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Biomedical subjects

T Shinkai

Publications and source records attributed to T Shinkai.

At least 109 records · Page 6Linked to original sources
PubMed1990

Phase II study of (glycolate-O,O') diammineplatinum(II), a novel platinum complex, in the treatment of non-small-cell lung cancer.

A total of 68 patients with non-small-cell lung cancer who either had not previously been treated (38) or had undergone prior therapy (30) were treated in a phase II study of (glycolate-O,O') diammineplatinum(II) (NSC 375 101D; 254-S), a new platinum complex. The drug was given as a single intravenous infusion at a dose of 100 mg/m2 every 4 weeks. All 68 patients could be evaluated for response and 62, for toxicity. Objective responses were seen in 10 of 68 cases (14.7%; 95% confidence interval, 7.3%-25.4%), and the median duration of response was 15 weeks (range, 8-23 weeks). The response rates were similar for previously untreated and treated patients (13% and 17%, respectively), including three previously treated with cisplatin. Myelosuppression was the dose-limiting toxicity. Thrombocytopenia (less than 100,000 platelets/mm3) and leukocytopenia (less than 3,000 WBC/mm3) were observed in 22 (35%) and 18 (29%) patients, respectively. Mild to moderate nausea and vomiting occurred in 45 cases (73%). No significant renal or neurotoxicity was observed. We conclude that as a single agent, 254-S is well tolerated but appears to have marginal activity against non-small-cell lung cancer.

Adenocarcinoma↗
PubMed1990

Subcutaneous administration of recombinant human granulocyte colony-stimulating factor (KRN8601) in intensive chemotherapy for patients with advanced lung cancer.

The efficacy and toxicity of recombinant human granulocyte colony-stimulating factor (rh G-CSF, KRN8601) given subcutaneously was evaluated in patients with advanced lung cancer undergoing intensive chemotherapy. Twenty-nine and 30 patients with or without prior therapy were enrolled in this study. At dose levels of 50, 90 and 130 micrograms/m2 of rh G-CSF for 14 consecutive days after chemotherapy, the mean neutrophil nadir counts, the mean neutrophil nadir ratios and the duration of neutropenia (days of less than 1000/mm3) were significantly improved. No significant differences were seen in frequency and duration of febrile episodes (greater than 38 degrees C). When rh G-CSF is given subcutaneously, the dose required for an equal effect in alleviating neutropenia is 50% of that required when it is given intravenously. The monocyte counts in the peripheral blood were also significantly increased after chemotherapy cycles with rh G-CSF. The cumulative plasma concentration of rh G-CSF showed a decrement after 7-9 days despite maintenance of the same dose of rh G-CSF for the entire 14 days. In conclusion, 50-130 micrograms/m2 of sc rh G-CSF increased the neutrophil nadir count and shortened the duration of neutropenia in patients undergoing intensive chemotherapy for lung cancer without intolerable side effects.

Adult↗
PubMed1990

Prediction from creatinine clearance of thrombocytopenia and recommended dose in patients receiving (glycolato-O,O')-diammine platinum (II) (NSC 375101D).

Thrombocytopenia is the most serious dose-limiting toxicity of (glycolato-O,O')-diammine platinum (II) (254-S; NSC 375101D), one of the new platinum analogues. A total of 38 patients treated with 100 mg of 254-S per m2 in a clinical phase II study were retrospectively analyzed to determine the factors influencing thrombocytopenia. Performance status, sex, age and prior chemotherapy did not affect either the percent reduction of platelets or the nadir platelet count. However, creatinine clearance (Ccr.: ml/min) was found to be a predictive variable for thrombocytopenia. There was a significant relationship between nadir platelet count and Ccr. (R2 = 0.637) or relative dose [RD = (dose of 254-S: mg/m2)/Ccr.] (R2 = 0.707). From these observations, the following equations for predicting nadir platelet count associated with administration of 254-S were proposed. [Nadir platelet count] = -64,264.7 + 2,783.4 x [Ccr.] (A) log [Nadir platelet count] = -1.6743 log [RD] + 5.32 = -1.6743 log [Dose/Ccr.] + 5.32 (B) If we administer 100 mg of 254-S per m2 to a patient with Ccr. of less than 40.3 ml/min, thrombocytopenia of grade 3 or more according to the Eastern Cooperative Oncology Group (ECOG) criteria (less than 50,000/mm3) can be predicted from equation (A). In these patients, dose modification using equation (B) is recommended.

