Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cysteamine”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,171 records · Page 65Linked to original sources
PubMed1997

Modulation of radiation-induced apoptosis by thiolamines.

Exposure to the thiolamine radioprotector N-(2-mercaptoethyl)-1,3-propanediamine (WR-1065) induced apoptosis in the mouse TB8.3 hybridoma after a 60-min (LD50 = 4.5 mM) or during a 20-h (LD50 = 0.15 mM) exposure. In contrast, a 20-h exposure to 17 mM L-cysteine or 10 mM cysteamine was required to induce 50% apoptosis within 20 h. Apoptosis was not induced by either a 60-min or 20-h exposure to 10 mM of the thiazolidine prodrugs ribose-cysteine (RibCys) or ribose-cysteamine (RibCyst). Thiolamine-induced apoptosis appeared to be a p53-independent process since it was induced by WR-1065 exposure in human HL60 cells. Exposure to WR-1065 (4 mM for 15 min) or cysteine (10 mM for 60 min) before and during irradiation protected cells against the induction of both DNA double-strand breaks and apoptosis, while exposure to RibCys (10 mM for 3 h) did not. Treatment with either WR-1065, cysteine, RibCys or RibCyst for 60 min beginning 60 min after irradiation did not affect the level of radiation-induced apoptosis. In contrast, treatment with either cysteine, cysteamine or RibCys for 20 h beginning 60 min after irradiation enhanced radiation-induced apoptosis. Similar experiments could not be conducted with WR-1065 because of its extreme toxicity. Our results indicate that thiolamine enhancement of radiation-induced apoptosis is not involved in their previously reported capacity to reduce radiation-induced mutations.

Animals↗
PubMed2004

Vanin-1-/- mice exhibit a glutathione-mediated tissue resistance to oxidative stress.

Vanin-1 is an epithelial ectoenzyme with pantetheinase activity and generating the amino-thiol cysteamine through the metabolism of pantothenic acid (vitamin B(5)). Here we show that Vanin-1(-/-) mice, which lack cysteamine in tissues, exhibit resistance to oxidative injury induced by whole-body gamma-irradiation or paraquat. This protection is correlated with reduced apoptosis and inflammation and is reversed by treating mutant animals with cystamine. The better tolerance of the Vanin-1(-/-) mice is associated with an enhanced gamma-glutamylcysteine synthetase activity in liver, probably due to the absence of cysteamine and leading to elevated stores of glutathione (GSH), the most potent cellular antioxidant. Consequently, Vanin-1(-/-) mice maintain a more reducing environment in tissue after exposure to irradiation. In normal mice, we found a stress-induced biphasic expression of Vanin-1 regulated via antioxidant response elements in its promoter region. This process should finely tune the redox environment and thus change an early inflammatory process into a late tissue repair process. We propose Vanin-1 as a key molecule to regulate the GSH-dependent response to oxidative injury in tissue at the epithelial level. Therefore, Vanin/pantetheinase inhibitors could be useful for treatment of damage due to irradiation and pro-oxidant inducers.

Amidohydrolases↗
PubMed1993

Role of somatostatin in glucose regulation during endotoxicosis in the rat.

This study assessed the role of somatostatin in regulating glucose homeostasis during endotoxicosis in the rat. Plasma levels of somatostatin, glucose, lactate, insulin, and glucagon were measured in control and endotoxin-treated rats. Cysteamine was used to block endogenous somatostatin release before endotoxin treatment. Early during the course of endotoxicosis, plasma levels of somatostatin-like immunoreactivity (SLI) were significantly elevated along with glucose, lactate, insulin, and glucagon. Pretreatment of endotoxic rats with cysteamine virtually blocked the elevated SLI levels and prevented the early appearance of hyperglycemia. Endotoxin-induced increases in lactic acid and glucagon levels were attenuated by cysteamine pretreatment, but elevated insulin levels were not appreciably altered. Elevated somatostatin levels appeared to support the occurrence of the early hyperglycemia and prevent the development of late hypoglycemia during endotoxicosis by sustaining elevated glucagon levels and thus facilitating the maintenance of glucose levels. The results suggest that somatostatin plays a significant role in the glucoregulatory response to endotoxicosis. Endotoxicosis may alter the relative "physiological" ability of somatostatin to inhibit the secretion of insulin and glucagon.

