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PubMed2005

Effect of the free radical scavenger MCI-186 on spinal cord reperfusion after transient ischemia in the rabbit.

OBJECTIVE: Paraplegia remains a serious complication of aortic operations. The production of free radicals during reperfusion after transient ischemia is believed to induce secondary spinal neuronal injury, resulting in paraplegia. The aim of the present study was to clarify the protective effect and method of administration of antioxidants on the neurological and histological outcome in the animal model for reperfusion injury after transient spinal cord ischemia. METHODS: New Zealand white rabbits underwent surgical exposure of the abdominal aorta that was clamped for 15 minutes to achieve spinal cord ischemia. Group A animals received two 10 mg/kg doses of 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186) at the time of release of the aortic clamp and 30 minutes later. In group B, MCI-186, 5 mg/kg, was given three times, at the time of aorta clamp release, 30 minutes and 12 hours later. In group C (control group), one dose of vehicle was administered. Neurological status was assessed using modified Tarlov's score until 168 hours after operation. Spinal cord sections were examined microscopically to determine the extent of ischemic neuronal damage. RESULTS: Groups A and B animals had better neurological function than group C (p < 0.001). In contrast, group C animals exhibited paraplegia or paraparesis with marked neuronal necrosis. The number of surviving neurons within examined sections of the spinal cord was significantly greater in group B than in group C (p < 0.001). CONCLUSION: In a 15-minute ischemia-reperfusion model using rabbits, systemic repetitious administration of MCI-186, a free radical scavenger, was found to have a protective effect on the spinal cord neurons both neurologically and histologically. We postulate that the drug minimizes the delayed neuronal cell death for reperfusion injury after transient ischemia by reducing the free radical molecules. Moreover, it was thought that we could protect delayed neuronal cell death more effectively by administering MCI-186 12 hours later.

Animals↗
PubMed1989

High-performance liquid chromatography of reducing carbohydrates as strongly ultraviolet-absorbing and electrochemically sensitive 1-phenyl-3-methyl-5-pyrazolone derivatives.

We found that 1-phenyl-3-methyl-5-pyrazolone reacts with reducing carbohydrates almost quantitatively to yield 2:1 compounds having no stereoisomers, which strongly absorb the uv light at 245 nm and are easily oxidizable on a glassy carbon electrode. Reverse-phase partition chromatography on a column of Capcell Pak C18 with uv or electrochemical detection allowed rapid analysis of aldoses and N-acetylhexosamines with the detection limit of 1 pmol or 100 fmol, respectively. This method proved especially useful for analysis of component monosaccharides of glycorproteins. It was also shown to be valid for separation of reducing oligosaccharides; maltodextrins with a degree of polymerization up to 19 were similarly derivatized and separated on this stationary phase.

Animals↗
PubMed1988

Activation of carcinogens by peroxidase. Horseradish peroxidase-mediated formation of benzenediazonium ion from a non-aminoazo dye, 1-phenylazo-2-hydroxynaphthalene (Sudan I) and its binding to DNA.

Horseradish peroxidase in the presence of hydrogen peroxide (HRP/H2O2) oxidizes a carcinogenic non-aminoazo dye, 1-phenylazo-2-hydroxynaphthalene (Sudan I) to the ultimate carcinogen, which binds to calf thymus DNA. The principal product of Sudan I oxidation by the HRP/H2O2 system is the benzenediazonium ion. Minor products are hydroxy derivatives of Sudan I, in which the aromatic rings are hydroxylated. The principal oxidative product (the benzenediazonium ion) is responsible for the carcinogenicity of Sudan I, because this ion, formed from this azo dye, binds to DNA.

Animals↗
PubMed1992

High-performance capillary electrophoresis of unsaturated oligosaccharides derived from glycosaminoglycans by digestion with chondroitinase ABC as 1-phenyl-3-methyl-5-pyrazolone derivatives.

This paper proposes a new method for simultaneous analysis of unsaturated disaccharides derived from glycosaminoglycans by enzymatic digestion with chondroitinase ABC, based on high-performance capillary electrophoresis (HPCE) of their 1-phenyl-3-methyl-5-pyrazolone derivatives. The O-sulphate group is stable in this derivatization, and this method allows reproducible microdetermination of glycosaminoglycans. This paper also demonstrates the applicability of this method to estimation of urinary chondroitin sulphates. Urinary creatinine as an inherent internal standard could also be estimated by HPCE, though in another mode of separation, i.e. ion-exchange electrokinetic chromatography.

