as a temporary measure in patients suspected of massive paracetamol overdose while awaiting estimation of blood paracetamol concentration.

Acetaminophen↗
PubMed1991

Identification of peroxidase-positive astrocytes by combined histochemical and immunolabeling techniques in situ and in cell culture.

A subpopulation of astrocytes in the vertebrate brain and in cysteamine-treated brain cell cultures contain cytoplasmic granules which exhibit an affinity for Gomori stains, orange-red autofluorescence, and non-enzymatic endogenous peroxidase activity. Visualization of these cells at the light microscopic level is confounded by the nonspecificity of the various histochemical methods routinely employed. In an attempt to circumvent this problem, we assayed for peroxidase-positive astrocytes using various combinations of diaminobenzidine (DAB) histochemistry and immunolabeling for the astrocyte-specific marker glial fibrillary acidic protein (GFAP). We determined that (a) DAB histochemistry in conjunction with avidin-biotin-immunoperoxidase labeling for GFAP specifically detects peroxidase-positive astrocytes in situ and (b) DAB histochemistry combined with indirect immunofluorescence for GFAP effectively demonstrates these cells in cysteamine-treated brain cell cultures.

Animals↗
PubMed1985

Lysosomal cystine storage in cystinosis and mucolipidosis type II.

Cultured fibroblasts from mucolipidosis II (ML-II) patients demonstrated an elevated cystine content which increased with time in culture compared to fibroblasts from cystinotic patients or normal controls under the same conditions. In both cystinotic and ML-II cells the increased levels of cystine could be derived either from endogenous proteolysis or from in vitro supplementation of the cultured cells with cysteine-glutathione mixed disulfide. Cystine was depleted from both cell types by cysteamine. When cysteamine was replaced with complete medium, the cystine reaccumulated in both cystinotic and ML-II cells within 24 h, although a lag of 4 h was seen with ML-II cells. The intracellular location of the increased cystine in cultured fibroblasts was examined utilizing free-flow electrophoresis and found to be in the purified population of secondary lysosomes of both cystinotic and ML-II cells. White blood cell and hepatic cystine, which was greatly increased in cystinotic patients, was not elevated in ML-II patients. Compared to normal control fibroblasts the efflux of cystine from isolated granular fractions was virtually absent in cystinotic fibroblasts and considerably reduced in ML-II fibroblasts. The examination of such similarities and differences in cystine accumulation and transport in tissues from cystinotic and ML-II patients has provided some insight into the defects in these diseases.

Cells, Cultured↗
PubMed1984

Inhibition by gastrin-releasing peptide of growth hormone (GH) secretion induced by human pancreatic GH-releasing factor in rats.

Intravenous injection of synthetic human pancreatic GH-releasing factor (1-44) [hpGRF(1-44)] (50 ng-1 micrograms/100 g BW) resulted in a dose-related increase in plasma GH levels in urethane-anesthetized male rats. Pretreatment with cysteamine (30 mg/100 g BW, sc, 4 h previously) or anti-SRIF rabbit serum (0.5 ml/rat, iv, 1 h previously) raised basal plasma GH levels and markedly exaggerated the plasma GH response to hpGRF (1-44) (80 ng/100 g BW, iv). The intraventricular injection of gastrin-releasing peptide (GRP) (1 micrograms/rat) completely inhibited the increase of plasma GH induced by hpGRF (80 ng/100 g BW, iv) in control rats. However, in the rats treated with cysteamine or anti-SRIF rabbit serum, the inhibitory effect of GRP on hpGRF-induced GH release was significantly attenuated. hpGRF (10(-11)-10(-8) M) stimulated in a dose-related manner GH release from rat anterior pituitary cells superfused in vitro. GRP (10(-5) M) did not affect pituitary GH release induced by hpGRF (10(-9) M) in vitro. These results indicate that hpGRF stimulates rat GH secretion by acting at the pituitary level and the hypothalamic SRIF interacts with the action of GRF, and that GRP inhibits GH secretion, at least in part, by stimulating SRIF release from the hypothalamus.

