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PubMed1994

Protein level in testes, kidneys and liver after AET or MEA treatment of mice.

The adult male Swiss mice were treated intraperitoneally with AET (2-aminoethylisothiouronium Br.HBr) or MEA (cysteamine HCl), in a toxic dose of 400 mg/kg body weight. The measurements of the protein content in crude homogenates of testes, kidneys and liver were done every fourth hour throughout a 24-hour period. Treatment of mice with AET and MEA resulted in different patterns of temporal changes in the protein content in testes, kidneys and liver expressed in mg per 1 g of fresh tissue and per the whole organ weight. The extent and timing of the alterations in the protein level appeared to depend on the particular organ chosen and the thiol agent applied.

Animals↗
PubMed1994

Fibrinogen Milano V: a congenital dysfibrinogenaemia with a gamma 275 Arg-->Cys substitution.

An abnormal fibrinogen was discovered in a clinically asymptomatic woman from Italy. Routine coagulation studies revealed prolonged thrombin and reptilase clotting times and a discrepancy between the plasma fibrinogen levels determined by the clotting assay and electroimmunoassay. Release of fibrinopeptides A and B from fibrinogen Milano V by thrombin was normal. Fibrin polymerization was strongly delayed in the presence of EDTA and was partially corrected at physiological calcium concentration. Normal migration of mercaptolysed polypeptide chains was observed in polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate. Moreover, there was no apparent abnormality in the charge of the reduced chains of the variant fibrinogen, as judged by two-dimensional gel electrophoresis. A fragment of the gamma-chain gene coding for the amino acids 259-350 was amplified and cloned. The amino acid gamma 275 arginine was found to be substituted by cysteine. Immunoblotting analysis with a rabbit antiserum against human serum albumin indicated that albumin was not linked to the odd sulphydryl group of fibrinogen Milano V. Treatment of fibrinogen Milano V with cysteamine, that is surmised to convert the mutant cysteine to a positively charged lysine analogue, did not improve the clotting properties of fibrinogen Milano V.

Afibrinogenemia↗
PubMedDate not supplied

Antioxidative activity of benzylideneascorbate and its effect on adriamycin-induced cardiotoxicity.

The in vitro antioxidative activity of benzylideneascorbate (SBA) and the in vivo effect on adriamycin (ADR)-induced cardiotoxicity in a mouse model were investigated. The radical-scavenging activity of SBA was assayed in terms of reduction of chemiluminescence induced by O2-, generated in xanthine/xanthine oxidase and macrophage/phorbol myristate acetate reaction systems. SBA showed a strong antioxidative activity (IC50 = 3 to 4 microM) in both assay systems, though its activity was weaker than that of ascorbic acid (Asc). In the assay of the antioxidative activity against auto-oxidation of linolenic acid, SBA was stable and retained its potency for a long period of time in comparison with Asc, 6-palmitoylascorbic acid (6-P-Asc) and cysteamine (CysNH2). Electron spin resonance examination indicated that SBA strongly scavenged both superoxide anion and hydroxy radical. The in vivo protective effect of SBA against ADR-induced cardiotoxicity, in which active oxygen radicals play a role, was examined. The serum creatine phosphokinase activity, a parameter of cardiotoxicity, was remarkably increased from the 3rd day until the 4th day after ADR treatment. This elevation was significantly suppressed by SBA treatment, whereas Asc, 6-P-Asc and CysNH2 were ineffective. SBA could have clinical potential for the treatment of diabetes and other disorders in which active oxygen species play a pathogenic role.

Animals↗
PubMed1994

Vitalethine modulates erythropoiesis and neoplasia.

