[Staining pattern of antinuclear antibody].
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Animals↗
Biomedical subjects
N Kurata
Publications and source records attributed to N Kurata.
Identification of antibodies to nuclear acidic antigens by counterimmunoelectrophoresis.
Saline extracts of rabbit thymus were found to contain many nuclear antigens that reacted with antibodies in the sera of patients with systemic rheumatic diseases. Counterimmunoelectrophoresis (CIE) was used to detect antibodies to nuclear acidic protein (Sm), nuclear ribonucleoprotein (RNP), and antibody to nuclear antigen B, which was reported previously in Sjögren's syndrome. All these nuclear antigens behaved as anions with different mobilities in CIE and could be distinguished from one another by the locations of the precipitin lines. They could also be distinguished by the facts that the nuclear RNP precipitin lines were abolished by digestion with ribonuclease whereas others were unaffected, and that Sm precipitin lines developed later than other precipitin lines. With this technique antibody to nuclear RNP was detected in 46% of patients with systemic lupus erythematosus (SLE) compared to 26% detected by the hemagglutination technique. Similarly the increased sensitivity of the CIE technique was able to show that antibody to B antigen was present in 12% of SLE patients, whereas this antibody was not detectable in the same group of patients by immunodiffusion. This study shows that CIE is a rapid and sensitive technique for detecting precipitating antibodies to a number of nuclear acidic antigens. Methods are described to identify the immunochemical specificities of the precipitin lines by the use of standard reference sera.
Antibodies, Antinuclear↗
Identification and characterization of two new soluble nuclear antigens reactive with sera of patients with connective tissue diseases.
Two antigens, temporarily referred to as MU and TM antigens after the original serum, that are closely related to the nucleolus have been identified in the nuclear soluble extract. Both antigens reacted with the sera of a small number of patients with various connective tissue diseases, and both were different from antigens described previously in these disorders. MU antigen was sensitive to the digestion with RNase and trypsin, and was shown to be equivalent to the nuclear ribosomal components in the nuclear extract. TM antigen was resistant to the digestion with RNase and trypsin, and was localized in the nucleolus and extranucleolar portion of nuclei, but the precise nature of TM has not been established.
Antibodies, Antinuclear↗
Effects of imidazole antimycotics on the liver microsomal cytochrome P450 isoforms in rats: comparison of in vitro and ex vivo studies.
We have studied the effects of three imidazole derivatives, clotrimazole (CLO), ketoconazole (KET) and miconazole (MIC) on the liver microsomal diazepam (DZ) metabolism. In in vitro experiments using rats and human liver microsomes, significant inhibition of CYP3A in terms of DZ-3-hydroxylase activity was observed. The inhibition of DZ metabolism was seen 1 h after CLO dosing. On the other hand, the induction of certain cytochrome P450 (CYP) isozymes was observed in in vivo studies 24 h after dosing. That is, CYP1A, CYP2B and CYP3A2, but not CYP2E, were observed 24 h after CLO or KET or MIC treatment. Under these conditions, CLO was the most potent inducer of CYP3A and MIC was a more potent inducer of CYP1A and CYP2B. KET induced CYP1A and CYP2B whereas the inducibility of KET was less than those of CLO and MIC. All of the imidazole derivatives tested here showed significant inhibition of CYP isozymes which overcame the induction of the CYP isozymes by those drugs in the data of Western blot analysis.
Animals↗
Phase I and pharmacologic study of oral (E)-2'-deoxy-2'-(fluoromethylene) cytidine: on a daily x 5-day schedule.
(E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC), one of the most potent inhibitors of ribonucleoside diphosphate reductase, was selected for clinical development because of its novel mechanisms of action, and strong antitumor activity against experimental tumor models. This study was designed to determine the toxicities, maximum-tolerated dose (MTD), and pharmacokinetic profile of FMdC. FMdC was given orally for 5 consecutive days every 3 or 4 weeks in patients with advanced solid tumors. The starting dose was 8 mg/m2/day. Pharmacokinetic studies were carried out on days 1 through 5 of the first cycle. Ten patients with non-small cell lung cancer received 15 courses of FMdC at doses which were de-escalated from 8 mg/m2/day to 2 mg/m2/day because of unexpected severe toxicities at the starting dose level. Neutropenia was the dose-limiting toxicity. Thrombocytopenia and anemia were mild. Flu-like symptoms and fever were the common non-hematologic toxicities. The MTD was 4 mg/m2/day, since four of six patients developed grade 3-4 neutropenia. At the 4 mg/m2/day dose level, the mean terminal half-life, maximum plasma concentration (Cmax), plasma clearance, and mean residence time on day 1 were 3.20 h, 15.8 ng/ml, 2.91 l/h/kg, and 4.03 h, respectively. The recommended dose for phase II studies with this schedule is also 4 mg/m2/day for 5 days. Further investigations are necessary to establish optimal dosing schedules and routes for the administration of FMdC.