Animals↗
PubMed1986

Differential isoform distribution between stored and secreted prolactin.

PRL exists within the mammotroph population in a number of different molecular forms. Three of these forms are best described as isoforms, as they have the same mol wt (24K) but differ in their net molecular charges. In this study we have examined the relative proportions of newly synthesized isoforms found in stored (intracellular) vs. secreted (extracellular) PRL. Dissociated cells from female rat anterior pituitaries were cultured for 48 h and then incubated in [35S]methionine (6 h; 37 C). Intracellular and medium proteins were then extracted and resolved by one- and two-dimensional polyacrylamide gel electrophoresis, followed by silver staining or autoradiography. Control experiments, in which biosynthetically labeled PRL was re-extracted, ensured that the isolation conditions did not in themselves promote isoform interconversion. The relative proportions of the PRL isoforms were determined by densitometric scanning of developed autoradiograms. In the cell extracts, the relative proportions were 13.6 +/- 2.1% isoform 1 (least negatively charged), 71.5 +/- 3.26% isoform 2, and 14.7 +/- 1.9% isoform 3 (most negatively charged). In the medium, the relative proportions were 60 +/- 2.89% isoform 1, 20 +/- 1.75% isoform 2, and 11 +/- 1.14% isoform 3. When the labeling was performed in the presence of 0.5 mM cysteamine (an agent we show to distinguish between newly synthesized and older stored hormone and, hence, between the previously described functional subpopulations of mammotrophs), the same ratios of newly synthesized isoforms were secreted from the cells. We conclude that secretion of the different isoforms is more complex than simple proportional release of each form, and based on the cysteamine results, this nonproportional release cannot be attributed to release of one isoform per functional subpopulation of mammotrophs.

Animals↗
PubMed1995

[Effect of newly developed analogue of growth hormone releasing peptide [D-Ala-D-beta Nal-Ala-Trp-D-Phe-Lys-NH2 (KP-102)] on growth hormone secretion in adult male rats].

The effect of a newly developed hexapeptide; D-Ala-D-beta Nal-Ala-Trp-D-Phe-Lys-NH2 (KP-102) on GH secretion was studied in adult male rats. KP-102 induced a large plasma GH response at a dose of 0.5 micrograms/kg BW in conscious rats, although GH-releasing abilities of KP-102 varied markedly depending on the phase of GH secretion. Among urethan-anesthetized rats, KP-102 alone exerted a small influence on GH secretion, but it produced a large plasma GH response in the presence of exogenous GH-releasing factor (GRF). The rest of studies were performed on urethan anesthetized rats. During intermittent administration of GRF, the somatotropes became refractory to a large bolus dose of GRF, but KP-102 induced a marked increase of plasma GH. The GH response to KP-102 alone or KP-102 with GRF was significantly augmented when cysteamine HCl was previously administered. Although KP-102 and GRF acted synergistically on GH secretion in control animals, they acted additively in cysteamine-administered rats. Taken together, these findings suggest that the KP-102-induced GH secretion largely depends on GRF and the secretagogue potentiates the GRF effect by antagonizing the SS action at the level of somatotropes. It is concluded that KP-102 alone or in combination with GRF provides a means of stimulating GH secretion in the face of elevated inhibitory tone mediated by SS.

Anesthesia↗
PubMedDate not supplied

Efficacy of sustained-release radioprotective drugs in vivo.