Animals↗
PubMed1995

Discordant effects of endogenous and exogenous somatostatin on growth hormone-releasing hormone secretion from perifused mouse hypothalami.

The role of somatostatin (SRIF) on growth hormone-releasing hormone (GRH) secretion has been controversial because of discordant findings that may be model dependent. We have examined possible explanations for these findings by altering endogenous and exogenous SRIF tone in a mouse hypothalamic perifusion system. Four mediobasal hypothalamic fragments were perifused in a single chamber for 6 h. After a 2-hour equilibration period, test substances were introduced and maintained throughout the perifusion. After an additional 2 h, fragments were submaximally stimulated with 30 mM K+. Depletion of tissue SRIF by 10(-3) M cysteamine increased K(+)-stimulated GRH release 2-fold without altering basal GRH secretion. Removal of endogenous SRIF tone by anti-SRIF serum also augmented the GRH response to K+. Perifusion of SRIF at concentrations ranging from 10(-12) to 10(-8) M significantly increased the GRH response to K+ in a dose-dependent manner. A significant increase was also observed during the perifusion of 10(-9) M octreotide. Simultaneous perifusion with anti-SRIF serum and 10(-9) M octreotide (to which the antibody does not bind) resulted in a response of GRH to K+ that was similar to that observed with anti-SRIF serum alone. Combined perifusion with cysteamine and 10(-9) M SRIF also resulted in a GRH response to K+ that did not differ from the response observed during cysteamine alone. The enhancement of GRH secretion by reduction of endogenous SRIF tone or tissue content implies an inhibitory role of endogenous SRIF on GRH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

An acid-independent antiulcer effect of M1 antimuscarinics in the rat.

In the rat, the antiulcer potencies of the M1 antimuscarinics telenzepine and pirenzepine, the H2 receptor blocker cimetidine, and the H+/K+-ATPase inhibitor omeprazole were compared with their antisecretory potencies. On a molar basis and with regard to inhibition of cysteamine-induced acid secretion, telenzepine ranked first, followed by omeprazole, cimetidine, and pirenzepine; cysteamine-induced duodenal ulcers were best inhibited by telenzepine, with pirenzepine, omeprazole and cimetidine ranking 2nd, 3rd and 4th. Up to the highest dose tested, cimetidine and omeprazole caused inhibition by 26 and 37%, respectively. While, with the antimuscarinics, lesion inhibition runs parallel with inhibition of acid secretion, the H2 receptor blocker and the H+/K+-ATPase inhibitor markedly impair acid secretion, but do not or merely negligibly inhibit cysteamine-induced formation of duodenal ulcers. This suggests that in this animal model the antiulcer effect cannot be attributed exclusively to the antisecretory action.

Animals↗
PubMed1976

Cystinosis. Intracellular cystine depletion by aminothiols in vitro and in vivo.

Certain aminothiols rapidly deplete cultured cystinotic skin fibroblasts of their abnormally high free (nonprotein) cystine pool. The free cystine content of these cells if reduced by over 90% in 1 h with 0.1 mM cysteamine. This is more rapid than previously known methods of removing free cystine from cystinotic fibroblasts. The disulfide, cystamine, is also able to deplete cystinotic cells of free cystine. A patient with nephropathic cystinosis and end-stage renal disease was treated with cysteamine, both intravenously and orally. Both methods of administration rapidly lowered the free cystine content of the patient's peripheral leukocytes. Study of the patient's urinary sulfur excretion did not conclusively determine the effect of this therapy on the total body cystine pool. Her renal status remained at end stage after 1 mo of oral cysteamine, when an episode of grand mal seizures prompted cessation of the study. Determination of the proper place of aminothiol therapy in this disease will depend upon further clinical trial with patients whose kidney function has not deteriorated to the point of irreversible change, accompanied by careful monitoring of plasma aminothiol levels.

Child↗
PubMed1982

Enhancement of residual arylsulfatase B activity in feline mucopolysaccharidosis VI by thiol-induced subunit association.