Antipyrine↗
PubMed1995

Paracrine function of endothelium-derived nitric oxide.

We explored whether endothelium-derived nitric oxide (EDNO) acts in an autocrine or paracrine fashion to activate the soluble guanylate cyclase by measuring the elevations of cGMP levels. Comparisons were made between two culture models in which EDNO can stimulate cGMP synthesis within the same cells (endothelial cells) where it is formed, or in the neighboring cells (smooth muscle cells). The basal amount of EDNO showed no difference in cGMP levels when the endothelial cells (EC) were cultured either alone (iso-culture) or together with the smooth muscle cells (SMC, co-culture). However, cGMP levels were synergistically increased by the BK-stimulated EDNO when EC were co-cultured with SMC. The synergistical increase was significantly inhibited by 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186), an extracellular radical scavenger. These findings suggest that the tonic formed basal EDNO has an autocrine effect on cGMP levels of EC themselves. In contrast, BK-stimulated phasic formed EDNO has not only an autocrine effect, but also a paracrine effect on cGMP levels of EC themselves and the adjacent SMC.

Animals↗
PubMed1986

Temporal effects on antipyrine metabolite kinetics in Aroclor 1254-treated rats.

The in vivo consequences of a single dose of Aroclor 1254 (50 mg/kg) on the drug metabolizing capacity of rats were investigated. A noninvasive method, employing [N-methyl-14C]-antipyrine where both 14CO2 exhalation and urinary excretion of 4-hydroxy-, 3-hydroxymethyl-, and norantipyrine were monitored, was used. A group of rats were sequentially tested over a 3-week period to characterize temporal patterns. The antipyrine metabolite kinetic approach demonstrated that induction of hepatic cytochrome P-450 is maximal 3-6 days after Aroclor 1254 administration and the effects were apparent for at least a further 14-17 days. Evidence is presented to suggest selective effects of Aroclor 1254 on different cytochromes P-450 are apparent in vivo.

Animals↗
PubMed1990

The effect of age on the oxidative metabolism of antipyrine by uninduced microsomal fractions of rat liver.

The influence of ageing on the metabolism of antipyrine by different forms of cytochrome P-450 was studied in vitro, by measuring the formation of antipyrine metabolites by microsomes isolated from untreated rats, which were grouped into 5 different ages. Km, Vmax and Vmax/Km values were determined for the metabolites: 3-hydroxymethylantipyrine (HMA), norantipyrine (NORA) and 4-hydroxyantipyrine (OHA). Km values for all metabolites ranged from 2.0 to 5.0 mM and Vmax values from 1.84 to 3.66 nmol/min per mg. The Vmax/Km ratios varied from 0.65 to 1.73 microliters/min per mg. With respect to the Km values, a decrease for HMA from 12 to 24 months, no change for OHA and an increase for NORA from 3 to 30 months, was observed. The Vmax values showed an increase for HMA from 3 to 24 months, a decrease for OHA from 12 to 30 months and no change for NORA. The absolute Vmax/Km ratios for all metabolites showed no significant changes during ageing. However, regarding the relative Vmax/Km ratios, an increase for HMA from 3 to 24 months, a decrease for OHA from 12 to 35 months and also a decrease for NORA from 3 to 24 months, was observed. It is concluded that ageing influenced the Km, Vmax and Km/Vmax ratio of the different P-450 isoenzymes involved in antipyrine metabolism, in different ways. However, the age-related changes are modest (10-100%), especially for the Vmax/Km ratio.

Aging↗
PubMed1995

Antipyrine clearance and metabolite excretion in patients with chronic hepatitis C.

BACKGROUND/AIMS: Our aim was to study whether chronic hepatitis C affects the three metabolic pathways of the model drug antipyrine differently. METHODS: We measured antipyrine clearance from saliva as well as urinary excretion of its main metabolites 4-hydroxy-antipyrine, 3-hydroxy-methyl-antipyrine, and nor-antipyrine in 24 patients with chronic hepatitis C and in 21 healthy control subjects. Due to incomplete urine collection, 12 liver patients and three controls were excluded. RESULTS: Antipyrine clearance (mean +/- SD) was significantly lower in patients with chronic hepatitis C, 1.2 +/- 0.7 l.h-1 (n = 12), than in controls (n = 18), 2.2 +/- 1.0 l.h-1 (p = 0.006). The urinary excretion of each of the metabolites was depressed to an equal extent in liver patients. The severity of the liver disease, as assessed by Child Pugh score, serum albumin and bilirubin, correlated significantly with antipyrine clearance and urinary excretion of the metabolite 3-hydroxy-methyl-antipyrine. The hepatitis activity index (Knodell) correlated with 3-hydroxy-methyl-antipyrine and 4-hydroxy-antipyrine, only. CONCLUSIONS: Moderate-severe chronic hepatitis C does not seem to depress the three main metabolic pathways of antipyrine differently.

