Biomedical subjects
Publications and source records attributed to T Kitani.
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The synthesis and in vitro antibacterial and beta-lactamase inhibitory activity of the 2-azetidinone-1-oxysulfonic acids having a substituent at C-4 position of the beta-lactam ring are described. The influence of C-4 substituents on the antibacterial activity was examined for the compounds having alpha-ureidoacetyl or alpha-oxyiminoacetyl group as acyl side chain at C-3 position. The antibacterial activity is correlated with the C-4 substituents and acyl side chain. Especially, 4(R)-methyl substituted derivatives exhibited excellent activity against Gram-negative bacteria and 4-dimethyl substituted derivatives exhibited strong activity against resistant Gram-negative bacteria except for Pseudomonas aeruginosa. 39 and 40 showed strong inhibitory activity against cephalosporinase of Enterobacter cloacae H-27.
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UNLABELLED: In a randomized controlled study, the efficacy of MCNU was compared with that of Busulfan in 95 patients with chronic myelogenous leukemia. Of the patients studied, 95 were entered among whom 77 were evaluable. These comprised 40 for an MCNU group (M) and 37 for a Busulfan group (B). No significant difference was found statistically between the two groups with regard to background factors, i.e., male-to-female ratio, age, white blood cell counts, platelet counts, splenomegaly or Ph1 chromosome. RESULTS: CR rate was 83% for M and 68% for B, and the number of days to CR was 88 for M and 155 for B. Blastic crisis was noted in 31% of M patients and 33% of B patients and the number of days to blastic crisis was 542.6 and 581.9, respectively for the two groups. Deaths accounted for 28% and 29% for each of M and B. Side effects were observed in 31% of M cases and 15% of B cases. A significant difference was observed only in the period to CR. MCNU showed almost equal efficacy to that of Busulfan but was superior to Busulfan in patients who required rapid response. Side effects were mild and transient. Despite its delivery by intravenous injection, the administration of MCNU is deemed convenient, considering the long interval possible between treatments, being comparable in this respect with oral Busulfan. MCNU therefore seems a very effective drug for chronic myelogenous leukemia.
Micronomicin (MCR) at a daily dose of 120 to 360 mg was administered to patients with severe infections who had hematopoietic disorders as underlying diseases. Efficacy and safety of the drug were evaluated. The underlying diseases in the 56 patients included in the evaluation of efficacy were acute myelocytic leukemia (24 cases), acute lymphocytic leukemia (8), acute promyelocytic leukemia (6), acute monomyelocytic leukemia (4), acute monocytic leukemia (1), erythroleukemia (1), chronic myelocytic leukemia-blastic crisis (4), malignant lymphoma (3), aplastic anemia (2), and others (3). The infections were septicemia in 9 patients, suspected septicemia in 48, respiratory tract infection in 7, and perianal abscess in 2. The clinical efficacy of MCR was 'excellent' in 12 patients, 'good' in 17, 'fair' in 7, 'poor' in 30 for an efficacy rate of 43.9%. The efficacy rate classified according to infections was 22.2% in septicemia, 56.3% in suspected septicemia. The organisms isolated from the patients with septicemia were Escherichia coli in 2, Klebsiella pneumoniae in 2, Pseudomonas aeruginosa in 1, alpha-Streptococcus in 1, Serratia marcescens in 1, and Acinetobacter sp. in 1. The efficacy rate was 15.4% in the 13 patients whose causative organisms were identified. The efficacy rate for patients who had failed to respond to prior antibiotic therapy was 43.9%. The efficacy rate in patients (34 cases) with an initial neutrophil count less than 100/microliter was 44.1%. Side effect which might have been caused by MCR was skin eruption in only one episode among 83 episodes those were evaluated for safety.
Twenty-five patients with malignant lymphomas were treated with etoposide oral capsule 200mg/day for 5 days, repeated 3-4-weekly. Twenty-one cases were evaluable. CR was achieved in four cases (19.0%) and PR in six cases (28.6%). The most serious adverse effect of the drug was leukopenia. In one patient (6.7%) the leukocyte count was lower than 1,000/mm3. Gastrointestinal toxicities such as anorexia, nausea, vomiting and diarrhea occurred in about 66.7% of patients but were not serious; alopecia was observed in 65.2%. In conclusion, etoposide is considered effective for malignant lymphomas.