The molecular pathology of the deficient arylsulfatase B activity in feline mucopolysaccharidosis (MPS) VI was investigated. Compared with the highly purified normal feline hepatic enzyme, the purified MPS VI residual activity had a 100-fold higher Michaelis constant (K(m)), an altered electrophoretic mobility, half the apparent native molecular weight, and markedly decreased thermo-, cryo-, and pH stabilities. Molecular weight and alkylation studies were consistent with the normal enzyme being a homodimer and the residual MPS VI enzyme a monomer. When incubated with various sulfhydryl reagents, the residual specific activity was enhanced several-fold, whereas the activity of the purified normal enzyme was un-affected or slightly inhibited. In the presence of dithiothreitol (DTT) and cysteamine, a lysosomotropic aminothiol, the residual activity had an electrophoretic mobility and native molecular weight similar to those of the normal feline enzyme. These findings suggested that the monomeric residual enzyme was dimerized in the presence of thiol-reducing agents. To determine if thiol-induced subunit association could therapeutically increase the residual activity and degrade the accumulated dermatan sulfate, in vitro and in vivo experiments were undertaken. When 2 mM DTT or cysteamine was incubated with heparinized whole blood from an MPS VI cat, the leukocyte residual arylsulfatase B activity increased 11- and 20-fold, respectively, and the accumulated dermatan sulfate was degraded in the presence of both thiol reagents. Intravenous administration of DTT (50 mg/kg) effected an immediate, but transient, increase in leukocyte residual activity; however, the substrate levels were not significantly decreased. In contrast, intravenous administration of cysteamine (15 mg/kg) increased leukocyte residual activity more than sixfold 30 min postinfusion; concomitantly, the leukocyte substrate was decreased to 35% of the initial level immediately after infusion and to about 45% of preinfusion values during the 120-min period studied. These results suggest that the defective residual activity in feline MPS VI can be therapeutically manipulated by thiol-induced subunit association. Furthermore, this animal analog provides a prototype for the investigation of human inborn errors of metabolism resulting from enzymatic defects that might be amenable to enzyme manipulation therapy.

Animals↗
PubMed2004

Vanin-1(-/-) mice show decreased NSAID- and Schistosoma-induced intestinal inflammation associated with higher glutathione stores.

Vanin-1 is a membrane-anchored pantetheinase highly expressed in the gut and liver. It hydrolyzes pantetheine to pantothenic acid (vitamin B5) and the low-molecular-weight thiol cysteamine. The latter is believed to be a key regulating factor of several essential metabolic pathways, acting through sulfhydryl-disulfide exchange reactions between sulfhydryl groups of the enzymes and the oxidized form, cystamine. Its physiological importance remains to be elucidated, however. To explore this point, we developed Vanin-1-deficient mice that lack free cysteamine. We examined the susceptibility of deficient mice to intestinal inflammation, either acute (NSAID administration) or chronic (Schistosoma infection). We found that Vanin-1(-/-) mice better controlled inflammatory reaction and intestinal injury in both experiments. This protection was associated with increased gamma-glutamylcysteine synthetase activity and increased stores of reduced glutathione, as well as reduced inflammatory cell activation in inflamed tissues. Oral administration of cystamine reversed all aspects of the deficient phenotype. These findings suggest that one cysteamine function is to upregulate inflammation. Consequently, the pantetheinase activity of Vanin-1 molecule could be a target for a new anti-inflammatory strategy.

Amidohydrolases↗
PubMed1985

Effect of elcatonin on experimental gastric and duodenal ulcers.

The antiulcer action of elcatonin, an analogue of natural eel calcitonin, was compared with that of cimetidine, secretin and solcoseryl. Elcatonin (3 to 10 mu/kg, s.c.) inhibited the development of gastric ulcers induced by pylorus ligation, water-immersion stress, aspirin and reserpine and duodenal ulcers induced by cysteamine in rats. Moreover, once daily injections of elcatonin (1 to 10 mu/kg/day, s.c.) promoted the healing of acetic acid-induced chronic gastric ulcers not only in rats but in dogs. The healing effect persisted after the cessation of administrations. Cimetidine (30 to 100 mg/kg, p.o.) inhibited the development of gastric ulcers induced by water-immersion stress, aspirin and reserpine and duodenal ulcers induced by cysteamine in rats. However, once daily administrations of cimetidine (30 to 100 mg/kg/day, p.o.) did not show significant effect on acetic acid-induced chronic gastric ulcers in rats. Secretin (30 to 100 mu/kg, s.c.) inhibited the development of gastric ulcers induced by pylorus ligation, water-immersion stress, aspirin and reserpine in rats, but was not effective on cysteamine-induced duodenal ulcers and acetic acid-induced chronic gastric ulcers in rats. Solcoseryl (2 ml/kg, s.c.) inhibited only the development of water-immersion stress-induced gastric ulcers in rats. These results suggest that elcatonin is different from these reference drugs in its properties of action on experimental ulcers. Mechanisms of the antiulcer action of elcatonin which has a superior effect on experimental ulcers are discussed.

