Biomedical subjects
Publications and source records attributed to K Koike.
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The human hepatoma cell line, huGK-14, containing integrated hepatitis B virus (HBV) DNAs, produced a large number of 23 nm spherical particles of HBV surface antigen (HBsAg) in a serum-free medium. These particles closely resembled the HBsAg particles found in the sera of HBV carriers and elicited a high antibody response in guinea pigs. The huGK-14 cells in a serum-free medium would provide a new, economic source of HBV vaccine.
The pD2-values for noradrenaline obtained from the veins of the body wall were quite different from those embryogenetically related to the digestive tract. Therefore, the difference in the post-junctional alpha 1-adrenoceptor mechanism was studied in venous smooth muscle preparations from the canine. The helical and longitudinal strips of the lateral saphenous, femoral and portal veins, and the inferior vena cava were prepared and set in an organ bath apparatus. The longitudinal strips of the lateral saphenous and femoral veins, and inferior vena cava did not or little respond to noradrenaline. The pD2-values for noradrenaline differed considerably among the veins, while the pA2-values for prazosin against noradrenaline were identical in all veins used. Negative log of dissociation constants, pKA-values, for noradrenaline obtained by the partial irreversible blockade of alpha 1-adrenoceptors with phenoxybenzamine were very similar in all the veins. Efficacies which were calculated by the same method differed considerably among the veins. The dissociation constants, KD-value and the maximum binding sites, Bmax-values for [3H]-prazosin were also estimated by Scatchard analysis of the specific binding of [3H]-prazosin to the microsomal fractions from veins. The KD-values for [3H]-prazosin were also identical. However, Bmax-values varied considerably among the veins. The Bmax-values are proportional to the 50% effective concentrations, whose negative logs were the pD2-values, and to the efficacies. The present results suggest that the regional difference in the pD2-values for noradrenaline in the canine veins is not due to the affinities to the alpha 1-adrenoceptors but to the receptor densities.
In hepatitis B virus (HBV) related hepatoma samples there is a high frequency of HBV-DNA integration into the chromosome, but the frequency of integration in the early-stage of carcinogenesis is expected to be even higher. Structural an analysis of integrated HBV-DNA and chromosomal flanking DNAs disclosed that the marked rearrangement of chromosomal DNA is not directly linked to carcinogenesis. HBV-DNA integration and chromosomal DNA depletion occur even in chronic hepatitis tissues. Integration is, therefore, thought to trigger a series of reactions which lead to carcinogenesis. However, the oncogene is not detected within the HBV genome, and the HBV integration site in the chromosome is variable. As one approach to clarifying the cause and effect relationship between HBV-DNA integration and liver carcinogenesis DNA transfection experiments were conducted using mouse NIH3T3 cells to detect hepatoma-related oncogenes. As a result, the well-known N-ras gene and an unknown oncogene were independently isolated from different hepatoma tissues.
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Biopsy specimens of lymph nodes with the histologic characteristics of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) were obtained from 9 cases (4 cases of AILD and 5 cases of AILD-like T lymphoma [AILD-T]) and histologically analyzed by the use of a double immunoenzymatic staining technique with the combination of a monoclonal antibody against lymphocyte membrane antigen and that against human DNA polymerase alpha (pol alpha), which is detectable in the nucleus of the cells in G1, S, and G2 phases. In all 9 cases, the pol alpha + proliferating cells had a peripheral T-cell phenotype with T11 and Leu-4 antigens, whereas proliferating B cells with B1 antigen were rarely observed. As for T-cell subset antigens, the proliferating T cells had T4+ helper/inducer phenotype in 7 cases, while T8+ suppressor/killer T cells proliferated in 2 cases, although a significant number of T4+ proliferating cells were also recognized. The study on malignant lymphomas that evolved in the 2 cases showed that the T-subset antigens on major proliferating tumor cells were the same as those found in the preceding AILD lesions, suggesting that lymphoma T cells originate from the AILD lesion. The results suggested that AILD without histologic manifestations of malignancy and AILD-T may be a neoplastic disease derived from either subset of peripheral T cells.
The distribution of cefuzonam (CZON, L-105) into the uterus and uterine adnexa was investigated and the usefulness and the safety of CZON in obstetric and gynecological infections were studied. The results are summarized as follows: 1. Following one shot intravenous injection of CZON 1 g, a good distribution of the drug into tissues of uterus and uterine adnexa was observed, with Cmax values of 15.7-33.9 micrograms/g, Tmax of 7.3-34.0 minutes and AUC values of 18.7-35.3 micrograms X hr/g. 2. In all of the 30 cases of obstetric and gynecological infections treated, CZON was evaluated effective. 3. Bacteriologically, 93.9% of total bacteria that had been isolated were eliminated by the administration of the drug. 4. Against all the strains of bacteria isolated before the treatment and replaced bacteria, MIC50, MIC80 and MIC90 of CZON were 0.20 micrograms/ml, 12.5 micrograms/ml and 25 micrograms/ml, respectively, showing low values. 5. Subjective and objective findings and clinical laboratory test values during and after the trial showed no side effects associated with CZON.
