[Development of live varicella vaccine].
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Biomedical subjects
Publications and source records attributed to H Kamiya.
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A live varicella vaccine (Oka strain) has been developed and used since 1974 in normal and diseased children, particularly those at high risk. Children with acute leukaemia were usually vaccinated while in remission when showing a normal cell-mediated immunity as assessed with phytohaemagglutinin (PHA) or other reagents, and during suspension of all anticancer therapy, except 6-mercaptopurine from 1 week before to 1 week after vaccination. While clinical reactions were observed in only 40 out of 263 (15.2%) of these patients, they were noted in 30 out of 72 (41.7%) children immunized without suspension of chemotherapy. Symptoms were mostly mild; only a few cases of the latter group with T-cell leukaemia or malignant lymphoma developed severe symptoms. An immune response was observed in most vaccinees, but some (11%) developed clinical symptoms after exposure to natural varicella due to immunodepression caused by continuing anticancer chemotherapy. In these cases, revaccination seems advisable. The incidence and severity of zoster in vaccinated acute leukaemic children were less than in those with natural infection. Satisfactory immune responses with few concomitant clinical reactions were observed in approximately 1,500 vaccinees having nonmalignant diseases and in about 4,000 normal children. A 7-10-year follow-up study revealed that the vaccine had conferred solid immunity on the children. These results indicate that live varicella vaccine of the Oka strain is useful in preventing varicella in high-risk as well as in normal children.
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Pharmacokinetic and clinical studies of ceftizoxime suppository (CZX-S) were performed in 10 children with the following results. CZX-S attained a peak serum concentration of 6.85 micrograms/ml 30 minutes after dosing with the drug 5.6 mg/kg (one suppository of CZX-S contains 250 mg of CZX in potency). The mean 6-hour urinary excretion rate in 4 children was 18.9%. The subjects consisted of 8 patients comprising 1 with pharyngitis, 3 with tonsillitis, 1 with gingivitis and 3 with urinary tract infection. The overall effect of CZX-S was "excellent" in 5 patients and "good" in 3, with an effectiveness rate of 100%. No side effects ascribable to CZX-S were encountered in any of the patients. A few patients complained of discomfort after the first or second insertion of the drug. However, the discharge of the suppository was as infrequent as 1.5% of the total 133 insertions. CZX-S is therefore well tolerated for clinical use in children. It is concluded that the unique suppository formulation of CZX-S is useful in the treatment of infections in children with heavy psychophysiologic disorders and in children who cannot take oral drugs because of severe vomiting.
Cefminox (CMNX, MT-141) is a new injectable cephamycin antibiotic, which was studied for its antibacterial activity, absorption and excretion after administration and clinical efficacy of patients with infections. The following results were obtained. Antibacterial activity The antibacterial activity of CMNX against 19 clinical isolates consisting of 11 species made the results that its activity against E. coli, P. vulgaris and C. jejuni was superior to CMZ and CEZ. Concentration in serum and urine CMNX was given intravenously to 3 groups at 20 mg/kg by one shot (2 cases), 40 mg/kg by one shot (2 cases) and 40 mg/kg by 1 hour drip infusion (1 case). The half-lives were between 1.15 to 1.80 hours. We obtained over 70% of its excretion to urine within 6 hours after injection. Clinical efficacy Clinical evaluation was made on a total of 18 patients with various infections, 11 of whom had underlying diseases. The result was excellent in 1 case, good in 11 cases, fair in 2 cases and poor in 4 cases, and the effective rate was 66.7%. Side effect Clinical and laboratory abnormal findings related to CMNX were not found. It is concluded that CMNX seems to be effective and safetive antibiotic in the field of pediatrics.
A 300-mg dose of UFT was administered daily for seven days prior to surgery for ovarian malignant tumors. The concentrations of FT, 5-FU and uracil in the serum, tumor tissue, adjacent normal tissue and ascitic fluid were measured. The results were as follows: 5-FU concentration in the serum was 0.008 +/- 0.006 micrograms/ml (n = 14) and the concentration in the ascitic fluid was 0.008 +/- 0.006 micrograms/ml (n = 4). The 5-FU concentration in the tumor tissue was 0.142 +/- 0.199 micrograms/g. This was approximately 3.0 times higher than the concentration in the adjacent normal tissue which was 0.048 +/- 0.030 micrograms/g and the T/B ratio (formula; see text) was approximately 17.8.