Novel compounds based upon the thiol N-(carboxy)-beta-alanyl-cysteamine (vitaletheine) have strikingly potent and seemingly diverse biological activities. Concentrations of vitaletheine modulators from 1 femtograms/ml to 100 picograms/ml medium regulate RBC production from progenitors initially deprived of erythropoietin. Similarly, as little as attograms/ml concentrations of the disulfide vitalethine stimulate immunological responses of murine splenocytes toward sheep RBC in a hemolytic plaque assay. Because dosages of vitalethine as low as femtograms/kg substantially diminish tumor size and incidence and increase survival to 80% in mice inoculated with a uniformly fatal melanoma (Cloudman S-91), activities of these compounds have in vivo significance. A preliminary probe of the benzyl derivative of vitalethine in a myeloma model (NS-1) suggests efficacy (100% survival) as well. The high potencies of the vitaletheine modulators, both in cell culture and in vivo, indicate that these or similar regulatory components, if constitutively present, probably occur endogenously at vanishingly small concentrations and may be prone to deficiency resulting from metabolic imbalances, irradiation, aging, diet, pathogenic or parasitic infections, or exposure to environmental pollutants. Pathways for the biosynthesis of vitaletheine are proposed and chemical syntheses of the vitaletheine modulators are described. Possible molecular mechanisms of action, including interactions with peptidyl hormones, other endogenous effectors, and xenobiotic and pharmaceutical compounds, are explored. Indications for the treatment of other diseases are identified.

Animals↗
PubMed1994

Seemingly diverse activities of beta-alethine.

beta-Alethine (beta-alanyl-cysteamine disulfide) exhibits striking biological activities in diverse systems. At an optimum of about 10 ng/ml, beta-alethine (a) adapts murine liver cells to culture (53 colonies/10(6) cells versus none in controls), (b) delays aging of human IMR-90 fetal lung fibroblasts (102 population doubling levels versus 47 in controls, producing 3 x 10(16) greater biomass), and (c) markedly stimulates antibody-producing plaque-forming cells from murine splenocytes (16,875/10(6) cells versus 55/10(6) cells in controls) or human peripheral blood leukocytes (1826/10(6) cells versus 0/10(6) cells in controls). Early interventions with beta-alethine (1 ng/kg to 100 micrograms/kg) successfully treat NS-1 myeloma in a syngeneic murine tumor model (NS-1 myeloma). Although there are indications in this model that beta-alethine is also effective when intervention is late, beta-alethine is ineffective in an allogeneic murine melanoma model (Cloudman S-91 melanoma). It is inferred that beta-alethine enhances cellular phenotypic expression, function, and vitality in diverse biological systems and may treat certain types of neoplasia. Because atomic spacings between the amide moieties in beta-alethine are the same as in the differentiating agent hexamethylene-bis-acetamide and because the radioprotectors WR 2721 and WR 1065 lack only the carbonyl oxygen of the thiol form (beta-aletheine), biological activities already reported for these compounds are compared with those presented herein for beta-alethine. Although these comparisons have not been made in the same systems, the tentative conclusion is that the amide moieties of beta-alethine may be critical to its potency and lack of obvious toxicity in cell culture and animal models.

Animals↗
PubMed1993

Temporary changes in acid phosphatase activity in the organs of mice treated with AET or MEA prior to 60Co gamma-irradiation.

Different patterns of temporary changes were observed in the acid phosphatase/E.C. 3.1.3.2./activity in the spleen, liver, and kidneys expressed in nkat per 1 mg of protein, 1 g of fresh tissue, and per whole organ weight in mice exposed to 60Co gamma-rays only and those irradiated after AET (2-aminoethylisothiouronium Br.HBr) or MEA (cysteamine HCl) treatment. The extent and timing of the alterations in enzyme activity was dependent on the particular organ chosen and the thiol agent applied. AET and MEA administered before irradiation modified the effects of exposure of mice to gamma-rays on the acid phosphatase activity in the organs studied.

Acid Phosphatase↗
PubMedDate not supplied

[Nephropathic cystinosis: report of 2 cases and review of the literature].

We describe two patients with infantile nephropathic cystinosis who presented nephrogenic diabetes insipidus in addition to Fanconi syndrome. After the diagnosis was confirmed by slit-lamp examination that showed crystallization of the cornea and by the presence of cystine crystals in the bone marrow, the patients underwent conservative and supportive treatment including correction of acidosis, replacement of fluid losses and protection from bone demineralization with replacement of phosphorus, calcium and vitamin D. Patient 1 deceased after an episode of bronchopneumonia complicated by profound acidosis. Patient 2 was started on cysteamine which effectively reduce cystine in body tissues and prevents or slows progression of end-organ damage.