Antizyme reversibly inhibits ornithine decarboxylase activity by direct binding to the enzyme. The velocity of the reaction between ornithine decarboxylase and antizyme was markedly accelerated as the concentration of sodium chloride in the medium was increased and as the temperature of incubation was lowered. The equilibrium constant (binding constant) of the reaction between ornithine decarboxylase and antizyme was a little increased by decreasing salt concentrations in the medium and by decreasing the temperature of incubation.
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One hundred and nine patients with infection accompanying hematologic disorders including leukemia and lymphoma were treated with aztreonam (AZT). Of the 90 patients in whom the efficacy could be evaluated, 17 (18.9%) responded markedly and 29 (32.2%) moderately, the effective rate being 51.1%. The efficacy rate classified according to infections was 25% in septicemia, 46.3% in suspected septicemia, 57.1% in pneumonia and 100% in urinary tract infection. The efficacy rate to the Gram-negative bacteria was 78.9% and to the Gram-positive bacteria was 20.0%. In 4 (66.7%) out of 6 patients in whom P. aeruginosa was the causative organism, AZT was effective. The efficacy rate was 52.2% in the 23 patients whose causative organisms were identified and 50.7% in 67 patients whose causative organisms were not identified. There was no significant difference in the efficacy rate between the patients who failed to respond to prior antibiotic therapy (53.6%) and those treated with AZT from the beginning. The initial neutrophil count did not affect the efficacy rate. Side effects which might have been caused by AZT were eruption and fever in 4 patients. Hepatic disorders and eosinophilia were observed in 7 patients. However, the relationship between AZT and these abnormal findings was not established. These results indicate that AZT is an effective and safe antibiotic for the treatment of infections accompanying hematologic disorders.
A protein inhibitor to ornithine decarboxylase, antizyme, was purified to homogeneity, as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, about 600,000-fold with a 15% yield from the liver cytosol of putrescine-treated rats. Antizyme was very labile but markedly stabilized in the presence of Tween 80 and 2-mercaptoethanol. The apparent molecular weight of antizyme was determined to be 22,000 by gel filtration on Sephadex G-75 and 19,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, indicating that antizyme may be composed of a single polypeptide chain. The isoelectric point of antizyme was found to be 6.8. The equilibrium constant of the reaction between antizyme and ornithine decarboxylase was estimated to be as high as 1.4 X 10(11) M-1. Some other properties of antizyme were also described.
A case of malignant lymphoma with a helper activity of neoplastic cells is reported. On admission, a significant number of plasma cells of polyclonal nature were seen in the peripheral blood, and polyclonal hypergammaglobulinemia was seen. The biopsied lymph node showed poorly differentiated lymphocytic lymphoma with marked proliferation of plasma cells. At the terminal stage, the patient became leukemic in contrast with the disappearance of plasma cells from the peripheral blood. Although the leukemic cells failed to form sheep erythrocyte rosettes, they were considered to be of T-cell origin morphologically. Cytochemically, they had a "dot"-like pattern of alpha-naphthyl acetate esterase and acid phosphatase activity. Ultrastructurally, they had highly convoluted nuclei, and cytoplasmic clustered dense bodies. They showed marked helper activity on pokeweed mitogen-induced B-cell differentiation in vitro. This case may provide a novel view concerning the cause of hypergammaglobulinemia induced by lymphoproliferative disorders.
The influence of salts on the subunit structure and the kinetics of purified rat ornithine decarboxylase (L-ornithine carboxy-lyase, EC 4.1.1.17) was examined. Salts were found to cause subunit dissociation of the enzyme, producing the monomeric form of molecular weight 55 000 in the presence of 0.25 M NaCl/10 mM sodium phosphate buffer (pH 7.0): the molecular weight was estimated to be 150 000 in 10 mM and 250 000 in 1 mM sodium phosphate buffer. Inclusion of NaCl in kinetic assays of rat ornithine decarboxylase had little effect on maximal velocity. However, the Km value for L-ornithine was dramatically increased with increasing sodium chloride concentration: the presence of 0.25 M NaCl resulted in a 10-fold increase of the Km. Thus, the presence of salts caused dramatic changes both in the subunit structure and in the catalytic property of the enzyme, although a direct correlation between both the changes was not evidenced.
