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Biomedical subjects

H Minami

Publications and source records attributed to H Minami.

At least 55 records · Page 3Linked to original sources

[Surgical treatment of intracardiac tumors in 25 patients].

For most intracardiac tumors, operation is the only means of therapy. In our institute, we have aggressively performed operation for intracardiac tumors regardless of histological type because resection for tumor had a beneficial effect on the hemodynamics with congestive heart failure. Twenty-five cases of cardiac tumors were operated upon from 1980 through 1998. The follow-up period ranged from 2 months to 19 years. The histological diagnoses of the tumors were as follows: benign tumors 24 (myxoma 21, papillary fibroelastoma 1, fibroma 1, angiomyolipoma 1) and malignant tumor (angiosarcoma 1). There was one hospital death in this series. In the New York Heart Association classification, the cardiac performances of intracardiac benign tumors after operation were Class I or II. The results of surgical treatment of intracardiac benign tumors were satisfactory both in short-term and in long-term. On the other hand the long term result of malignant tumor was extremely poor. A patient with angiosarcoma died 8 months later due to bone metastasis.

Aged↗

[Evidence for Taxotere treatment with solid tumors].

Evidence based medicine is essential to further develop the state of the art for cancer treatments. We introduce the levels of evidence for Taxotere treatment against various solid tumors. Most evidence for Taxotere therapy was produced in other countries. However, in Japan we have some data from phase II clinical trials for the approval of Taxotere. We review these domestic results, which reveal its usefulness and toxicity in Japanese patients. In addition, we analyze the evidence from the data of clinical trials of Taxotere conducted by investigators in the USA/Europe. Japanese physicians or academies must build a consensus for the application of Taxotere to Japanese patients with solid tumors.

Antineoplastic Agents, Phytogenic↗

Role of human cytochrome P450 3A4 in metabolism of medroxyprogesterone acetate.

Medroxyprogesterone acetate (MPA) is a drug commonly used in endocrine therapy for advanced or recurrent breast cancer and endometrial cancer. The drug is extensively metabolized in the intestinal mucosa and in the liver. Cytochrome P450s (CYPs) involved in the metabolism of MPA were identified by using human liver microsomes and recombinant human CYPs. In this study, the overall metabolism of MPA was determined as the disappearance of the parent drug from an incubation mixture. The disappearance of MPA in human liver microsomes varied 2.6-fold among the 18 samples studied. The disappearance of MPA in the same panel of 18 human liver microsomes was significantly correlated with triazolam alpha-hydroxylase activity, a marker activity of CYP3A (r = 0.764; P < 0.001). Ketoconazole, an inhibitor of CYP3A4, potently inhibited the disappearance of MPA in 18 human liver microsomes. Anti-CYP3A antibody also inhibited 86% of the disappearance of MPA in human liver microsomes. Although sulfaphenazole (an inhibitor of CYP2C9) and S-mephenytoin (an inhibitor of CYP2C19) partially inhibited the disappearance of MPA, no effect of the anti-CYP2C antibody was observed. The disappearance of MPA did not correlate with either the activity metabolized via CYP2C9 (diclofenac 4'-hydroxylase activity) or the activity metabolized via CYP2C19 (S-mephenytoin 4'-hydroxylase activity). Among the 12 recombinant human CYPs (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5) studied, only CYP3A4 showed metabolic activity of MPA. These results suggest that CYP3A4 is mainly involved in the overall metabolism of MPA in human liver microsomes.

Animals↗

[Accelerated titration design].

To reduce the number of patients treated at low and biologically inactive doses in phase I trials of anticancer agents, attempts to decrease the number of patients per dose level and to conduct a larger dose escalation have been made. Among them, accelerated titration designs were proposed and evaluated by simulation; designs 2 and 4 were reported to be acceptable (J Natl Cancer Inst 89: 1138-1147, 1997). Both designs 2 and 4 included only one patient per cohort during the initial accelerated phase. Dosage steps for the accelerated phase were defined using the modified Fibonacci method for design 2 and 100% escalation for design 4, respectively. The accelerated phase continued until one patient experienced dose-limiting toxicity or two patients experienced grade 2 toxicities. Dose escalation was conducted based on the information from the first course in design 2 and from the first three courses in design 4. In the simulation, both designs successfully reduced the total number of patients and the number of undertreated patients without increasing the number of overtreated patients. However, the safety of design 4 was assured as long as all patients received three courses of chemotherapy, which is unusual in phase I studies in Japan. Decision-making on dose escalation based on the information on toxicity in three courses might be cumbersome. Therefore, in Japan, design 2 would be recommended among the proposed accelerated designs. The performance of the design should be investigated by applying it to actual phase I studies and by evaluating the number of undertreated and overtreated patients.