Adolescent↗
PubMed1993

Effect of a novel xanthine derivative on experimental ulcers in rats.

The effects of the novel xanthine derivative 3-ethyl-1-(6-hydroxy-6-methylheptyl)-7-propylxanthine (A90 6119, CAS 134072-58-5) on various experimentally induced ulcers was investigated in rats. A90 6119 produced a dose-dependent inhibition of gastric ulcers induced by water immersion stress and absolute ethanol with ED50- values of 2.4 and 2.8 mg/kg, p.o., respectively. The erosion induced by oral administration of 1.5% NH4OH (3 ml/rat) was significantly reduced by A90 6119 at 10 and 30 mg/kg, p.o. Likewise, A90 6119 caused a dose-dependent inhibition of gastric erosions and intestinal hemorrhage induced by platelet activating factor (PAF) with ED50- values of 8.7 and 11.9 mg/kg p.o., respectively. Duodenal ulcer induced by cysteamine was also dose-dependently inhibited by A90 6119 with an ED50-value of 0.3 mg/kg, i.p. When doses of cimetidine (200 mg/kg) and A90 6119 (10 mg/kg), equipotent in the water immersion stress model, were orally given twice daily for 5 consecutive days before the induction of gastric ulcers by stress, the H2-receptor antagonist aggravated significantly the ulcer formation while the xanthine derivative did not show such an effect. These data suggest that the 3-ethylxanthine A90 6119 possesses pronounced anti-ulcer activity and that its repeated administration might not aggravate ulcer formation and might reduce the incidence of recurrence.

Ammonium Hydroxide↗
PubMed1993

Classic nephropathic cystinosis as an adult disease.

OBJECTIVE: To delineate the clinical characteristics of infantile nephropathic cystinosis in adult patients who have undergone renal transplantation. DESIGN: Case series. SETTING: Clinical research unit. PATIENTS: All 36 adult patients with nephropathic cystinosis referred to the National Institutes of Health. OUTCOME MEASURES: Longevity, growth, renal allograft survival, visual acuity, endocrine insufficiency, myopathy and swallowing dysfunction, cerebral calcifications, and occupational status. RESULTS: Of the 36 patients, seven were dead, five with functioning allografts. The 1-year and 5-year graft survival rates for 30 cadaveric allografts were 90% and 75%, respectively. The patients' mean height and weight were severely retarded. Five patients were legally blind, and three others had severely impaired vision in one eye. Thirty-one (86%) of 36 patients required thyroid hormone replacement therapy. One third had a distal myopathy, and 21 had moderate to severe swallowing abnormalities. Eight patients had cerebral calcifications on computed tomographic scan. Despite these complications, the sighted patients engaged in a normal variety of occupations. Only 11 patients were receiving adequate cystine-depleting therapy with cysteamine (mercaptamine) or phosphocysteamine. CONCLUSIONS: Adult patients with nephropathic cystinosis suffer serious complications of the disease.

Adult↗
PubMed1996

Effects of sulphur-containing compounds and X-rays on the mouse erythropoietic system assayed by in-vivo peripheral blood micronucleus test.

PURPOSE: The protective effect of the sulphur-containing agents, MEA (cysteamine HCl), AET (2-aminoethyl-isothiouronium Br.HBr), and WR-2721 (S-2/3-aminopropylamino/ethylphosphorothioic acid) against induction of micronuclei in the erythropoietic system by X-rays was assessed. METHODS: The mouse peripheral blood micronucleus assay was applied. The frequency of micronucleated polychromatic erythrocytes (MNPCE) in the peripheral blood of adult male Swiss mice was determined 24 h after MEA, AET, or WR-2721 treatment, at a dose of 200 mg/kg body weight, and whole-body X-ray exposure to a dose of 6 Gy. RESULTS: After X-irradiation of mice, the number of MNPCE was distinctly increased. MEA, AET, or WR-2721 administration, 15 min prior to X-irradiation resulted in a reduction of the X-ray-induced elevation of the frequency of micronuclei. So, the radioprotection of the sulphur-containing drugs against the induction of MNPCE in the erythropoietic system by X-rays was shown. CONCLUSION: The mouse peripheral blood micronucleus test can be used to screen potential radioprotective agents.