Mutants of Escherichia coli K-12 have been isolated that suppress cer mutants, ColE1 mutants that are unable to replicate as the plasmid. These host suppressors were designated her, for host factor affecting ColE1 replication. Each her suppressor showed a characteristic pattern of suppression depending on the cer mutation used for selecting the mutant bacteria. One of the suppressors, named herA, that suppressed cer6, a single-base-pair alteration 160 base pairs upstream of the ColE1 replication origin, was genetically identified as an alteration of the rnh gene (RNase H). HerA was recessive to its wild-type allele. RNase H activity of herA cell extracts was defective. Conversely, rnh mutants that were isolated independently of ColE1 replication supported replication of cer6 DNA. Some rnh mutants manifested the HerA phenotype only above a certain transition temperature, and their RNase H activity was found to be temperature sensitive. Therefore, replication of cer6 DNA in vivo is sensitive to RNase H activity. Under the conditions that suppressed cer6, the wild-type colE1 replicon replicated normally. Then, ColE1 replication in vivo proceeds in the absence of RNase H activity, which has been shown to be required for in vitro replication of the DNA.
The leukaemic cells of 11 patients with Japanese adult T-cell leukaemia (ATL) were characterized in terms of phenotype employing various monoclonal antibodies against T-cell surface antigens. The leukaemic cells of all ATL patients except patient no. 11 displayed the phenotype OKT4+/OKT8-. However, the % of OKT3+ cells varied from 3 to 98. In 1 case, cells with phenotype OKT4+/OKT8+, which is characteristic of T-cells at an early stage of differentiation, were found. These results suggest that some ATL cells may be in an immature differentiation stage. Among the 11 patients, 2 with unusual ATL cell phenotypes (1 case with OKT3- cells and 1 case with Ia+/EAC+ cells) showed spontaneous regression of leukaemic cells. Characterization of leukaemic cells from a larger number of ATL patients may demonstrate a significant relationship between cell phenotype and prognosis.
To investigate the precise structure of eucaryotic primer RNA made in vivo, short DNA chains isolated from nuclei of Drosophila melanogaster embryos were analyzed. Post-labeling of 5' ends of short DNA chains with polynucleotide kinase and [gamma-32P]ATP revealed that 7% of the DNA fragments were covalently linked with mono- to octaribonucleotide primers at their 5' ends. Octaribonucleotides, the major component (ca. 30%), formed the cap structure in the reaction with vaccinia guanylyltransferase and [alpha-32P]GTP, indicating that they were the intact primer RNA with tri- (or di-) phosphate termini, and the shorter ribooligomers were degradation intermediates. The intact primers started with purine (A/G ratio, 4:1), and the starting few ribonucleotide residues were rich in A.
One hundred patients with severe infections associated with hematologic disorders, including leukemia and lymphoma, were treated with ceftizoxime (CZX) in daily doses of 4 approximately 9 g for an average of 8.9 days. In the 84 patients who completed the trial, response was excellent in 27 (32.1%) and moderate in 25 (29.8%). The rate of effectiveness was 61.9%. The only side effect seen during the treatment was skin rash in 3 patients. Hepatic disorders were observed in 5 patients. The relation between CZX and these abnormal findings was not established. These results indicate that CZX is a therapeutically effective and safe antibiotic for the treatment of severe infections in patients with underlying hematologic disorders.
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Six patients with hairy cell leukemia (HCL) were studied for surface immunoglobulin ( sIg ). In all five sIg -positive cases, the heavy chain isotype was IgG. We performed cytologic and cytochemical studies of sIgG + lymphocytes in normal peripheral blood and compared them with hairy cells. Normal sIgM + lymphocytes were also examined. sIgG + and sIgM + lymphocytes made up 0.9% and 6.1% of normal peripheral blood lymphocytes, respectively. Under a phase-contrast microscope, 76% of sIgG + lymphocytes showed cytoplasmic processes similar to those found on hairy cells, whereas most sIgM + lymphocytes had smooth surfaces. Tartrate-resistant acid phosphatase (TRAP) staining revealed that TRAP-positive cells accounted for 65% of sIgG + lymphocytes and 19% of sIgM + lymphocytes. Some (8.3%) of the sIgM + lymphocytes expressed sIgG concomitantly. When sIgM +, sIgM +, sIgG + lymphocytes were excluded, the percentages of cells with surface processes and of TRAP-positive cells in the remaining sIgM +, sIgG - lymphocytes were 10% and 12%, respectively. A very small proportion (0.2%) of sIgM -, sIgG - lymphocytes had cytoplasmic processes. These results indicate that normal sIgG + lymphocytes are cytologically and cytochemically different from most sIgM + lymphocytes and that the phase-contrast microscopic appearances and TRAP activity of sIgG + lymphocytes are similar to those of HCL tumor cells.