Antineoplastic Agents↗

Study of dose escalation and sequence switching of administration of the combination of docetaxel and doxorubicin in advanced breast cancer.

The objectives of the present study were to evaluate whether a schedule-dependent pharmacokinetic and/or pharmacodynamic interaction exists between two sequences of docetaxel and doxorubicin administration and to determine the maximal tolerated dose (MTD) of this combination. Patients with chemotherapy-naïve metastatic or recurrent advanced breast cancer were enrolled. In the crossover design, tandem dose escalation of docetaxel and doxorubicin was performed. Docetaxel, in doses ranging from 50-70 mg/m2, was administered for 1 h by drip infusion either just before or after a 5-min bolus i.v. injection of doxorubicin at dosages from 40-50 mg/ m2. The sequence of drug administration was switched after the first course in each patient, and the sequence of drug administration thereafter depended on the patient's choice. Twenty-five patients were initially assessable for toxicity. The MTD in the sequence of doxorubicin after docetaxel was 40 and 50 mg/m2, respectively, with the dose-limiting toxicity of neutropenia. On the other hand, the MTD of the sequence of docetaxel after doxorubicin was 70 and 50 mg/m2, respectively. The dose-limiting toxicities in this sequence were neutropenia and diarrhea. Duration of grade 4 neutropenia in the sequence of docetaxel followed by doxorubicin was significantly longer than that in the alternate sequence (P = 0.0062). However, there was no difference in pharmacokinetic parameters of docetaxel, doxorubicin, and doxorubicinol between the two sequences. The sequence of 50 mg/m2 doxorubicin followed by 60 mg/m2 docetaxel is recommended for subsequent clinical trials for practical reasons.

Adult↗

Multi-institutional validation study of carboplatin dosing formula using adjusted serum creatinine level.

Creatinine clearance (Ccr) is widely used as a practical substitute for glomerular filtration rate (GFR) in the Calvert formula: carboplatin dose (mg) = target area under the concentration versus time curve (AUC, mg ml(-1) min) x [GFR (ml min(-1)) + 25]. However, it causes systematic overdosing when the creatinine levels are measured by an enzymatic peroxidase-antiperoxidase method (PAP-Cr). We previously suggested an amended dosing formula to adjust this overdosing: carboplatin dose (mg) = AUC (mg ml(-1) min) x [adjusted Ccr (ml min(-1)) + 25], where the Ccr was adjusted by adding 0.2 (mg dl(-1)) to serum PAP-Cr. In this study, we prospectively validated this formula in 55 patients from six institutions. Target AUC ranged from 3 to 7 mg ml(-1) min, and Ccr was measured by 24-h urine collection. Estimation of carboplatin clearance with the amended formula was unbiased [mean prediction error (MPE) +/- SE = 2.9 +/- 3.4%] and acceptably precise [root mean squared error, (RMSE) = 24.7%], whereas the Calvert formula using non-adjusted Ccr overpredicted carboplatin clearance systematically (MPE +/- SE = 24.9 +/- 4.9% and RMSE = 36.1%). The improvement in the bias and precision of the estimation was seen in all of the participating institutions as shown by decrease in the absolute value of MPE and RMSE for each institution. The Chatelut formula also highly overestimated carboplatin clearance when PAP-Cr was used, but the adjustment of PAP-Cr yielded a decrease in MPE by 30.4% and in RMSE by 21.3%. These results confirmed the necessity of adjusting the serum PAP-Cr in carboplatin dosing formulas.

Adult↗

Lung carcinoma in patients age younger than 30 years.

BACKGROUND: To the authors' knowledge, no study regarding lung carcinoma patients age <30 years has been published. Therefore, this study was undertaken to define the characteristics of lung carcinoma patients age <30 years. METHODS: Information regarding 26 patients with primary lung carcinoma who were age <30 years was obtained from 10 medical institutions and reviewed retrospectively. For comparison, 304 patients age > or = 30 years who were admitted to the First Department of Internal Medicine at Toyama Medical and Pharmaceutical University between 1980-1996 were studied. RESULTS: Among the characteristics observed in the group of lung carcinoma patients age <30 years was a high incidence of female gender, no history of smoking, so-called "low grade malignancy," American Joint Committee on Cancer Stage I disease, and previous surgical resection. In addition, a low incidence of squamous cell carcinoma was noted, and a more favorable prognosis was observed. CONCLUSIONS: The current study noted clinical features that could be defined clearly in lung carcinoma patients age <30 years.