With advances in the understanding of intracellular nucleic acid metabolism, the biochemical modulation of the action of antimetabolites by MTX was discussed as an approach towards the development of more selective chemotherapy. Using high-performance liquid chromatography, the sequential changes occurring in the acid-soluble intra cellular nucleotide pools of L1210 mouse leukemic cells were analysed after treatment with MTX, and a reduction of the dTTP pool to 46% of the control level was observed. Declines in the dCTP, ATR and GTP pools were also reduced to 36%, 30% and 24%, respectively, of the control level after treatment with MTX. Using MTX-5-FU combination chemotherapy, pretreatment with MTX enhanced the intracellular level of FUTP which is one of the active metabolites of 5-FU. There was, however, no significant difference in the value of dTTP levels between MTX-5-FU and 5-FU alone. One of the mechanisms of the synergistic interaction between MTX and 5-FU might therefore be stimulated phosphorylation of 5-FU with an increased PRPP level, which occurs as a result of the MTX-blocked purine de novo pathway. Using MTX-ara C combination chemotherapy, MTX enhanced the intracellular production of ara-CTP, which occurs as a result of MTX reducing the intracellular dCTP pools, following activation of deoxycytidine kinase. More clarification of the effects on intracellular nucleic acid metabolism will aid the development new and increasingly effective drug combinations involving thiopurines. The methods of combination chemotherapy will become more sophisticated as the biochemical modulation effect of the drug is clarified.
In a previous study, we showed that methotrexate (MTX) enhanced the intracellular production of ara-CTP. The study described in the present paper has elucidated the mechanism of this MTX-enhanced ara-CTP production, which occurs as a result of MTX reducing the intracellular dCTP pool, and the decreased dCTP pool then allowing activation of deoxycytidine Kinase. One of the mechanisms of synergistic interaction between 1-beta-D-arabinofuranosylcytosine (ara-C) and MTX might therefore be the stimulated phosphorylation of ara-C with MTX-activated deoxy-cytidine kinase. Using high-pressure liquid chromatography, the sequential changes occurring in the acid-soluble intracellular nucleotide pools of L1210 mouse leukemic cells were analysed after treatment with MTX (12mg/kg). At 3 hr after treatment with MTX a reduction of the dTTP pool to 46% of the control level was observed. The dCTP pool was also reduced to 36% of the control level after treatment with MTX. The levels of the dATP and dGTP pools were not significantly changed, at least during the observation period. Pyrimidine ribonucleotide pools were almost unchanged at 3 hr, but in the sequential changes observed in purine ribonucleotide pools after treatment with MTX, both diphosphate and triphosphate pools were seen to be on the decline, the reduction of triphosphate pools being especially marked. A decline in ATP and GPT to 24-30% of control levels was observed at 3 hr after treatment with MTX.
Fundamental and clinical studies were performed with aspoxicillin (ASPC), a new developed injectable broad penicillin, in pediatric infectious diseases, and the following results were obtained. Pharmacokinetics ASPC was administered to 2 cases at a dose of 20 mg/kg by one shot intravenous injection. The mean half-life (T 1/2) was 1.17 hours. The mean urinary excretion rate was 58.4% during 6 hours after ASPC treatment. In 3 cases of intravenous drip infusion with a period of 1 hour at a dose of 10 mg/kg (2 cases) and 20 mg/kg (1 case), the half-lives (T 1/2) were 1.7 hours, 3.5 hours and 1.0 hour, respectively. The urinary recovery rate during 6 hours after administration was 57.7%, 32.6% and 42.7%, respectively. At only one case treated with 10 mg/kg intravenous drip infusion, the half-life was prolonged and urinary excretion rate was lower than other 2 cases. Clinical study ASPC was administered 50-80 mg/kg/day for 4-8 days to 22 children comprising 6 tonsillitis, 2 bronchitis, 6 pneumonia and 8 urinary tract infections. Clinical efficacy was excellent in 13 cases, good in 8 cases and fair in 1 case, the total cure rate was 95%. As for the clinical response classified by diagnosis, the each efficacy rate of tonsillitis, bronchitis and pneumonia was 100%, and that of urinary tract infection was 87.5%. Clinical side effect and abnormal laboratory findings were not observed in any cases. From the above results, it was concluded that ASPC was one of the useful secure drug for treatment of infections in pediatric field.