Administration, Oral↗
Studies on induction of metabolism of ethyl carbamate in mice by ethanol.
Acute administration of ethanol, acetaldehyde, dimethyl sulfoxide and several other compounds has been reported previously by this laboratory to inhibit the metabolism of ethyl carbamate (E.C.) in mice. Since many enzyme systems that are inhibited by a compound are also induced by that chemical, the effect of chronic administration of ethanol on the metabolism of E.C. was studied in male, A/JAX mice. Ethanol was given in three pretreatment schedules: 1, 5% in drinking water for 7 days with a 24-hr washout before E.C.; 2, 10% in drinking water 48-12 hr before E.C.; 3, 5 g/kg orally as 10% in saline 48 and 24 hr before E.C. E.C. (11.125 mg/kg) in saline was administered orally and blood samples taken at frequent intervals for analysis of E.C. by a GC/MS technique developed in this laboratory. AUCs of E.C. concentration vs. time were calculated by trapezoidal estimation. From these data, E.C. blood clearance values (dose/AUC; ml hr-1kg-1) were calculated: control, 751 +/- 49.7; group 1,803 +/- 43.5; group 2, 1225 +/- 24.6; group 3, 815 +/- 75.4. Only group 2 was significantly different (p less than 0.01) from control and other groups by Newman-Keuls test. These results indicate that ethanol may be an inducer of E.C. metabolism only under certain limited conditions. The induction may be detected 12 hr after ethanol administration but is not apparent at 24 hr after ethanol pretreatment.
Animals↗
Studies on inhibition and induction of metabolism of ethyl carbamate by acetone and related compounds. Evidence for metabolism by cytochromes P-450.
Ethanol and a variety of other compounds previously have been shown to acutely inhibit the metabolism of ethyl carbamate (EC) when given concurrently in mice. On the other hand, ethanol pretreatment (10% in drinking water for the period 48 to 12 hr prior to EC treatment) is known to have the opposite effect and enhance the clearance of EC from blood of mice. In the present work, acetone has been shown to act similarly. Concurrent acetone treatment inhibits the metabolism of EC (11.1 mg/kg po) in male A/JAX mice in a dose-response manner. Blood clearance (Cl) of this po dose of EC from mice following concurrent acetone treatment (50 mg/kg, 0.86 mmol/kg ip) averaged 185 +/- 5.4 (SE) ml hr-1 kg-1 vs. controls of 804 +/- 24.6 ml hr-1 kg-1. Comparing doses that produce equal effects on the blood clearance values of EC, acetone is approximately 50-fold more potent as an inhibitor than ethanol. Pretreatment of mice with acetone (2 g/kg ip) 48 hr and 24 hr before EC administration po increased the clearance of EC approximately 3-fold (CI = 2623 +/- 123 ml hr-1 kg-1). 2-Propanol was found to be at least as potent as inhibitor as acetone, but with a longer duration of inhibition; this longer duration was explained by the longer persistence of acetone in blood from conversion of 2-propanol to acetone.(ABSTRACT TRUNCATED AT 250 WORDS)
1-Propanol↗
Inhibition of the metabolism of ethyl carbamate by acetaldehyde.
Ethyl carbamate is an animal carcinogen when administered in large doses; it is naturally present in minute concentrations in fermented foods and beverages. Previous studies from this laboratory have demonstrated that ethanol, in vivo, inhibits the metabolism of ethyl carbamate in mice, but the enzyme system has not been identified. In an effort to further characterize the enzyme system responsible, the metabolic products of ethanol metabolism were studied to determine whether ethanol or either of its metabolites is inhibitory. Acetaldehyde (400 mg/kg) is a potent inhibitor of ethyl carbamate metabolism for about 2 hr in vitro, but sodium acetate is not. Paraldehyde (250 mg/kg) has a slower onset and longer duration of inhibition, suggesting that its conversion to acetaldehyde produces the inhibitory molecule. Disulfiram (200 mg/kg) has a prolonged inhibitory effect; this effect is enhanced and extended when the disulfiram is combined with acetaldehyde (400 mg/kg). D-Penicillamine, given in a regimen of 1.2 g/kg 0.5 hr before and 0.6 g/kg 1.5 and 3.5 hr after ethyl carbamate, is not inhibitory; however, it abolishes the inhibitory effect of acetaldehyde, presumably from sequestration of acetaldehyde. These studies demonstrate that acetaldehyde is an inhibitor of the metabolism of ethyl carbamate and suggest that acetaldehyde is one, and perhaps the only, molecule responsible for the inhibition seen when ethanol is administered to mice. In vitro incubation studies determined that ethyl carbamate was not metabolized by human plasma.
Acetaldehyde↗