Adult↗
PubMed1988

The first identification of the benzenediazonium ion formation from a non-aminoazo dye, 1-phenylazo-2-hydroxynaphthalene (Sudan I) by microsomes of rat livers.

1-Phenylazo-2-hydroxynaphthalene (Sudan I) is converted by microsomal enzymes of rat livers in vitro to 5 products. Hepatic microsomes from 5,6-benzoflavone-treated rats are more effective for the metabolism of Sudan I than those from phenobarbital- or Sudan I alone-treated rats. Major products formed by microsomes are identified as the ring-hydroxyderivatives of benzene and naphthalene rings. The formation of the benzenediazonium ion evolved by oxidative splitting of the azo group of Sudan I by microsomal enzymes is also proved. The oxidative splitting of Sudan I by microsomal enzymes may be considered as the possible mechanism of the Sudan I activation to the ultimate carcinogen (benzenediazonium ion).

Animals↗
PubMed1991

High-performance liquid chromatographic method for the determination of the three main oxidative and 3-carboxylic antipyrine metabolites in human urine.

The oxidative metabolism of xenobiotics is usually explored using the antipyrine test, which consists of determining the production clearances and urinary percentages of three major antipyrine metabolites 4-hydroxyantipyrine, norantipyrine and 3-hydroxymethylantipyrine. The total forms of these compounds are generally determined by high-performance liquid chromatography (HPLC). However, the 3-carboxylic acid metabolite (3-carboxyantipyrine), which is the ultimate oxidation form in the 3-hydroxylation pathway, should also be taken into account, but so far its determination by HPLC has not been reported. A simple and accurate HPLC method has now been developed to determine the three major metabolites plus 3-carboxyantipyrine. In this method, all compounds are extracted in an aprotic non-polar solvent, at pH 3.5 for the major metabolites and unchanged antipyrine, then at pH 0.9 for 3-carboxyantipyrine. Total forms are evaluated after enzymatic hydrolysis. Throughout the procedure, attention is paid to the relative instability of norantipyrine and 4-hydroxyantipyrine. Recovery, accuracy and precision are discussed. The method has been applied to the determination of relative amounts (percentage of the dose administered) excreted in the urine of ten adult subjects 48 h after ingestion of antipyrine (600 mg). The proportion of 3-carboxyantipyrine excreted was 4.5 +/- 0.2%, which is in agreement with published values obtained by gas chromatography. The excretion rates of the major metabolites also were similar to those reported in the literature, thereby confirming that the reported method is valid. 3-Carboxyantipyrine is totally excreted as the free form and norantipyrine almost completely as glucuroconjugate.

Antipyrine↗
PubMed1989

Assay of antipyrine and its main metabolites 3-hydroxymethylantipyrine, norantipyrine and 4-hydroxyantipyrine in urine.

Two assay methods for antipyrine (AP) and its main metabolites 3-hydroxymethylantipyrine (3-HMA), norantipyrine (NORA) and 4-hydroxyantipyrine (4-HA) in urine samples have been compared. Method I involved a 3 h incubation at 37 degrees C with beta-glucuronidase, whereas method II used acid hydrolysis with 3 M hydrochloric acid to convert NORA glucuronide to the aglycone and 24 h incubation at 37 degrees C with beta-glucuronidase for hydrolysis of 3-HMA and 4-HA glucuronides. The precision of both sample preparation procedures was evaluated by means of HPLC with UV detection. The relative standard deviation (RSD) for the metabolites were considerably greater than 10% with method I. Application of method II, however, led to intra-assay and inter-assay RSD of less than 10%.

Antipyrine↗
PubMed1988

Preventive effect of MCI-186 on 15-HPETE induced vascular endothelial cell injury in vitro.