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Pharmacokinetics, in vitro, and in vivo effect of aztreonam (SQ 26,776, AZT), a newly synthesized monobactam antibiotic, were investigated in pediatric patients. The pharmacokinetics were studied in 12 children without renal or hepatic impairment, each of whom received single 10, 20 and 40 mg/kg intravenous doses of drug. Serial samples of serum and urine were assayed for AZT. Serum pharmacokinetics of AZT were described by an open, linear, two-compartment kinetic model. After intravenous administration, AZT was eliminated primarily by urinary excretion of unchanged drug (60.4%). The average biological half-lives of AZT in serum were 1.33 (10 mg/kg, n = 1), 1.69 +/- 0.40 (20 mg/kg, n = 8), and 1.51 +/- 0.61 (40 mg/kg, n = 3) hours. The antibacterial activity of AZT against E. coli and P. aeruginosa was equal or slightly stronger than that of CPZ, LMOX, and CTX. It had no antimicrobial activity against Gram-positive cocci. In vivo effect of AZT was evaluated in 13 children with various infections. The result was excellent in 7 cases, good in 1 case, fair in 3 cases and poor in 1 case, with effective ratio of 66.7%. Exanthema or elevation of GOT and GPT were noticed in 3 patients.
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Amino acid derivatives of fluorescein isothiocyanate have been separated by reverse-phase high-performance liquid chromatography in 45 min, using a linear gradient formed from acetone and 10 mM sodium phosphate buffer (pH 7.0) at 60 degrees C. The fluorescence of the derivatives has been used for detection giving a sensitivity of less than 0.5 pmol for a single component. Applications of this method to the sequence analyses of egg white lysozyme and salmon beta-melanotropin are also described.
A series of T-cell-specific monoclonal antibodies (Leu-1, Leu-2a, and Leu-3a) and B-cell-specific monoclonal antibody (HLB-1) were used to detect the localization and intensity of infiltration of lymphocyte subpopulations and T-cell subsets in frozen sections of 17 patients with the oral cancer. The vast majority of the lymphocyte infiltrates in the oral cancer tissues were reactive with Leu-1. In contrast, B cells were detectable with HLB-1 in only 2 of 17 cases. Leu-2a-positive cells were dominant in four cases, whereas Leu-3a positive cells were dominant in only three cases. In seven cases, both cells infiltrated to the same degree. Leu-2a positive cells tended to be dominant in the cases with earlier clinical stages.
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A total of 52 acute leukemic children have been safely and effectively vaccinated with live varicella (Oka strain) vaccine given under close clinical and immunological observation. The incidence of zoster in the vaccinated children group was slightly less than that in the group that had experienced natural varicella.
A cytolytic factor partially purified from eggs of the sea hare Aplysia kurodai was examined for cytolytic activity against various target cells. All kinds of tumor cells tested were lysed in vitro by the cytolytic factor in the range of 10-100 ng protein/ml. In contrast, normal spleen cells were lysed by 10 micrograms/ml of this factor and red cells were not lysed even at this higher concentration. Tumor lysis was time-dependent and was complete within 10 hr. This factor inhibited DNA and RNA syntheses of tumor cells but not protein synthesis. The cytolytic activity was lost on heat-treatment (60 degrees) and at pH 2, and was partially inhibited by treatment with 8M urea and at pH 12, but the factor was resistant to treatments with trypsin, periodate and 2-mercaptoethanol. Neutralizing activity was observed in vivo on pretreatment of MM46 and L1210 cells with the factor. This cytolytic factor also inhibited the growth of solid-type MH134 tumor and ascitic-type MM46 tumor. These results indicate that Aplysia eggs contain a novel cytolytic factor that lyses tumor cells in vitro and inhibits tumor growth in vivo.
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