Biomedical subjects
Publications and source records attributed to T Ichihara.
From the dried aerial parts of RABDOSIA INFLEXA, two new diterpenoids, named inflexarabdonin G and inflexarabdonin H were isolated and the structures were elucidated as ENT-1beta,3alpha,11alpha-trihydroxy-kaur-16-en-15-one 3,11-diacetate and ENT-1beta,3alpha,11alpha-trihydroxy-kaur-16-ene-6,15-dione 1,3-diacetate, respectively, on the basis of spectroscopic and chemical evidence.
Methotrexate (MTX) is metabolized intracellularly to MTX-polyglutamates (MTX-PGs), which markedly inhibit several folate-dependent enzymes. Polyglutamation defect, therefore, is one of the important factors in drug resistance. In this study, reversal of MTX cytotoxicity by l-leucovorin (l-LV) was investigated using normal human bone marrow granulocyte progenitor cells (G-CFCs), and MTX-sensitive and -resistant leukemic K562 cell lines; the latter showed diminished polyglutamation. Cytotoxicity of 10(-7)M MTX to G-CFCs was completely reversed by an equimolar concentration of l-LV, but with higher MTX concentrations, relatively more l-LV was required. The reversal of MTX cytotoxicity by l-LV was more effective against bone marrow cells than MTX-sensitive K562 cells; this reversal seemed to be correlated to the total intracellular MTX levels as well as MTX-PG formation (low in bone marrow cells and high in K562 cells). When MTX-sensitive and -resistant K562 cells were incubated with MTX under conditions in which the total intracellular MTX levels of both cells were similar, successful reversal of MTX toxicity by l-LV was demonstrated in MTX-resistant cells, but not in MTX-sensitive cells, suggesting that an increase of MTX-PG formation in MTX-sensitive cells may explain the failure of l-LV to overcome MTX cytotoxicity. In addition to competitive reversal of MTX cytotoxicity by LV, noncompetitive reversal relating to variable formation of MTX-PGs is suggested to be another important factor in the mechanism of the reversal of MTX cytotoxicity by LV.
Inorganic constituents of the leaves of several kinds of plants growing on different soil types were investigated using energy-dispersive X-ray fluorescence spectrometry. The results can be summarized as follows: (1) Each plant exhibited a characteristic metals profile, even if they were grown on similar soil types. (2) As we would expect, the metals profile of the plant leaves depends on the inorganic constitution of the soil on which it is grown. However, the degree of the influence of the soil types on the metals profile of the plant differs according to the kind of inorganic element: Ca and Cu are almost independent of the soil types, but the Ti and Fe content is dependent upon the soil types. (3) Sr content of plant leaves is closely related to the ratio of Sr to Ca of the soil on which the plants are grown. (4) This information should be helpful in identifying the producing district or original plant of a crude drug by its metals profile.
A synthetic amino acid, L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS), can be converted to (-)-norepinephrine (NE) by aromatic L-amino acid decarboxylase (AADC) in various mammalian tissues. Recent studies have indicated the pressor and diuretic effects of L-threo-DOPS. In this study, we examined the effects of L-threo-DOPS on renal hemodynamics and function in anesthetized rats, and evaluated possible mechanisms of the diuresis. Intravenous infusion of L-threo-DOPS at 120 micrograms/kg/min exerted a significant increase in mean arterial pressure (MAP). There was a slight but nonsignificant decrease in renal blood flow (RBF). Although the glomerular filtration rate (GFR) remained at a constant level, urine flow (UF) and urinary sodium excretion (UNaV) increased significantly during the drug infusion. Pretreatment with AADC inhibitor, benserazide, completely blocked both the pressor and diuretic effects of L-threo-DOPS. When the renal perfusion pressure was protected from the pressor effect of the drug by using a Blalock clamp, the drug-induced diuresis was abolished. The diuretic effect of L-threo-DOPS was markedly attenuated by the administration of phentolamine. There was a positive correlation between plasma NE concentration and UF during the infusion of L-threo-DOPS. Intrarenal arterial infusion of L-threo-DOPS at 20 micrograms/kg/min was without effect on renal function. These results indicate that diuresis and natriuresis induced by L-threo-DOPS are dependent on the pressor effect of NE via peripheral alpha-adrenoceptor activation.