Amifostine↗
PubMed1977

Acetaminophen toxity.

A case report of an acetaminophen overdose is described, and the toxicity, clinical course and treatment of acetaminophen overdose are discussed. Treatment modalities include removal of the acetaminophen by emesis or gastric lavage, the use of activated charcoal and a saline cathartic. Several antidotes have been proposed, most notably cysteamine and acetylcysteine.

Acetaminophen↗
PubMedDate not supplied

Antiulcer activity of pentacaine and some of its derivatives: effect on experimentally induced gastric and duodenal lesions and on gastric acid secretion in rats.

The antiulcer, gastroprotective, and antisecretory effects of selected carbanilates were tested in rats. The compounds K-1905 and K-2002 were found to have beneficial effects similar to those of pentacaine in phenylbutazone- and ethanol-induced gastric injury and in cysteamine-induced duodenal lesions; their antisecretory activity was also comparable to pentacaine in pylorus-ligated rats. Compounds P2 and P3 were generally less effective than pentacaine, and compound P1 was gastrotoxic. Thus pentyloxy-substitution on the benzene ring of the parent structure (K-1905 and K-2002) is more suitable for antiulcer and gastroprotective activity than methoxy-substitution on the meta-position (P3) or alkyloxy-substitution on the para-position (P2, P1). The results indicate that the two carbanilates K-1905 and K-2002 can be considered prospective antiulcer drugs.

Animals↗
PubMed1996

Prevention of radiolysis of monoclonal antibody during labeling.

UNLABELLED: Monoclonal antibody may undergo loss of immunoreactivity due to radiation damage when labeled with large amounts of 131I or 90Y for therapy. Our aim was to develop a method to protect an antibody during the labeling procedure. METHODS: As a model we used T101, a murine monoclonal antibody directed against CD5 antigen. Iodine-125-T101 (100 micrograms, 1 ml) was mixed with 90Y-DTPA (0.64 MBq to 165.9 MBq) for 24 hr in order to deliver doses of 5 Gy to 1280 Gy to the solution. In separate experiments, 125I-T101 solutions were irradiated with 60Co external beam delivering radiation doses of 40 Gy to 1280 Gy. The effect of radiation on T101 immunoreactivity was tested by using the CCRF-CEM cell line, and the bound T101 radioactivity was determined. In a final experiment, we directly labeled a DTPA conjugated T101 using 561 MBq of 90Y under conditions delivering approximately 640 Gy to the solution. Previously used radioprotectants including human serum albumin, cysteamine and glycerol were evaluated. We focused on ascorbic acid because it is an FDA approved drug that does not interfere with the radiolabeling process. RESULTS: The immunoreactivity of 125I-T101 was approximately 83%, but at 640 Gy the immunoreactivity decrease to 7%. In contrast, in the presence of radioprotectants this decrease could be abrogated. External irradiation also showed a dose dependent decrease in immunoreactivity to as low as 0.3% at 1280 Gy. Adding ascorbic acid (5.5 mg/ml) to the solutions prior to the irradiation largely abrogated this decrease. The immunoreactivity of T101 labeled with 90Y without protectant showed 46% immunoreactivity whereas, in presence of ascorbic acid (11 mg/ml) full retention of immunoreactivity was observed. CONCLUSION: Various radioprotectants can successfully prevent the loss of immunoreactivity or breakdown as a result of radiolysis. Ascorbic acid is an effective radioprotectant that can be used to prevent loss of antibody immunoreactivity during the labeling process.

Animals↗
PubMed1996

Binding of radioprotective thiols and disulfides in Chinese hamster V79 cell nuclei.