Acetates↗
PubMed1975

The effects of sulphydryl reagents on the binding and mixed function oxidation of hexobarbital in rat hepatic microsomes.

1. The effects of the sulphydryl reagents p-chloromercuribenzoate, N-ethylmaleimide and iodoacetamide on the binding spectrum, oxygen consumption and formation of a suspected substrate-cytochrome P-450-oxygen complex for hexobarbital in rat liver microsomes were investigated. 2. The oxygen consumption caused by hexobarbital oxidation was inhibited non-competitively by all three agents, with 50% inhibition at 4 times 10(-5) M for p-chloromercuribenzoate, 3-7 times 10(-4) M for N-ethylmaleimide and 1-9 times 10(-3) M for iodoacetamide. Cysteamine protected and at least partially reversed this inhibition. 3. p-chloromercuribenzoate inhibited the formation of the cytochrome P-450-substrate-oxygen complex, while N-ethylmaleimide and iodoacetamide also inhibited the formation of this complex but to a lesser extent. The p-chloromercuribenzoate inhibition was protected against and reversed by cysteamine. 4. p-Chloromercuribenzoate and N-ethylmaleimide caused a 50% reduction in the magnitude of the hexobarbital-induced binding spectrum, and this was paralleled by the conversion of cytochrome P-450 to cytochrome P-420. Cysteamine protected against this effect but could not reverse it. Iodoacetamide had no effect on the binding spectrum of hexobarbital and failed to convert cytochrome P-450 to cytochrome P-420. 5. Points of attack within the reaction sequence of drug oxidation are tentatively ascribed to the sulphydryl reagents used in this study.

Animals↗
PubMed1991

Volatile N-nitrosamines in fish meal, with special reference to the mechanism of formation of N-nitrosothiazolidine.

Volatile N-nitrosamines in 32 commercial Japanese fish meal samples were analysed, and three compounds, N-nitrosodimethylamine, N-nitrosopyrrolidine and N-nitrosothiazolidine (NT), were detected. We also examined the mechanism of formation of NT during fish meal production. Both cysteamine and thiazolidine were found to be precursors of NT. The cysteamine content decreased during boiling and drying of the fish; but that of thiazolidine increased during boiling. N-Nitrosothiazolidine 4-carboxylic acid (NTCA) was formed in sardine meal after treatment with nitrogen dioxide gas, and the rate of formation of NT from NTCA added to sardine meal was as high as 10% when the meal was heated at 160 degrees C for 60 min. We propose two pathways for NT formation during fish meal manufacture: (1) cysteamine----thiazolidine----NT; and (2) cysteine----(thiazolidine 4-carboxylic acid)----NTCA----NT.

Carcinogens↗
PubMed1975

Functional deacylases of pigeon liver fatty acid synthetase complex.