In previous publications from this laboratory we suggested the use of radioprotective drugs in a sustained-release form as a practical way to cope with their high toxicity and quick metabolism and excretion. Cysteine and cysteamine, well-established radioprotectants, were used as model drugs and compressed at various concentrations (0-65%) into an insoluble tablet matrix, composed of ethylcellulose and stearic acid at various ratios and compression pressures. We demonstrated in vitro that when the release rate of the radioprotectants was measured under nitrogen, the kinetic data conformed with the Higuchi square root of time equation, indicating that the release of both drugs correlates with Higuchi's diffusional mechanism. In the present in vivo study, tablets containing cysteine or cysteamine in a slow-release matrix were implanted, into the stomachs of female rats. The rats were irradiated at various time intervals up to 12 h after implantation and their survival recorded daily. Utilizing a 1:3 ratio of ethylcellulose:stearic acid as a matrix, the protective effect of the drugs was remarkable eight hours after tablet implantation. The results reported indicate that slow-release tablet formulation is a possible method for delivering of radioprotective drugs over an extended period of time.

Animals↗
PubMed1984

Is somatostatin a true local inhibitory regulator of insulin secretion?

Pancreatic somatostatin was depleted after oral administration of cysteamine to rats, yet the B-cells in the isolated islets were morphologically and functionally intact. Compared with islets from the rats not given cysteamine, the somatostatin-depleted islets released larger amounts of insulin during 1 h of incubation by glucose or 3-isobutyl-1-methylxanthine stimulation. Therefore, the possibility that pancreatic somatostatin may locally regulate the inhibitory effects of insulin secretion has to be considered.

1-Methyl-3-isobutylxanthine↗
PubMed1993

Dependence of glycine conjugation on availability of glycine: role of the glycine cleavage system.

1. Glycine conjugation of benzoic acid was investigated in anaesthetized rats by measuring the disappearance of benzoate from blood, and the appearance of benzoylglycine in blood and urine. 2. Administration of glycine (1-10 mmol/kg,i.v.) increased the capacity of benzoylglycine formation in a dose-dependent fashion, with a maximal rate (8.1 mumol/kg per min) occurring after administration of 5 mmol/kg glycine. The normal endogenous glycine supply (1.7 mM in liver) permits glycine conjugation only at an approximate half-maximal rate (4.5 mumol/kg/per min). 3. The increase in benzoylglycine formation in response to exogenous glycine supply is also a function of the benzoate dosage. Decreased responsiveness at high benzoate dosage indicates that the availability of coenzyme A is another factor that also limits the capacity of glycine conjugation. 4. Cysteamine (200 mg/kg, i.p.), a potent inhibitor of the mitochondrial glycine cleavage system, rapidly increased hepatic glycine concentration 2-3-fold without affecting the concentration of the other co-substrates (i.e. coenzyme A and ATP) of glycine conjugation. 5. Administration of cysteamine increased the blood clearance of benzoate by 50%, the appearance of benzoylglycine in blood, and the urinary excretion of benzoylglycine. 6. It is concluded that the activity of glycine cleavage system is an important determinant of glycine supply and, thereby, the capacity of glycine conjugation of xenobiotics.

Animals↗
PubMed1992

Thiol adducts of ethacrynic acid increase outflow facility in enucleated calf eyes.

Ethacrynic acid (ECA), a sulfhydryl (SH)-reactive diuretic drug, has been shown to increase outflow facility (C) both in living monkey eyes and in the calf eye, in vitro (Epstein et al. 1987). In an attempt to increase the therapeutic index of this drug for potential clinical use in glaucoma, we explored the effect of various thiol adducts of ECA on C in the calf eye in vitro. These adducts might be expected to liberate ECA by a reversible retro-Michael type reaction. Enucleated calf eyes were perfused at 25 degrees C at 15 mm Hg for 5 hours with various ECA-thiol adducts. ECA-cysteine at 0.25 mM (for each) increased outflow facility 104% compared to 38% in sham manipulated eyes (n-10; p less than .005). A dose response effect was demonstrated from 0.01 mM to 0.25 mM. A relative potency table (for increasing C) was established for several ECA-thiol adducts: Cysteine = cysteamine greater than glutathione greater than N-Acetyl cysteine greater than thiosalicylic acid greater than N-Acetyl cysteamine. This study identifies the potential of utilizing various derivatives of ECA as outflow pathway acting agents.