The influence of 16,16-dimethyl prostaglandin E2 (16,16-dm PGE2; an agent used for the prevention of stress ulcer after hepatectomy of the cirrhotic liver) on liver regeneration after hepatectomy was studied in rats. The following results were obtained. Ulceration after the stress of 6 h of water immersion was markedly suppressed in rats treated with 30 r/kg of 16,16-dmPGE2 as compared with the untreated controls. In animals that received hepatectomy alone, the gastric pH and gastric mucosal blood flow showed significant reduction from the preoperative levels. In animals that received hepatectomy plus 16,16-dmPGE2 treatment the postoperative reduction in the gastric pH and gastric mucosal blood flow was suppressed, suggesting the effectiveness of 16,16-dmPGE2 treatment in the prevention of stress ulcer after hepatectomy of the cirrhotic liver. The 3H-thymidine uptake percentage and thymidine activity 24 h after hepatectomy and the DNA content 30 h after hepatectomy were significantly higher in animals treated with 16,16-dmPGE2 than in the untreated controls. In animals that were treated intraperitoneally with 50 mg/kg of indomethacin 6 h before hepatectomy the mitotic index 30 h after hepatectomy was markedly lower than that in untreated controls. This indomethacin-induced reduction in the mitotic index tended to be normalized by treatment with 16,16-dmPGE2. These results suggest that 16,16-dmPGE2 treatment effectively prevents stress ulcer and favorably affects hepatic regeneration after hepatectomy of the cirrhotic liver.
The effect of recombinant human interleukin 6 (rhIL-6) on the in vitro growth of human bone marrow myeloid progenitors (granulocyte-macrophage colony-forming units, CFU-GM) was investigated. Recombinant human IL-6 by itself did not induce colony formation. When rhIL-6 at various concentrations was added to the CFU-GM colony cultures containing recombinant human granulocyte colony-stimulating factor (rhG-CSF) or recombinant human granulocyte-monocyte/macrophage colony-stimulating factor (rhGM-CSF), rhIL-6 significantly suppressed the colony formation induced by rhG-CSF, but not by rhGM-CSF. This suppressive effect of rhIL-6 on rhG-CSF-induced, but not rhGM-CSF-induced colony formation was confirmed by using an MY10(+)-cell-enriched population. Neither interleukin 3 nor interleukin 1 alpha suppressed the growth of myeloid progenitors. The preincubation of bone marrow cells with rhIL-6 for a short time (30 min) resulted in a reduction of colonies induced by rhG-CSF, but not by rhGM-CSF. The suppressive effect of rhIL-6 on rhG-CSF-induced colony formation was not observed when the cells were preincubated together with rhG-CSF at a high ratio of rhG-CSF to rhIL-6. The rhIL-6-mediated suppressive effect was further confirmed by blocking the effect by the anti-IL-6 antibody. These results suggest antagonistic interaction between IL-6 and G-CSF in the later differentiation of myeloid progenitors.
Preventive effect of dopamine on stress ulcer formation was investigated in rats. Dopamine 1-10 micrograms/kg/min suppressed the elevation of ulcer index significantly after water immersion and restraint stress in a dose-dependent fashion, however ulcer indices of 25 micrograms/kg/min of dopamine were higher than 10 micrograms/kg/min. Dopamine 1-10 micrograms/kg/min suppressed the decrease of gastric mucosal blood flow, gastric mucosal prostaglandin E2 content and gastric transmucosal potential difference during stress loading in a dose-dependent manner, although the suppression of them in 25 micrograms/kg/min of dopamine was smaller than in 10 micrograms/kg/min also. Dopamine suppressed the increase of gastric acid secretion and gastric motility during stress loading in a dose-dependent fashion up to 25 micrograms/kg/min. These results indicates that dopamine suppresses the formation of stress ulcer by increasing defensive factors and decreasing aggressive factors.
123I-Metaiodobenzylguanidine (MIBG) is expected to be useful agent for functional evaluation of the myocardial sympathetic innervation. The aim of this paper is to investigate serial change of 123I-MIBG myocardial concentration in patients (pts) with dilated cardiomyopathy (DCM) as compared with 201Tl uptake. Eight pts with DCM and six non-cardiac subjects (controls) were examined. After injection of 111 MBq (3mCi) 201Tl and 111 MBq (3 mCi) 123I-MIBG, simultaneous myocardial imaging in anterior view was performed for both tracers in every 30-60 minutes during 5 hours (6 images). Myocardial uptake ratio per pixel to the injected dose was calculated for each tracer with background and cross-talk correction on each image. In pts with DCM, myocardial uptake ratio of 123I-MIBG did not differ significantly from that of controls. The washout of 123I-MIBG from the myocardium, however, was significantly increased in pts with DCM as compared with controls. The % decrease of the radioactivity in 3 hours was 46.9 +/- 13.8% in DCM, whereas 18.0 +/- 7.7% in controls (p less than 0.05). Especially, the decrease in the early phase (less than 1 hour) was significantly larger in DCM than controls (21.2 +/- 7.5% vs 5.3 +/- 4.0%, p less than 0.01). For 201Tl, on the other hand, neither uptake ratio nor washout rate, differed significantly between the two. In conclusion, the rapid washout of 123I-MIBG in the early phase may reflect some sympathetic dysfunction in pts with DCM.