Fatty acid synthetase complex (Mr = 500,000) purified from pigeon liver homogenates is inactivated by phenylmethylsulfonyl fluoride. A well characterized inhibitor of serine esterases. Pseudounimolecular kinetics are followed at all inhibitor concentrations studied (0.05 to 1.0 mM). The second order rate constant obtained at pH 7.0, 30 degrees in 0.05 M potassium phosphate, 1 mM EDTA is 250 plus or minus 10 M-1 min-1 and appears to be independent of pH between 6 and 7.9. The inactivation of the enzyme complex appears to be selective since only one of the several component enzymes of fatty acid synthesis, palmityl-CoA deacylase, is inhibited. Acetyl- and malonyl-CoA-pantetheine transacylase activities as well as the kinetics of the reduction and dehydration steps are nearly identical for the native and the modified enzymes. The rate of approach of the condensation-CO2 exchange reaction (substrates: hexanoyl-CoA, malonyl-CoA, CoA, and H14CO3-) is slightly slower in the modified enzyme, though this change is not large enough to account for total loss of activity for fatty acid synthesis. The rate of loss of palmityl-CoA deacylase activity at a constant inhibitor concentration follows biphasic kinetics. Complete inactivation is achieved only after 2 mol of the inhibitor are bound per mol of the enzyme complex. Acetyl-, butyryl-, and hexanoyl-CoA thioesters (at 1.0 mM concentrations) protect the enzyme complex against inactivation by phenylmethylsulfonyl fluoride whereas CoA has no effect. Malonyl-CoA on the other hand, promotes inhibitor-mediated inactivation. Of the N-acetyl cysteamine derivatives tested, S-acetyl-N-acetyl cysteamine (at 10 mM) gives almost complete protection against inactivation whereas S-acetoacetyl-, S-beta-hydroxybutyryl-, and S-crotonyl-N-acetyl cysteamine thioesters exhibit either slight or no protection. These data demonstrate that phenylmethylsulfonyl fluoride is a selective reagent for the inactivation of functional fatty acyl deacylase component(s) of the pigeon liver fatty acid synthetase complex, and that it has no effect on malonyl or acetyl transacylases. The data are also in accord with the postulation that the inhibitor interacts at two catalytic centers of the enzyme complex. Furthermore, the patterns of protective effects shown by saturated acyl-CoA asters and malonyl-CoA point to different mechanisms of deacylation for these esters.

Acetyl Coenzyme A↗
PubMedDate not supplied

Formaldehyde quantitation in air samples by thiazolidine derivatization: factors affecting analysis.

A new method for the determination of trace levels of formaldehyde in air was developed and validated. The method is based on the reaction of formaldehyde with cysteamine to form thiazolidine. Air samples containing trace levels of formaldehyde were prepared from paraformaldehyde. The percent yield of formaldehyde from paraformaldehyde was 85.1 +/- 1.14%. Air samples were bubbled into an aqueous cysteamine trap. Thiazolidine formed from formaldehyde and cysteamine in the trap was determined by gas chromatography with a fused silica capillary column and a nitrogen-phosphorus detector (NPD). The lowest detection level for thiazolidine was 17.2 pg, equivalent to 5.80 pg formaldehyde. The recovery efficiency of trace gas phase formaldehyde in air was greater than 90%. Formaldehyde levels in ambient laboratory air were 48.9-56.2 ppb (v/v).

Air↗
PubMed1989

Role of sulfhydryls in mucosal injury caused by ethanol: relation to microvascular permeability, gastric motility and cytoprotection.

The relationship between gastric mucosal glutathione (GSH) levels, vascular permeability, gastric motility and mucosal injury caused by ethanol was investigated in rats. Oral administration of 50% ethanol (1 ml) produced elongated reddish bands of lesions in the mucosa with a significant reduction of GSH levels and increase of microvascular permeability. These lesions were significantly inhibited by pretreatment with s.c. administered diethylmaleate (DEM: 1 ml/kg), cysteamine (100 mg/kg) and 16, 16-dimethyl prostaglandin E2 (dmPGE2, 10 micrograms/kg) but worsened markedly by N-ethylmaleimide (NEM: 10 mg/kg). Irrespective of whether the animals were treated with 50% ethanol or not, the mucosal GSH levels were significantly decreased or increased, respectively, by DEM or cysteamine, and were not affected by both NEM and dmPGE2. NEM significantly enhanced the vascular permeability in the absence or presence of ethanol (greater than 10%), whereas other agents significantly inhibited only the increased vascular permeability caused by ethanol. On the other hand, gastric motility was potently and persistently inhibited by either DEM, cysteamine or dmPGE2 at the doses which prevented ethanol-induced mucosal injury, whereas NEM had no effect on the motility. These results suggest that 1) the mucosal GSH levels do not relate directly to either development or prevention of ethanol-induced gastric injury, 2) potentiation by NEM of the mucosal injury may be accounted for by its enhancement of the vascular permeability and 3) inhibition of gastric motility may be associated with prevention of mucosal lesions.