Adolescent↗

Does pressure antagonize anesthesia? High-pressure stopped-flow study of firefly luciferase and anatomy of initial flash.

The antagonizing effect of high pressure against anesthesia is well known. With purified firefly luciferase, however,. Biophys. J. 60:1309-1314) reported that high pressure did not affect the initial flash intensity. Firefly luciferase emits a burst of light when the substrates luciferin and ATP are added in the presence of O2. The light intensity decays rapidly and the weak light lasts for hours. The initial flash is a transient event and is not in a steady state. The steady state is represented by the slope of the linear part of the integral of the light output. The present study used a high-pressure stopped-flow system to compare the pressure effects on the initial flash intensity and the steady-state light intensity. The flash intensity did not change by the application of hydrostatic pressure in the presence or absence of chloroform or 1-octanol. In contrast, high pressure increased the steady-state light intensity. The application of 12 MPa pressure increased the steady-state light intensity of firefly luciferase inhibited by 5 mM chloroform or 0.7 mM 1-octanol by 19.7% and 18.8%, respectively. When analyzed by the rapid reaction kinetics of the transition state theory, the initial peak intensity represents the total amount of active enzyme and is unrelated to the reaction rate. Anesthetics inhibited the initial flash by unfolding the protein, thereby decreasing the concentration of the active enzyme. Pressure affected the steady-state light intensity by changing the reaction rates.

Anesthesia↗

Low-grade B-cell lymphoma of mucosa-associated lymphoid tissue in the lung: a report of a case with pleural dissemination.

A 79-year-old man with an abnormal shadow on a chest radiograph was referred to our hospital for further examination. Open lung biopsy revealed numerous nodules on visceral pleura and the tumor, obtained by wedge resection of the left upper lobe of the lung, consisted of centrocyte-like cells and lymphoplasmacytoid cells, expressing CD20 and CD79a. These cells invaded bronchiolar epithelium to form lymphoepithelial lesions. The pleural-based nodules were similarly composed of the same cells as those in the left upper lobe tumor. To our knowledge, pleural dissemination of low grade B-cell lymphoma of mucosa-associated lymphoid tissue has not been reported previously.

Aged↗

Chemical conversion of vibsanin C to vibsanin E and structure of 3-hydroxyvibsanin E from viburnum awabuki

Vibsanin E (4), a tricyclic vibsane-type diterpene, has been prepared in 50% yield from vibsanin C (2), a seven-membered ring vibsane-type diterpene by reaction with BF3.OEt2 at -78 degrees C. This chemical correlation not only established structure, including absolute configurations, but also has demonstrated a possible biosynthetic route to 4 via 2 derived from vibsanin B (1). The structure of 3-hydroxyvibsanin E (5), another example of a tricyclic seven-membered ring vibsane, isolated from the leaves of Viburnumawabuki, has been established by extensive analyses of 2D NMR data and comparison of its spectral data with those of 4.

Journal Article↗

Hypoxia potentiates ultraviolet A-induced riboflavin cytotoxicity.

Flavins are thought to be important chromophores for chronic photo-induced skin injury, but the mechanism is not well known. We have reported that the primary cytotoxicity remaining in ultraviolet A-irradiated riboflavin solution is attributable to hydrogen peroxide. Because the dermis is more hypoxic than the atmosphere, we investigated the cytotoxicity of riboflavin solution during and after ultraviolet A irradiation under hypoxia. Riboflavin solution showed stronger cytotoxicity during irradiation under hypoxia than under air. Riboflavin solution that had been irradiated under hypoxia at lower ultraviolet A doses showed stronger cytotoxicity and contained more hydrogen peroxide than solution irradiated under air at the same doses. At higher ultraviolet A doses, however, the cytotoxicity and hydrogen peroxide quantity were similar in riboflavin solutions irradiated under different oxygen conditions. The effect of a singlet oxygen quencher, sodium azide, on the induction of cytotoxicity and production of hydrogen peroxide by ultraviolet A irradiation of riboflavin solution was examined. The presence of sodium azide in the solution during ultraviolet A irradiation suppressed the cytotoxicity and hydrogen peroxide production to similar levels at various ultraviolet A doses regardless of oxygen conditions. At the maximum suppression by sodium azide, hydrogen peroxide production decreased to 10% of the unsuppressed production. About 40% of the oxygen molecules of hydrogen peroxide produced was thought to be derived from oxygen dissolved in the riboflavin solution.