Animals↗
PubMed1977

Effect of radioprotective aminothiols on the induction and repair of single-strand breaks in the DNA of irradiated mammalian cells.

The effect of cysteamine and 2-mercapto-propionyl-glycine on the induction and repair of single-strand breaks in the DNA of Chinese hamster cells by irradiation in vitro in the presence of oxygen or in anoxia was investigated. The substances protected against the formation of breaks by irradiation both under oxic and anoxic conditions. The substances also exhibited a toxic effect which resulted in degradation of DNA. Cysteamine inhibited the rejoining of breaks after radiation exposure.

Amino Acids, Sulfur↗
PubMed1978

Irradiation of mice pre-treated with radiation protective substances. A pathologic and haematologic investigation.

CBA male mice were irradiated with single doses of 7.1, 8.6, 10.0, 11.4 or 12.8 Gy, respectively. A protective substance, 2,2-Dithiobis(N-[(1-adamantyl)methyl]acetamidine)-dihydrochloride, here called S-75, was administered orally, 45 min before start of irradiation. Cysteamine-HCl was used as a reference protective substance. Pathologic and haematologic examination of irradiated animals was performed. Cysteamine had somewhat better protective abilities than did S-75, but the latter had some other properties which indicate its possible usefulness in practice.

Acetamides↗
PubMed1981

Comparison between two radiation protective substances in irradiated mice. Effect on splenic haemopoiesis.

The radiation protective action of 2,2'-Dithiobis(N-[(1-adamantyl)-methyl]-acetamidine)-dihyrochloride (S-75) and cysteamine was compared in splenectomized and non-splenectomized mice. Cysteamine was found to have better and more general protection properties. Several indications of a specific effect of S-75 on the spleen were observed. It is suggested that the protection properties of S-75 should be tested in another laboratory animal not having such a marked splenic haemopoiesis as the mouse.

Acetamides↗
PubMed2006

Bromophenacyl bromide, a phospholipase A2 inhibitor attenuates chemically induced gastroduodenal ulcers in rats.

AIM: To study the effect of bromophenacyl bromide (BPB), a phospholipase A2 inhibitor on gastric secretion and to protect chemically induced gastric and duodenal ulcers in rats. METHODS: Acid secretion studies were undertaken in pylorus-ligated rats with BPB treatment (0, 5, 15 and 45 mg/kg). Gastric and duodenal lesions in the rats were induced by ethanol and cysteamine respectively. The levels of gastric wall mucus, nonprotein sulfhydryls (NP-SH) and myeloperoxidase (MPO) were also measured in the glandular stomach of rats following ethanol induced gastric lesions. RESULTS: BPB produced a dose-dependent inhibition of gastric acid secretion and acidity in rats. Pretreatment with BPB significantly attenuated the formation of ethanol induced gastric lesion. BPB also protected intestinal mucosa against cysteamine-induced duodenal ulcers. The antiulcer activity of BPB was associated with significant inhibition of ethanol-induced depletion of gastric wall mucus, NP-SH and MPO. These findings pointed towards the mediation of sulfhydryls in BPB induced gastrointestinal cytoprotection. CONCLUSION: BPB possesses significant antiulcer and cytoprotective activity against experimentally induced gastroduodenal lesions.

Acetophenones↗
PubMed1993

Synthesis and structure-activity relationships of new dimeric mitomycin derivatives; 7-N,7'-N'-bis(omega-thioalkyl)dimitomycins.

The reaction between mitomycin A (1) and cysteamine afforded 7-N,7'-N'-bis(2-thioethyl)dimitomycin C (7), 7-N-[2-[(2-aminoethyl)dithio]ethyl]mitomycin C (8), and 7-methoxy mitosenes (10, 11). The structures of 7 and 8 were elucidated on the basis of spectroscopy and reactions between 1 and 8, and 1 and cystamine. The observation of the time course for the reaction revealed the mechanism of the formation of 7 and 8. The rapid oxidation of cysteamine by the quinone of 1 gave cystamine, which was trapped by 1 to give 8, and 8 was additionally reacted with 1 to give 7. Since 7 showed significant antitumor activities, related 7-N,7'-N'-bis(omega-thioalkyl)dimitomycins were synthesized. They also showed remarkable antitumor activities against HeLa-S3 in vitro, sarcoma 180 (sc-ip), leukemia P388 (ip-ip) in vivo. In these evaluations, compound 7 demonstrated unique potency.