Adult↗
PubMed1990

[Preliminary screening for antiviral AIDS drugs. I. Report on fiscal year 1988].

Preliminary screening for antiviral AIDS drugs has been carried out, using three different in vitro assay systems. Among 105 samples tested, 13 were found to inhibit the growth of HIV in vitro. Eleven of 13 were well-known anti-HIV chemicals, while the remaining two of plant origin were new chemicals whose anti-HIV activities have not been reported elsewhere.

Antiviral Agents↗
PubMed1990

Negative phase II study of 5-fluorouracil with high-dose leucovorin in non-small cell lung cancer.

Fourteen patients with inoperable or recurrent non-small cell lung cancer (NSCLC) were treated with 5-fluorouracil (5-FU) plus high-dose leucovorin (LV). The administration schedule was 2 h infusion of LV at a dose of 500 mg/m2 and 30 min infusion of 5-FU at a dose of 600 mg/m2 given 1 h after the start of the LV infusion. This regimen was followed weekly, six times. No objective (complete or partial) response was seen in any of the patients. Ten patients showed no change and there were four with progressive disease. One patient experienced grade 3 leukopenia after two courses of treatment. Another experienced grade 2 leukopenia. One patient experienced grade 2 vomiting and six, skin pigmentation. Other myelosuppressive effects and non-hematologic toxicities, including diarrhea and mucositis, were mild. It was concluded that the schedule of 5-FU with high-dose LV therapy employed could not be expected to produce a response rate greater than or equal to 20% against NSCLC. 5-FU plus high-dose LV therapy was, therefore, considered to be ineffective against NSCLC with the schedule of administration followed.

Adult↗
PubMed1989

Dose escalation study of recombinant human granulocyte-colony-stimulating factor (KRN8601) in patients with advanced malignancy.

To evaluate the toxicity and efficacy of recombinant human granulocyte-colony-stimulating factor (rh G-CSF) administered with intensive chemotherapy, 39 patients with advanced pulmonary cancers were enrolled in a dose escalation trial of rh G-CSF. Three days after initiation of chemotherapy rh G-CSF was administered i.v. for 14 consecutive days at five dose levels (50-800 micrograms/m2). Absolute neutrophil counts showed a dose-dependent increase with an increasing dose of rh G-CSF and the durations of neutropenia (less than 1000/mm3) shortened significantly at doses of 200, 400, and 800 micrograms/m2 compared to those at 50 micrograms/m2 (P less than 0.01). The duration of neutropenia was shortened significantly at all five dose levels following treatment with rh G-CSF compared to treatment without rh G-CSF (P less than 0.05). Adverse side effects associated with rh G-CSF administration were fever higher than 38 degrees C (21%), chest pain, and low back pain (13%). No intolerable side effects were experienced. It can be concluded that rh G-CSF is effective in shortening the duration of neutropenia following intensive chemotherapy at a dose level of 100 to 200 micrograms/m2 i.v. a 400-micrograms/m2 dose of rh G-CSF is recommended in patients with prior treatment because of the possibility of a lower bone marrow response.

Adult↗
PubMed1989

Phase I study of combination therapy with interleukin 2 and beta-interferon in patients with advanced malignancy.

Based on a preclinical study demonstrating the synergistic antitumor effect of recombinant interleukin 2 (rIL-2) and beta-interferon (IFN-beta) on mouse tumors and previous results of a phase I study of rIL-2, a phase I study of combination therapy with human rIL-2 and IFN-beta was conducted in 26 patients with advanced malignancy. Patients were given rIL-2 by 24-h continuous i.v. infusion and IFN-beta by 2-h i.v. infusion for 5 days each week for 4 weeks. The common side-effects were fever, malaise, chills, appetite loss, and diarrhea. Leukocytosis and eosinophilia were observed in 56% and 69% of the patients, respectively. Transient leukopenia and thrombocytopenia were also observed in some patients. Dose-limiting manifestations were intolerable fatigue and liver dysfunction, and it was concluded that the maximum tolerated doses of rIL-2 combined with IFN-beta were 1.1 x 10(6) U/m2/day for rIL-2 and 6.0 x 10(6) IU/m2/day for IFN-beta. No patients achieved complete and partial response to therapy in this study. One patient with pulmonary metastasis from pharyngeal cancer showed a minor response. Natural killer (NK) and lymphokine-activated killer (LAK) activities increased during the 5 days of treatment and decreased during the 2-day intermission. The percentage of IL-2 receptor-positive cells increased markedly until Day 12, and gradually decreased thereafter. The percentage of OKT 4-positive cells and the OKT 4/OKT 8 ratio increased. In contrast, the percentage of Leu 7- or Leu 11-positive cells decreased over the 4-week treatment. A phase II study of this combination therapy is ongoing against head and neck cancer, and renal cell carcinoma.