Using cultured bovine aortic endothelial cells, the effects of MCI-186, a radical scavenger, were studied on arachidonic acid metabolism and on the cell injury caused by 15-HPETE. MCI-186 at 3 X 10(-5) M enhanced prostacyclin production in the intact endothelial cells without affecting phospholipase A2. When endothelial cell homogenates were used as an enzyme source, it was found that MCI-186 stimulated the conversion of arachidonic acid to prostacyclin like phenol, perhaps by trapping OH radicals produced in the process of the conversion of PGG2 to PGH2. On the other hand, MCI-186 was found to inhibit lipoxygenase metabolism of arachidonic acid in cell free homogenates of rat basophilic leukemia cells. The lipoxygenase inhibition caused by 3 X 10(-5) M MCI-186 was almost equivalent to that caused by 3 X 10(-6) M BW 755C. MCI-186 remarkably protected against endothelial cell damage caused by 15-HPETE. 3 X 10(-5) M of 15-HPETE caused endothelial cell death in about 60% of the population: however, pretreatment of the cells with 10(-5) M of MCI-186 or concomitant addition of 10(-5) M of MCI-186 with 15-HPETE to the cultures prevented the cell death completely. These results suggest that MCI-186 may become an unique anti-ischemic drug.

Animals↗
PubMed2004

MCI-186 reduces oxidative cellular damage and increases DNA repair function in the rabbit spinal cord after transient ischemia.

BACKGROUND: Paraplegia is a serious complication of operations on the thoracic and thoracoabdominal aorta. To investigate the mechanism by which motor neurons are damaged during these operations, we have reported a rabbit model of spinal cord ischemia. We also tested whether a free radical scavenger MCI-186 that is useful for treating ischemic damage in the brain can protect against ischemic spinal cord damage. METHODS: Fifteen minutes of ischemia was induced, then MCI-186 or vehicle was injected intravenously. Cell damage was analyzed by observing the function of the lower limbs and by counting the number of motor neurons. To investigate the mechanism by which MCI-186 prevents ischemic spinal cord damage, we observed the immunoreactivity of 8-hydroxy-2'-deoxyguanosine as an oxidative DNA damage marker and redox effector as a DNA repair marker. RESULTS: In sham control, 8-hydroxy-2'-deoxyguanosine was not observed, and the nuclear expression of redox effector was observed. In vehicle injection group (group I), the nuclear expression of 8-hydroxy-2'-deoxyguanosine was observed at 1 and 2 days after reperfusion. The nuclear expression of redox effector was observed at 8 hours and 1 day, and disappeared at 2 days after transient ischemia. In MCI-186 injection group (group M), the nuclear expression of 8-hydroxy-2'-deoxyguanosine was not observed, and redox effector was observed at 8 hours and 1 and 2 days. CONCLUSIONS: These results suggest that redox effector decreased in motor neurons after transient ischemia and this reduction preceded oxidative DNA damage. MCI-186 works as a radical scavenger and reduced oxidative DNA damage, so redox effector did not disappear. MCI-186 could be a strong candidate for a use as a therapeutic agent in the treatment of ischemic spinal cord injury.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2006

Effect of the free radical scavenger MCI-186 on pulmonary ischemia-reperfusion injury in dogs.

BACKGROUND: Free radical scavengers and superoxide dismutase have been found to protect against cerebral ischemic damage, and it was suggested that oxygen free radicals contribute to ischemia-reperfusion injury induced by cerebral ischemic damage. MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one) is a potent scavenger and inhibitor of hydroxyl radicals and protective agent of peroxidative injury. The purpose of this study was to evaluate the effects of MCI-186 on pulmonary ischemia-reperfusion injury in a simulated transplanted lung model. METHODS: Fourteen dogs were divided into two groups (n = 7 each). In the MCI group, MCI-186 was continuously administered at 3 mg/kg/hour intravenously (IV) from 30 minutes before reperfusion until 30 minutes after reperfusion (total administration time 1 hour). Vehicle was administered in the control group. Warm ischemia was induced for 3 hours by clamping the left pulmonary artery and veins. Simultaneously, the left stem bronchus was bisected and then anastomosed before reperfusion. The right pulmonary artery was ligated 15 minutes after reperfusion, and the right stem bronchus was then bisected. RESULTS: The respiratory gas exchange, hemodynamic changes, wet-to-dry weight ratio (WDR) and malondialdehyde (MDA) concentration in the tissue were significantly improved (p < 0.05) in the MCI group. The histologic damage was more severe in the control group and polymorphonuclear neutrophil (PMN) infiltration was reduced in the MCI group. CONCLUSION: MCI-186 has a protective effect on pulmonary ischemia-reperfusion injury through the inhibition of lipid peroxidation.