Cell Line↗

Prognostic factors for short-term survival in patients with stage IV non-small cell lung cancer.

Prognostic factors which can forecast short-term survival in patients with stage IV non-small cell lung cancer have not been well evaluated. Characteristics of such factors may be different from those for overall survival, and would be an important eligibility criterion for clinical trials of chemotherapy. We retrospectively analyzed the data of 158 patients with stage IV non-small cell lung cancer whose performance status was 0, 1 or 2. Univariate and multivariate logistic regression models revealed demographic variables which significantly correlated with the survival at 8 or 12 weeks. The univariate model showed the following significant variables: T factor, N factor, number of organs with metastases, grade of performance status, weight loss within 6 months, evidence of metastasis either at bone or lymph node, and lactate dehydrogenase level. The subsequent multivariate model demonstrated that both grade of performance status under 2 and number of metastasized organs less than 3 are important factors for 8- or 12-week survival. The survival rate in patients meeting the two criteria (grade of performance status under 2 and number of metastasized organs less than 3) and in those meeting only one of them was 93% versus 80% at 8 weeks (P = 0.030) and 88% versus 62% at 12 weeks (P < 0.001), respectively. Grade of performance status and number of organs with metastases appear to be important prognostic factors for short-term survival in patients with stage IV non-small cell lung cancer.

Adult↗

Pharmacokinetics and pharmacodynamics of 9-aminocamptothecin infused over 72 hours in phase II studies.

A novel derivative of camptothecin, 9-aminocamptothecin (9-AC), is currently under Phase II evaluation in various cancers. Exceptionally mild toxicities were observed in patients with brain tumors who were treated with anticonvulsants. To investigate a pharmacokinetic interaction between 9-AC and anticonvulsants, and to evaluate the pharmacodynamics of 9-AC, we investigated the clinical pharmacology of 9-AC, administered by a 72-h infusion, in three Phase II studies. Plasma concentrations of total 9-AC (lactone plus carboxylate) at a steady state were measured in 56, 10, and 14 patients with non-small cell lung cancer, malignant glioma, and head and neck cancer, respectively. For lung cancer or glioma patients, 9-AC was infused at 45 (51 patients) or 59 (15 patients) microg/m2/h, and 9-AC was infused at 35.4 microg/m2/h in head and neck cancer patients. All glioma patients had been treated with phenytoin or carbamazepine. 9-AC clearance did not differ among the dosage rates, but differed according to the diseases (P = 0.002). Glioma patients had a higher clearance (1.0-18.0; median, 2.0 liters/h/m2) than lung cancer patients (0.3-5.1; median, 0.9 liters/h/m2). A logistic regression model described the relationship between the 9-AC concentration and the probability of grade 4 neutropenia, which was the main toxicity. Observed incidences of grade 4 neutropenia for patients with model-predicted probability of 0-20%, 20-40%, and 40-100% were 10%, 32%, and 67%, respectively, and corresponded to 9-AC concentration of <54, 54-86, and >86 ng/ml, respectively. Anticonvulsants seem to induce the clearance of 9-AC, and the concentration of 9-AC predicts the probability of grade 4 neutropenia.

Adult↗

[New screening method for coagulation abnormality including AT III deficiency during CABG].

In our institute, 1 ml of heparin is administered to the patients undergoing CABG before dissection and mobilization of the internal thoracic arteries (ITAs) and/or right gastroepiploic artery (GEA) to prevent possible thrombosis or coagulation tendency. Two patients with AT III deficiency underwent CABG and one of them died. The aim of this study is to know whether ACT check before and after administration of 1 ml of heparin is useful as a screening test of coagulation abnormalities including AT III deficiency. One hundred patients (84 males and 16 females) undergoing CABG were studied. Age ranged from 41 to 79 years (mean 64.8 +/- 8.0 years). One ml of heparin was administered to all the patients before ITAs and/or GEA were dissected and mobilized. ACT was doubly checked before (control ACT: c-ACT) and after (heparinized ACT: h-ACT) administration of heparin. ACT extension was defined as follows: ACT extension = (c-ACT)-(h-ACT). Mean c-ACT was 124 +/- 12 sec., h-ACT 188 +/- 26 sec. and ACT extension 64 +/- 24 sec. There were only 3 cases which ACT extension were less than 30 sec.: two of them were combined with AT III deficiency and the other was due to insufficient administration of heparin. In conclusion, examination of ACT after 1 ml administration of heparin is new, simple and convenient screening method for coagulation abnormalities including AT III deficiency during CABG.