Adult↗
PubMed1989

Pharmacokinetics of (glycolate-0,0')-diammine platinum (II), a new platinum derivative, in comparison with cisplatin and carboplatin.

The pharmacokinetics of (glycolato-0,0')-diammine platinum (II) (254-S; NSC 375101D), one of the new platinum analogues, was examined in a phase I study of this drug and compared with that of cisplatin and carboplatin. All drugs were given in short-term (30-min) i.v. drip infusions; the doses of 254-S, cisplatin, and carboplatin were 100, 80, and 450 mg/m2, respectively. Platinum concentrations in whole plasma, plasma ultrafiltrate, and urine were determined by atomic absorption spectrometry. After the infusion, the plasma concentration of total platinum for the three agents decayed biphasically. Ultrafilterable platinum in plasma decreased in a biexponential mode after infusions of 254-S and carboplatin, whereas the free platinum of cisplatin showed a monoexponential disappearance. The peak plasma concentrations and AUC for free platinum were 5.31 micrograms/ml and 959 micrograms/min per ml for 254-S, 3.09 micrograms/ml and 208 micrograms/min per ml for cisplatin, and 19.90 micrograms/ml and 3446 micrograms/min per ml for carboplatin, respectively. The mean ratio of plasma ultrafilterable platinum to total platinum were calculated, and the results showed that the protein-binding abilities of 254-S and carboplatin were almost identical. More than 50% of the 254-S was excreted in the urine within the first 480 min after its administration. Thrombocytopenia was reported as a dose-limiting toxicity for both 254-S and carboplatin. This similarity in side effects may mainly be due to the comparable pharmacokinetic behavior of these two platinum compounds.

Antineoplastic Agents↗
PubMed1989

Serial measurement of sister chromatid exchanges in the peripheral lymphocytes of patients with lung cancer receiving chemotherapy in relation to bone marrow toxicity.

The frequencies of sister chromatid exchanges (SCE) in the peripheral lymphocytes of patients with lung cancer before and after initial chemotherapy were serially measured and the correlation between SCE frequencies and bone marrow toxicity was evaluated. The addition of mitomycin C to vindesine plus cisplatin increased SCE frequencies significantly in patients with non-small cell lung cancer. A significant increase in frequencies of SCE was observed in patients treated with cyclophosphamide plus adriamycin plus vincristine as compared with those treated with cisplatin plus etoposide in small cell lung cancer. A significant inverse correlation was observed between SCE frequencies in the peripheral lymphocytes 7 days after treatment (x) and the nadir value/pretreatment value of platelets (y)(r = -0.685, P = 0.0007, y = 0.842-0.022x). The relation between SCE frequency and leukopenia showed the same trend as thrombocytopenia, but the correlation was not statistically significant (r = -0.444, P = 0.057). SCE assay may have potential clinical use for the prediction of chemotherapy-induced thrombocytopenia.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Phase II study of carboplatin in non-small cell lung cancer.

Forty four patients with advanced non-small cell lung cancer (NSCLC) were treated with carboplatin (CBDCA; cis-diammine-1, 1-cyclobutane dicarboxylate platinum II) at a dose of 400-450 mg/m2 intravenously every four weeks in a phase II study. Forty three patients were evaluated for response and toxicity. Two patients achieved responses resulting in an overall response rate of 4.7% (95% confidence limits: 0.6-15.8%); one of these had not been treated previously and the other had been treated previously with vinblastine. The durations of their responses were 5 and 7 months, respectively. The response rate in 28 previously untreated patients was 3.6% (1/28; 95% confidence limits: 0.1-18.3%). Myelosuppression was the most commonly found toxicity, and thrombocytopenia especially was dose-limiting. Thrombocytopenia (less than 75,000/mm3) was observed in 12 patients (28%). Leukopenia (less than 3,000/mm3) was observed in 14 patients (33%). No serious infection or bleeding occurred, however. Treatment with 400-450 mg CBDCA/m2 was well tolerated in the good risk patients in this study. Mild to moderate emesis was observed in 28 patients (65%). No renal toxicity, neurotoxicity or ototoxicity was seen. It was demonstrated that CBDCA had little efficacy in NSCLC at the dose and schedule given in the present study.