Binding of thiols of varying charge (Z) in nuclei prepared in suspension was determined to assess the extent to which histones, Mg2+ spermine and chromatin structure influence counter-ion condensation of cationic thiols and co-ion depletion of anionic thiols at DNA. The nuclei were prepared in suspension buffer, washed and incubated in buffer containing thiol and graded amounts of Mg2+ and spermine. The nuclei were separated from the incubation medium by centrifugation through silicone oil, and the thiols were determined in the nuclear pellet and in the incubation buffer by labeling with monobromobimane and HPLC. Measurements of the water content of nuclei indicated that chromatin was fully condensed in buffer containing 5 mM MgCl2 and 115 mM KCl. Under these conditions nuclei incubated in 1 mM substrate had concentrations of 0.80 +/- 0.21 mM glutathione (Z = -1), 1.05 +/- 0.12 mM 2-mercaptoethanol (Z = 0), 0.95 +/- 0.15 mM cysteine (Z = 0), 0.75 +/- 0.29 mM cysteamine (Z = +1), 2.5 +/- 0.3 mM WR-1065 (Z = +2), 3.4 +/- 0.5 mM WR-35980 (Z = +3) and 12 +/- 2 mM WR-33278 (disulfide of WR-1065, Z = +4), respectively. Spermine up to 1 mM in the presence of 5 mM Mg2+ had little effect upon the binding of these thiols and disulfide, but did suppress the binding of 0.1 mM WR-33278, the results indicating that WR-33278 and spermine compete for the same sites with comparable affinity. From the results observed and the assumption that deviations from the bulk solution concentration (1 mM) result from counter-ion condensation within 3 nm of DNA, we estimate that WR-1065 (Z = +2), WR-35980 (Z = +3) and WR-33278 (Z = +4) were concentrated near DNA 6-, 8- and 20-fold, respectively, in the presence of histones, 5 mM Mg2+ and 1.0 mM spermine.

Animals↗
PubMed1996

A method for simultaneous recording and assessment of gut contractions and relaxations in vivo.

The normal gut exhibits both contractions and relaxation from a resting tonus. Pathological and pharmacological information may be gleaned from separate measurement of these activities. Methods for recording and analyzing gut contractions have been presented before. We present an extension to the methods, utilising simple foil strain gauges tested here in male Sprague-Dawley rats. Coupled with a computer-based data acquisition and analysis system, we could assess the relaxation and contraction waves recorded simultaneously and from different gut regions in vivo. In contrast with the antrum, where spontaneous motor activity consisted of low frequency relaxations and random contractions, spontaneous duodenal motility was patterned into periodic groups of intense activity interposed by periods of low amplitude, low frequency contractions and relaxations. This grouped activity was propagatory, reminiscent of migrating myoelectrical complexes. When challenged with the ulcerogen cysteamine-HCl (56 mg/100 g s.c.), only duodenal motor activity was affected. Moreover, this treatment had differential effects in the duodenum. Patterned motility was no longer distinguishable, and contraction frequency and amplitude were increased while relaxation amplitude was decreased. This method affords a particularly sensitive and more precise assessment of both contractile and relaxant motor activity in vivo, before and after drug treatment.

Animals↗
PubMed1996

The dynamics of endogenous zinc in different animal models of gastroduodenal ulceration.

The body possesses many various endogenous substances that enable it to protect itself from various noxious events. One of the nonspecific reactions is the increase of endogenous zinc concentrations in various tissues. The aim of this study was to focus on the changes of zinc serum and tissue concentrations in well-established models of gastric (24 h restraint stress and 5 min ethanol) and duodenal ulceration (24 h cysteamine). Ten female Wistar rats, weighing 180-250 g were used in each of the experimental groups. Upon sacrificing, the ulcer index was recorded. Zinc serum and tissue concentrations were determined using atomic absorption spectrophotometry. Ten unstressed animals served as a healthy control group. The results of our study clearly indicated certain changes in serum zinc in all these ulcer models. Changes in tissue concentrations, varying from model to model, were also observed. In conclusion, all this data confirm the fact that endogenous zinc represents a natural line of the body's defense system when exposed to stress.