16,16-Dimethylprostaglandin E2↗
PubMed1985

Detection and characterization of carrier-mediated cationic amino acid transport in lysosomes of normal and cystinotic human fibroblasts. Role in therapeutic cystine removal?

The discovery of a trans-stimulation property associated with lysine exodus from lysosomes of human fibroblasts has enabled us to characterize a system mediating the transport of cationic amino acids across the lysosomal membrane of human fibroblasts. The cationic amino acids arginine, lysine, ornithine, diaminobutyrate, histidine, 2-aminoethylcysteine, and the mixed disulfide of cysteine and cysteamine all caused trans-stimulation of the exodus of radiolabeled lysine from the lysosomal fraction of human fibroblasts at pH 6.5. In contrast, neutral and acidic amino acids did not affect the rate of lysine exodus. trans-Stimulation of lysine exodus was observed over the pH range from 5.5 to 7.6, was specific for the L-isomer of the cationic amino acid, and was intolerant to methylation of the alpha-amino group of the amino acid. The lysosomotropic amine, chloroquine, greatly retarded lysine exodus, whereas the presence of sodium ion was without effect. The specificity and lack of Na+ dependence of this lysosomal transport system is similar to that of System y+ present on the plasma membrane of human fibroblasts. In addition, we find cystine exodus from the lysosomal fraction of cystinotic human fibroblasts to be greatly retarded as compared to that of normal human fibroblasts with half-times of exodus similar to those reported for the lysosomes of cystinotic and normal human leukocytes (Gahl, W. A., Tietze, F., Bashan, N., Steinherz, R., and Schulman, J. D. (1982) J. Biol. Chem. 257, 9570-9575). In contrast, normal and cystinotic human fibroblasts did not show any differences with regard to lysine efflux or its trans-stimulation by cationic amino acids. An important mechanism by which cysteamine treatment of cystinosis allows cystine escape from lysosomes may be the ability of the mixed disulfide of cysteine and cysteamine formed by sulfhydryl-disulfide exchange to migrate by this newly discovered system mediating cationic amino acid transport.

Amino Acids↗
PubMed1968

Improved method for the preparation of malonyl coenzyme A.

Malonyl coenzyme A is synthesized by transacylating S-malonyl-N-decanoyl cysteamine with coenzyme A. A simplified procedure for the preparation of S-malonyl-N-decanoyl cysteamine, using cysteamine as starting material, is described.

Coenzyme A↗
PubMed1980

Interaction of sulfur-containing radioprotectors with DNA: a spectrophotometric study.

The interaction between sodium-compensated DNA and several aminothiol radioprotectors [cysteamine; methyl-2-cysteamine; cysteamine phosphorothioate; N-(2-mercaptoethyl) 1,2-diaminoethane; N-(2-mercaptoethyl)-1,3-diaminopropane; N-(3-aminopropyl)-2-aminoethyl phosphorothioic acid] has been studied by spectrophotometry. In all cases, elevation of the melting point (Tm) of the DNA-radioprotector complex was observed. The interaction of these ionized aminothiols with phosphate groups of DNA is essentially an electrostatic one, like that for metallic cations, and can be expressed by the Schildkraut-Lifson equation Tm = a log Cradio + b, where a and b are adjustable parameters and Cradio is the concentration of the radioprotectors.

Amifostine↗
PubMed1978

Serum alkaline phosphatase isoenzymes in lymphoproliferative diseases.

A new isoenzyme of alkaline phosphatase (EC 3.1.3.1) has been reported to occur in sera from patients with lymphoproliferative diseases. This enzyme is characterized by an inability to hydrolyze cysteamine S-phosphate. We find that the 5,5'-dithobis(2-nitrobenzoic acid)-coupled assay method for cysteamine S-phosphate hydrolysis is not suitable for serum, and we were unable to confirm the existence of this isoenzyme in serum by this assay method. We were unable to detect to detect this new isoenzyme by polyacrylamide gel electrophoresis with activity stains or by the reported high sensitivity of this enzyme to inhibition by cysteamine S-phosphate when p-nitrophenyl phosphate is the substrate. We were also unable to confirm reports of a unique inhibitor of normal alkaline phosphatase in the serum of patients with infectious mononucleosis.

Alkaline Phosphatase↗