Adult↗
PubMed1989

Prognostic factors in small cell lung cancer: multivariate analysis in the National Cancer Center Hospital (Japan).

Consecutive series involving 172 patients with small cell lung cancer were analyzed retrospectively using eight pretreatment and two treatment-related prognostic factors in respect of their influence on survival. All the patients received chemotherapy with or without chest irradiation, according to phase II or phase III trial protocols of the National Cancer Center Hospital, Tokyo, from 1970 to 1987. The influence on survival of the various factors was investigated using univariate methods and Cox's proportional hazards model. In patients who survived for more than one year, a performance status of 0-1, limited disease, an age greater than 60 years, the absence of liver metastasis, radiotherapy to primary site and response to chemotherapy were determined by univariate analysis to be favorable prognostic factors. By multivariate analysis, performance status (P = 0.005), age (P = 0.026) and response to induction chemotherapy (P = 0.0001) proved to be valuable prognostic survival factors. The extent of disease which had been considered one of the most significant prognostic factors, was shown not to be a significant independent variable by multivariate analysis. Staging procedures may influence the prognostic analysis. Although classifying the limited or extensive stage of disease is still recommended, the current staging system lacks stringency and may not, in fact, reflect the tumor burden accurately. A simpler and meaningful staging system needs to adopted universally in order to continue the build-up of data for comparison from all institutions.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Control of cisplatin-induced delayed emesis with metoclopramide and dexamethasone: a randomized controlled trial.

Forty-two patients with advanced lung cancer undergoing chemotherapy containing cisplatin (80 mg/m2) were submitted to a randomized controlled trial to evaluate the effect of the combination of metoclopramide and dexamethasone for the treatment of delayed cisplatin-induced emesis occurring more than 24 hours after cisplatin administration. All patients received intravenously (i.v.) high-dose metoclopramide and dexamethasone on the day of cisplatin treatment. Excellent emetic control (no emesis during the 24 hours following cisplatin administration) was achieved in 30 out of 41 patients (73%) with this combination. Patients treated i.v. with metoclopramide and dexamethasone on days 2-7 experienced less delayed emesis, nausea and anorexia compared to those treated with a placebo (delayed emesis, 25 vs 50%, respectively, P = 0.105; more than four days of nausea, 10 vs 35%, respectively, P = 0.059; less than three days of anorexia, 80 vs 50%, respectively, P = 0.048). Although the results of the study showed no statistically significant advantage with the combination of i.v. metoclopramide and dexamethasone for patients treated with cisplatin, in view of the short duration of anorexia and the marginal reduction in nausea. Female patients tended to have more emetic episodes and extrapyramidal side effects (except akathisia) than male patients, but the differences were not statistically significant except for acute emesis (P less than 0.005).

Adult↗
PubMed1988

Cytogenetic effect of carboplatin on human lymphocytes.

Carboplatin, a second generation cisplatin analogue, was tested for induction of sister chromatid exchange (SCE) as well as chromosomal aberrations in human lymphocytes in vitro and in vivo. A dose-dependent effect was observed for increased frequency of metaphases with SCE (r = 0.984, P less than 0.001) as well as chromosomal aberrations (r = 0.994, P less than 0.001), primarily chromatid gap or break, in vitro. SCE induction by carboplatin was less than that by cisplatin at the same concentration. When patients were treated with a single dose of carboplatin at a dose of 450 mg/m2, the frequency of SCE and chromatid type aberrations increased significantly. However, even when considering dose and peak plasma concentration in patients receiving carboplatin, it appears that the ability of carboplatin to induce SCE and chromosomal aberrations is weaker than that of cisplatin. SCE frequencies induced by carboplatin decreased with time going by, and in one patient who was tested 5 weeks after treatment, SCE frequency showed a decrease to the pretreatment level. It thus appears that carboplatin has an improved therapeutic index over the parent compound, cisplatin, because of its less mutagenic or carcinogenic hazard, in addition to the largely reduced incidence of untoward effects.

Aged↗
PubMed1988

A birefringence, electron microscopy, and histochemical survey of chromosomal structure in the sperm nuclei of an echinothurid sea urchin, Araeosoma owstoni.