Adult↗

Pharmacological analysis of etoposide in elderly patients with lung cancer.

To analyze the pharmacological characteristics of etoposide in elderly patients, we conducted a Phase I trial of a 14-day administration of oral etoposide on 12 chemotherapy-naive patients, ages 75 years or older, with lung cancer. The pharmacological profiles of etoposide in elderly patients were compared with those of younger patients in our previous studies (H. Minami et al., J. Clin. Oncol., 11: 1602-1608, 1993; H. Minami et al., J. Clin. Oncol., 13: 191-199, 1995; Y. Ando et al., Jpn. J. Cancer Res., 87: 200-205, 1996). The sigmoid Emax model and logistic regression model were used for pharmacodynamic analysis. The maximum tolerated dose for elderly patients was 75 mg/body/day. The apparent oral clearance in elderly patients was 37+/-10 (mean +/- SD) ml/min, which was not different from that in younger patients (44+/-12 ml/min). The area under the concentration-versus-time curve of etoposide over the treatment period (total AUC) that produced a 50% decrease in absolute neutrophil counts was significantly different between elderly and younger patients, 14.3+/-2.5 and 21.6+/-2.7 mg x min/ml, respectively (P = 0.048). The incidence of grade 3 or 4 neutropenia at total AUC of 30 mg x min/ml (corresponding to a plasma concentration of 1.5 microg/ml for 14 days) was 81% in elderly patients but only 48% in younger patients. Although there was no pharmacokinetic difference between elderly and younger patients, equivalent exposure to etoposide resulted in severer myelosuppression in elderly patients. These findings suggest that prolonged etoposide administration with plasma concentration maintained at 1-2 microg/ml may cause severe myelotoxicity in elderly patients.

Administration, Oral↗

[Clinical study of emergency coronary artery bypass surgery].

Between January, 1996 and December, 1998, 29 patients were undergone emergency coronary artery bypass grafting (CABG) in our institute. Age ranged 34 to 85 years (mean 65 +/- 11 years, male:female = 25:4). Of 29 emergency cases, 3 were hospital death. Hospital mortality rate was 10.7%, which was significantly higher than the hospital mortality of elective CABG (1.4%) during the same period. The necessity of IABP before CABG was 72% in emergency cases (elective surgery: 0%). Thus the use rate of arterial grafts were 86.2% in emergency cases (elective surgery: 100%), the patency of the arterial grafts were 100%. It is important to make stable condition of the patients before the operation, and therefore it is important to make contact closely with the cardiologists for making stable condition and for lowering the operative mortality. And, we should use arterial grafts for the long term result as much as possible if it is an urgent operation.

Adult↗

[Predonation and transfusion in open heart surgery].

The efficacy of predonation of autologous blood in reducing the use homologous blood during open heart surgery was investigated. Between January 1997, and February 1998, predonation and transfusion was studied in 100 consecutive open heart operations (CABG, 77; valve surgery, 17; ASD, 5; myxoma, 1). The guidelines for autologous predonation were as follows: an age < 70 years, a weight > 40 kg and a hemoglobin > 12 g/dl. Patients in NYHA class IV or undergoing emergency operation were excluded. The blood loss during operation ranged from 195 to 1,850 ml (mean; 670 ml), being from 305 to 1,850 ml (723 ml) for CABG, from 260 to 1,020 ml (493.5 ml) for valve surgery and from 195 to 570 ml (342 ml) for ASD. The blood loss was not significantly dependent on sex or age and did not differ elective and emergent operations. Only 36.6% of patients with autologous predonation needed homologous transfusion versus 63.4% of those without predonation. Homologous transfusion was done in only 5% of the those with predonation of 800 ml versus 69% at 400 ml and 71% at 200 ml. In conclusion, autologous blood transfusion is effective for reducing the homologous blood requirement. It also seems that predonation of 800 ml may be sufficient to allow open heart surgery without blood transfusion.

Adolescent↗