Animals↗
PubMed1999

New method for determining cystine in leukocytes and fibroblasts.

BACKGROUND: Cystinosis is a rare inborn error of cystine transport, leading to accumulation of cystine in the lysosomes. To diagnose cystinosis and monitor treatment with cysteamine, adequate measurements of cystine concentrations in leukocytes and cultured fibroblasts are required. METHODS: Cells were sonicated in the presence of excess N-ethylmaleimide to prevent oxidation of cysteine to cystine and disulfide exchange reactions of cystine with available sulfhydryl moieties. Cystine was measured as cysteine after reduction with sodium borohydride and derivatization with monobromobimane, followed by separation with automated HPLC and fluorescence detection. RESULTS: The assay was linear to 200 micromol/L cysteine. Within-run and day-to-day (total) imprecision (CV) was <5%, and the detection limit was 0.3 micromol/L. Added cysteine, up to 200 micromol/L, was completely removed, and recovery of added cystine was 69-86%. Cystine was stable for at least 2 months in leukocytes frozen in liquid nitrogen and stored at -80 degrees C CONCLUSIONS: Oxidation of cysteine to cystine and disulfide exchange reactions of cystine with sulfhydryl moieties are prevented by N-ethylmaleimide. The detection limit for the determination of cystine is adequate to measure cystine in leukocytes and cultured fibroblasts for diagnosis of cystinosis and monitoring treatment with cysteamine.

Adult↗
PubMed2000

The effect of pantethine and ultraviolet-B radiation on the development of lenticular opacity in the emory mouse.

PURPOSE: Few studies have examined the impact of long-term treatments or exposures on the development of cataract in maturity-onset animal models. We studied the effect of treatment with D-pantethine and exposure to ultraviolet-B (UVB) radiation on the development of lenticular opacity in the Emory mouse. METHODS: A total of 164 Emory mice were randomized by litter at weaning to exposure to UVB light at 12 mJ/cm(2) for 6 hr/day (UV) or usual room light (A), and within litter, were further randomized to bi-weekly intra-peritoneal injections of 0.8 g/kg pantethine (T) or no treatment (C). Retro illumination lens photos were taken at 2, 4, 6, 8, and 10 months after weaning, and graded in masked fashion. The animals were sacrificed at 10 months and the lenses analyzed for total pantethine and total cysteamine. RESULTS: Lens pantethine and cysteamine levels were significantly (P < 0.001) higher for the T as compared to C litters. Mean cataract grade increased monotonically over time for all four groups. Unadjusted mean grade for the AT group at 8 (1.32) and 10 (1.86) months appeared lower than for the other groups (AC: 2.17, 2.39; UVC: 1.77, 2.40; UVT: 1.88, 2.37). However, the mean grade for the pantethine-treated litters did not differ significantly from the untreated litters except at 2 months (when untreated litters had significantly lower grades), when adjusting for UV treatment, gender and litter effect. No significant difference in cataract score existed between UV-exposed and ambient litters. Mortality was higher among pantethine-treated (hazard ratio = 1.8, p = 0.05) and UV-exposed animals (hazard ratio = 1.8, p = 0. 03) than among the untreated and unexposed litters. CONCLUSION: Significantly increased lens levels of pantethine are achieved with long-term intra-peritoneal dosing. The impact of pantethine on the progression of lenticular opacity in the Emory mouse is less than has been reported in other models. This level of chronic UVB exposure appeared to have no effect on the development of cataract in this model.

Animals↗