The mature sperm head of Araeosoma owstoni, an echinothurid sea urchin, showed positive birefringence reflecting that the overall orientation of DNA molecules was semiperpendicular toward the nuclear axis of the sperm head. Transmission electron microscopical observation of sperm in this species revealed a highly electron-dense cylindrical coil with an empty central core extending along the major axis of the sperm head. This coil had seven to eight turns along its entire length of 3.5 micron. The maximum width was 0.35 micron near the distal end of the nucleus, and the minimum width was 0.17 micron near the apical end. Lamellar substructures were also present in the sperm nucleus, appearing at the periphery of the electron-dense cylinder in a radial manner. Staining with Feulgen's reaction and acid-orcein indicated that the coil was probably composed of sperm chromosomes.

Animals↗
PubMed1988

Phase II study of carboplatin in small cell lung cancer.

Carboplatin (CBDCA; cis-diammine-1, 1-cyclobutane dicarboxylate platinum II), a new platinum analogue, was administered to 18 patients with small cell lung cancer (SCLC) at a dose of 300-450 mg/m2 intravenously every four weeks, in a phase II study. All patients could be evaluated to assess response and 17 for toxicity. The overall response rate was 28% (5/18), including one complete response. Of eight patients previously untreated, four (50%) showed a response, including one complete response. The response rate in patients with no previous cisplatin-treatment was 50% (5/10). Response durations in five responders were 2, 3, greater than 4, greater than 10 and 11 months. Toxicity was primarily hematologic, with thrombocytopenia being dose-limiting. Thrombocytopenia (less than 75,000/mm3) was observed in 12 patients (71%), six requiring platelet transfusion. Leukopenia (less than 3,000/mm3) was observed in 11 patients (65%). There were no episodes of serious infection or bleeding, however. Myelosuppression was more severe in heavily pretreated patients than in patients previously untreated. Dose reductions were required following multiple treatments for cumulative myelotoxicity. Mild to moderate nausea and vomiting occurred in seven patients (44%). Nephrotoxicity and ototoxicity were not observed. Carboplatin was demonstrated to be an active agent against SCLC. Further investigation into dose and schedule of CBDCA in combination chemotherapy is warranted.

Aged↗
PubMed1988

Three schedules of recombinant human interleukin-2 in the treatment of malignancy: side effects and immunologic effects in relation to serum level.

Recombinant human interleukin-2 (rIL-2) was administered to 34 patients with advanced malignancy. Three schedules of rIL-2 administration employed were as follows: (A) 2-hr iv infusion of 6.7 X 10(5) U/m2/day (A1, 6 cases) or 2.2 X 10(6) U/m2/day (A2, 8 cases) for five consecutive days; (B) 24-hr continuous iv infusion of 3.3 X 10(5) U/m2/day (B1, 3 cases), 6.7 X 10(5) U/m2/day (B2, 7 cases) or 1.1 X 10(6) U/m2/day (B3, 5 cases) for 28 consecutive days; and (C) 24-hr continuous iv infusion of 6.7 X 10(5) U/m2/day (C, 5 cases) for 5 consecutive days per week for four weeks. The common side effects were fever (79%), eosinophilia (61%), malaise (56%), erythema or rash (50%), chills (38%) and nausea or vomiting (35%), with the dose-limiting toxicities being hypotension in group A, and renal dysfunction with fluid retention in groups B and C. In the case of 2-hr iv infusion, rIL-2 was rapidly cleared from the plasma, with a half life of about 30 min, while in the case of 24-hr continuous infusion, more than 1 U/ml serum IL-2 activity was maintained for 14 days in group B3. Natural killer (NK) and lymphokine-activated killer (LAK) activities were augmented by rIL-2 administration in patients of groups A, B3 and C. In eight patients of group B, NK and LAK activities transiently decreased after rIL-2 administration, and recovered by day 3. The percentage of IL-2 receptor and Leu HLA-DR positive cells reached the peak level on day 7 in group B. In patients of group C, the percentage of Leu HLA-DR positive cells as well as NK and LAK activities increased upon rIL-2 administration and decreased during an intermission of two days. However, the percentage of rIL-2 receptor positive cells increased during the intermission of rIL-2. The most effective schedule of rIL-2 administration was considered to be the schedule of group C on the basis of this study.

Adult↗