A 23-year-old man suffering from Behçet's disease developed a tracheoesophageal fistula. Subtotal esophagus was stripped and replaced with a gastric tube along greater curvature. The defect of membranous portion of the trachea (2 X 1 cm) was closed with a pedicled pericardial patch and covered with omentum. Transient postoperative recurrent nerve palsy was recovered in about 2 months. He is going well without any significant complaints. He received steroid hormone administration and platelets transfusion because of complicated ITP (Idiopathic Thrombocytopenic Purpura).
A left IMA graft to LAD associated with c-c graftings using saphenous vein were simultaneously performed in 70-year old man and 44-year-old man with multiple coronary disease. Postoperative catheterization showed patency in both cases. It is advisable to perform c-c bypass for patients with calcification of ascending aorta or stenosis of distal RCA such as 4-PD or 4-AV.
We treated 448 patients for peptic ulcer from 1970 to 1988. Among them, 52 cases were bleeding peptic ulcer in the elderly. 32 cases (61.6%) had a duration of illness of less than 3 months, and the most common symptom was abdominal pain (51.9%). 22 cases (44.0%) were in shock and 32 cases (62.7%) had accessory diseases. Twelve cases were treated medically, while 40 cases were treated surgically. Elective operations were performed in 15 cases, and their mortality was 6.7%. Emergent operations were performed in 25 cases, and their mortality was 28.0%. The mortality of of cases involving both shock and accessory diseases was 57.1%, and of this group, all 3 cases treated medically died. When bleeding exceeded 2000cc was the mortality 46.7%. Regarding cases of emergent operation involving shock or accessory diseases, the mortality was 18.2% in the cases treated medically for less than 4 days and had the episodes of massive bleeding less than 3 times, but 62.5% in other cases. The results of this study suggest that aggressive surgical treatment in an early stage may reduce the mortality in elderly patients with peptic ulcer.
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A Monte Carlo simulation was performed to estimate quantitatively the scattered photons in planar images of SPECT. As a phantom we used a water-filled cylinder with a line source and calculated the energy spectra of primary and multiple scattered photons separately at each pixel of the planar images. The energy spectra of primary and scattered photons were studied on following parameters: the size of the phantom; the location of the source; the width of the energy window centered at 72.3 (Tl-201), 141 (Tc-99m), and 159 keV (I-123); and the view angle of the planar images. Obtained results were; (1) the energy spectra of Compton scattered photon varied with the phantom size, the source location, and the photopeak energy, (2) the scattered photons within energy windows of 10-30% centered at the photopeak energy were mainly composed by Compton scatter of the first order, (3) the higher order scattering component of the Compton photons did not represent the location of the line source on the planar image, and (4) the scatter fraction defined by the ratio of the scattered photons to the primary photons increased with increasing the size of the phantom and the width of energy window at the low photopeak energy. From the results, we discussed on the scatter subtraction methods.
A three-headed single-photon emission computed tomography (SPECT) system was developed, and the fundamental SPECT performance and clinical applications were investigated. The full width at half maximum (FWHM) of the SPECT system is 10.8 mm at the center of rotation with a radius of 20 cm. In clinical applications, 201Tl myocardial images with the three-headed system demonstrated a distincter and thinner myocardium compared to those with the dual-headed system. The right ventricular wall was observed even in patients without right ventricular overload. Owing to both the increased sensitivity and resolution, the three-headed system has high performance capability in clinical use such as ECG-gating and dynamic studies.
Transcatheter arterial chemoembolization therapy using polylactic acid microspheres containing aclarubicin hydrochloride (ACR) was performed in 62 patients with primary hepatocellular carcinoma. These microspheres were about 200 microns in diameter and contained 10% (w/w) aclarubicin. A single dose of polylactic acid microspheres containing ACR (50-100 mg of ACR) was administered 1 to 8 times with a mean of 2.2 doses (a total of 160 treatments) in 62 patients. Antitumor effects were observed from the decrease in serum alpha-fetoprotein levels (82.1% of the patients) and in two dimensional size of tumor on computed tomography (93.6%). The cumulative survival rate was 54.3% at 1 year, 24.6% at 2 years, and 19.2% at 3 years, respectively, among 59 patients with unresectable tumors. In 3 resected liver specimens, there was a significant accumulation of ACR in the tumor, and severe necroses of the tumors were observed histologically. Systemic toxicity was mild and all patients tolerated this treatment. These results suggest that transcatheter arterial chemoembolization with the use of polylactic acid microspheres containing ACR is a useful tumor-targeting chemotherapy and is effective in the treatment of hepatocellular carcinoma.