Animals↗
PubMed1997

Mercury-stimulated histamine uptake and binding in cultured astroglial and cerebral endothelial cells.

The effects of mercuric compounds on histamine uptake and binding to uptake carrier in cultured rat astroglial and cerebral endothelial cells were investigated. Experimental results showed that mercuric compounds produced strong stimulation of glial and cerebroendothelial histamine uptake over a concentration range of 25-500 microM. The stimulated histamine uptake showed characteristics similar to those described for basal uptake in terms of sensitivity to inhibitory agents (e.g., impromidine) and the requirement of external Na+. Mercury-induced stimulation of histamine uptake could be abolished by sulfhydryl agents, dithiotreitol and cysteamine, indicating a complete reversal of, and not simply a protection from, the action of mercury. Basal and stimulated uptake of histamine represent bindings to uptake carrier with high and closely equal affinities but markedly higher capacities for stimulated uptake. In controls, the mean value of apparent KD (derived from saturation kinetics at equilibrium) was obtained as 26.7 +/- 3.9 nM for astroglial cells; and 100 microM mercuric chloride did not modify it significantly. In contrast, the apparent Bmax values differed markedly; found as 0.63 +/- 0.10 pmol/mg protein and 3.32 +/- 0.47 pmol/mg protein in the absence and the presence of 100 microM mercuric chloride respectively. For the cerebral endothelial cell line, RBE4, the apparent KD was calculated as 22.5 +/- 3.2 nM and was comparable to that obtained for astroglial cells in control and mercury-stimulated conditions. The apparent Bmax values were less, but markedly different in these conditions, obtained as 0.18 +/- 0.03 pmol/mg protein and 1.2 +/- 0.36 pmol/mg protein in the absence and the presence of mercuric ion respectively. In both cells, impromidine, the potent inhibitor of basal and stimulated histamine uptake, decreased the enhanced capacities of histamine binding (Bmax) (without affecting the dissociation constant, KD) in micromolar range, comparable to its inhibiting potency. Results confirmed that mercuric ion might enhance the binding capacity of histamine carrier and protein sulfhydryls might play a role in this effect. The observed stimulations by mercuric compounds suggest close similarities in the mechanism of histamine uptake and the structure of histamine carrier in astroglial and cerebral endothelial cells.

Animals↗
PubMed1998

Modification of the reductive pathway in gamma-irradiated DNA by electron scavengers: targeting the sugar-phosphate backbone.

Several electron scavengers that irreversibly form potential hydrogen-abstracting species upon one-electron reduction have been tested as agents for conversion of reductive damage to DNA bases into damage to the sugar-phosphate backbone. Electron spin resonance spectroscopy is employed to follow the production of radicals and transformations after irradiation. The scavengers tested included neutral (acrylamide, iodoacetamide) and cationic [triphenylsulfonium (Ph3S+), o,o'-diphenylenebromonium (DPB) and o,o'-diphenyleneiodonium (DPI)] compounds. Modification of reductive radiation damage in DNA is found to occur by scavenging of initial mobile electrons at low temperatures as well as thermally activated electron transfer from DNA electron-gain centers upon annealing. Electron transfer from the bases to hydrogen-bonded acrylamide has the smallest activation energy among other scavengers but produces a secondary alkyl radical incapable of abstracting hydrogen from the sugar-phosphate backbone. A primary alkyl radical generated from iodoacetamide has been shown to abstract preferentially from the thymine methyl group but not from deoxyribose moieties. Aryl radicals generated from aromatic onium salts such as Ph3S+, and especially DPI and DPB, are found to be the agents which best abstract hydrogen atoms from the deoxyribose portion of DNA. The use of DPB and DPI as radiation modifiers allows the elimination of undesirable side reactions of aryl radicals and through hydrogen abstraction results in high yields of a species identified as the DNA C1'. sugar radical. The second reaction pathway found for DPI and DPB in DNA is addition of an aryl radical to the thymine 5,6 double bond. Cysteamine is shown to preferentially eliminate sugar radicals upon annealing and to have little impact on the thermal stability of the thymine adduct radical.

Acrylamide↗