Animals↗
PubMed2005

Influence of the labeling group on ionization and fragmentation of carbohydrates in mass spectrometry.

The ionization and fragmentation behaviors of carbohydrate derivatives prepared by reaction with 2-aminobenzamide (AB), 1-phenyl-3-methyl-5-pyrazolone (PMP), and phenylhydrazine (PHN) were compared under identical mass spectrometric conditions. It has been shown that the intensities of signals in MS spectra depend on the kind of saccharides investigated and reducing end labels used. PMP sialyllactose, when ionized by ESI/MALDI, produced a mixture of [M + H]+, [M + Na]+, [M - H + 2Na]+ ions in the positive mode and [M - H]-, [M + Na - 2H]- ions in the negative mode. The AB and PHN derivatives formed abundant [M + H]+ and [M - H]- ions in ESI, and by matrix-assisted laser desorption/ionization (MALDI) produced abundant [M + Na]+ ions. PMP- and reduced AB-sialyllactose produced only Y-type fragment ions under both MS/MS sources. In the electrospray ionization (ESI)-MS/MS spectrum of PHN-sialyllactose, abundant ions corresponded to B, Z cleavages and in its MALDI-MS/MS spectrum, the abundant ions were consistent with Y glycosidic cleavages with the concurrence of B, C, and cross-ring fragment ions. In the MALDI-MS spectra of oligosaccharides acquired immediately after derivatization, it was possible to detect only PHN derivatives. After purification, spectra of all three types of derivatives showed high signal-to-noise ratios with the most abundant ions observed for AB reduced saccharides. [M + Na]+ ions were the dominant products and their fragmentation patterns were influenced by the type of the labeling and the kind of oligosaccharide considered. In the MALDI-PSD and -MS/MS spectra of AB-derivatized glycans, higher m/z fragment ions corresponded to B and Y cleavages and the loss of bisecting GlcNAc appeared as a weak signal or was not detected at all. Fragmentation patterns observed in the spectra of hybrid/complex PHN and PMP glycans were more comparable-higher m/z fragments corresponded to B and C glycosidic cleavages. For PHN glycans, the abundance of ions resulting from the loss of bisecting GlcNAc depended on the number of residues linked to the 6-positioned mannose. Also, PHN and PMP derivatives produced cross-ring cleavages with abundances higher than observed in the spectra of AB derivatized oligosaccharides. For high-mannose glycans, the most informative cleavages were provided by AB and PHN type of labeling. Here, PMP produced dominant Y-cleavages from the chitobiose while other ions produced weak signals.

Antipyrine↗
PubMed2005

High performance liquid chromatographic determination of N-butyryl glucosamine in rat plasma.

PURPOSE: A high performance liquid chromatography (HPLC) method for determination in plasma of N-butyryl glucosamine (GLBU), a highly water-soluble compound with no chromophore was developed. METHOD: To 100 muL of plasma containing GLBU was added fucose as internal standard. GLBU and fucose were derivatized using 1-phenyl-3-methyl-5-pyrazolone in the presence of sodium hydroxide at 70 degrees C for 30 min. The solution was neutralized with hydrochloric acid and the excess derivatizing reagent was extracted with chloroform. The aqueous layer was injected into an isocratic HPLC system consisting of an autoinjector, a single pump and a UV detector set at 245 nm. Two different 25 cm reversed phase columns were used, a 4 and a 10 microm C(18) columns. The mobile phase was a mixture of phosphate buffer (pH 7) and acetonitrile (80:20), which was run through a pump at a flow rate of 1.0 mL/min at ambient temperature. RESULTS: Derivatized fucose and GLBU appeared 24 and 28 min, and at 34 and 37 min using 4 and 10 microm columns, respectively. The assay was linear over the range of 0.2-200 microg/mL with a limit of quantification of 0.2 and 1 microg/mL for the 4 and 10 microm columns, respectively. The method was applied to the determination of GLBU in rat plasma after oral administration of 233 mg/kg of GLBU. CONCLUSION: The present assay is precise, and accurate with sufficient sensitivity for pharmacokinetic studies following therapeutically relevant doses.

Administration, Oral↗