Intrapancreatic extension of pancreatic duct cell carcinoma in 19 resectable cases was evaluated by both hematoxylin and eosin (H&E) staining and quick immunostaining using antibodies against cancer-associated antigens--e.g., CA19-9, DUPAN 2, and CEA--on the intraoperative frozen-section biopsy during the course of laparotomy. By H&E staining, malignant lesions were identified in four of 19 cases (21%). By the immunostaining method, however, cancer cells were detected in 10 of 19 cases (52.6%). This immunostaining method was particularly useful in defining cancer cells surrounded by dense fibrous connective tissue, in which cancer cells are usually difficult to evaluate by H&E staining. Thus, the application of such immunostaining, together with H&E staining, on the cryostat sections of biopsy specimens may provide important information for the appropriate operative method. Retrospective study of permanent sections revealed that pathological diagnosis by quick immunostaining was more accurate than diagnosis by H&E staining.
The rapid immunostaining of gastrointestinal cancer-associated antigens, CA19-9, CEA, DUPAN2, and CA50, for intraoperative pathological diagnosis of pancreatic cancer can be completed in only 13 min by applying microwave irradiation, which was used to accelerate the incubation of the primary antibody. Only 3 s irradiation at 500 W for fresh-frozen sections produced specific antigen staining of greater intensity than that obtained with longer incubation, and tissue preservation was satisfactory with minimal non-specific background staining. This rapid immunoperoxidase staining method on the cryostat section of pancreatic biopsy specimens can provide important information for determining an appropriate operative method for pancreatic cancer patients.
A novel antitumor compound, N-beta-dimethyl-aminoethyl 9-carboxy-5-hydroxy-10-methoxybenzo[a]-phenazine-6-carboxamide sodium salt (NC-190) was evaluated for its antitumor activity in experimental murine tumor systems. In the initial studies with P388 leukemia (i.p.-i.p.), NC-190 led to an increase of greater than 200% in life span (ILS), and 75% of the mice were alive on day 30, when the optimal dose (50 mg/kg, days 1-5) was given. Additionally, the compound had significant activities against i.p. inoculated mouse L1210 leukemia, B16 melanoma, M5076 reticulum cell sarcoma, sarcoma 180, mouse hepatoma MH134, and rat Yoshida sarcoma and Yoshida ascites hepatoma AH130. The optimal dose resulted in a greater than 280% ILS with a 30-day survival of 50% in mice with L1210 leukemia (100 mg/kg, days 1-5), a 156% ILS in mice with B16 melanoma (50 mg/kg, days 1-5), a 98% ILS with a 90-day survival of 25% in mice with M5076 reticulum cell sarcoma (25 mg/kg, days 1, 5, 9, and 13), a greater than 300% ILS with a 60-day survival of 50% in mice with sarcoma 180 (50 mg/kg, days 3-10), a 148% ILS with a 60-day survival of 25% in mice with MH134 (25 mg/kg, days 1-5), a 129% ILS with a 60-day survival of 12.5% in rats with Yoshida sarcoma (12.5 mg/kg, day 3-10), and a greater than 161% ILS with a 60-day survival of 50% in rats with AH130 (6.3 mg/kg, days 3-10). In the experiments with s.c. inoculated tumors, NC-190 not only inhibited tumor growth, but also increased the life span of mice with Lewis lung carcinoma or B16 melanoma. The 60-day survivors accounted for 60% and 30% in mice with Lewis lung carcinoma and B16 melanoma, respectively. The compound significantly inhibited the spontaneous lung metastasis of Lewis lung carcinoma by more than 90% when eight daily i.v. injections were given. NC-190 was active by the i.p., s.c., and i.v. routes. Five consecutive daily i.p. doses (days 1-5) were more effective than a single dose (day 1), two doses (days 1 and 5), or three doses (days 1, 5, and 9). NC-190 warrants further study as a potential antineoplastic agent against human neoplasms, as it has a broad spectrum of antitumor activity and inhibits metastasis.