Ceftriaxone (CTRX) was studied regarding its penetration into the adnexa uteri and uterine tissues, as well as its utility and safety in the treatment of patients with obstetric and gynecologic infections. The results obtained are summarized below. 1. When 1 g of CTRX was administered by intravenous bolus injection, Cmax in tissues of adnexa uteri and uterus ranged from 42.2 to 80.5 micrograms/g, Tmax ranged from 0.42 to 0.81 hour, and the AUC ranged from 314.9 to 606.9 micrograms.hr/g. Thus, drug penetration into these tissues was good. 2. Clinical efficacy of CTRX was evaluated in 29 obstetric and gynecological patients. The clinical efficacy was good in all cases. 3. Bacteriological effects of CTRX were very good, and 90% of the organisms isolated before treatment were eradicated. 4. Laboratory testing revealed an occurrence of mild eosinophilia in 1 case.
Aggregation responses to low concentrations of ADP, epinephrine, collagen and cationophore A23187 in platelets from two family members with marked bleeding tendencies were virtually absent, whereas shape change with ADP was normal. The contribution to factor X activation by collagen-treated platelets was markedly decreased. Glycoproteins IIb and III were also significantly reduced. The patients' platelets had normal stores of secretable constituents, but secretion of adenine nucleotides and acid hydrolases in response to low concentrations of thrombin and A23187 was drastically reduced compared to normal platelets; secretion of platelet factor 4 was normal. Agonist concentrations that normally produce maximal responses induced only partial aggregation and secretion in the patients' platelets. After prelabelling with [3H]arachidonate thrombin caused less changes in the [3H]phosphatidylinositol, [3H]phosphatidylcholine and free [3H]arachidonate in platelets from the patients than in platelets from normals. We conclude that the patients' platelets have an impairment in part of the signal processing mechanism that is common for all agonists and responses. This platelet abnormality, which has a superficial resemblance to thrombasthenia, represents a hitherto undescribed qualitative platelet disorder.
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Anti-asthmatic drug, KC-404, inhibited specifically spontaneous contraction and leukotriene (LT) D4-induced contraction of guinea-pig trachea. Relaxation of spontaneous contraction by KC-404 was reduced by the treatment of the guinea-pig trachea with a cyclooxygenase inhibitor, flurbiprofen. Some parallel shift of the concentration-action curve of LTD4 by KC-404 was still observed in the presence of flurbiprofen. Specific binding of [3H]LTD4 to the microsomal fraction of guinea-pig trachea was partially inhibited by KC-404. These results suggest that the relaxing action of trachea of KC-404 is due to the interference of interaction between LTD4 and its receptor and to the product(s) via cyclooxygenase pathway.
Ca-antagonistic activities of cerebral vasodilators, nicardipine and 1-(3,4-dimethoxyphenyl)-2-(4-diphenylmethylpiperazinyl)ethanol dihydrochloride (NC-1100) were tested on basilar and renal arteries, thoracic aorta and portal vein of rabbit, and rat vas deferens. Both the cerebral vasodilators used herein had a selectivity to basilar arteries. The selectivity to the basilar arteries is considered to be one of the factors in deciding the pharmacological property of the cerebral vasodilators.
Blocking activities of alpha- and beta-adrenoceptors by 4-(2-hydroxy-3-[(1-methyl-3-phenylpropyl)amino]propoxy)benzeneacetamide (KF4317) were tested on the isolated muscles, compared with the action of labetalol. In blocking the beta 1-adrenoceptor, KF4317 was almost as active as labetalol. KF4317 was about 1/10th as potent as labetalol in blocking the beta 2-receptor. KF4317 was beta 1-adrenoceptor selective. KF4317 was about 1/50th as potent as labetalol in blocking the alpha 1-receptor. KF4317 did not interact with the alpha 2-adrenoceptor in concentrations up to 10(-5) M. The present results indicate that KF4317 is a selective beta 1- and alpha 1-adrenoceptor blocker, though the alpha 1-adrenoceptor blocking action is weak.
Single cells were prepared from the guinea-pig taenia caecum and used for the study of drug-receptor interactions. The cells showed a graded response to carbachol, the dose response curve being shifted in a parallel fashion by atropine, indicating a competitive antagonism. The pA2-value of atropine was in agreement with that estimated using the intact tissue. [3H]QNB (quinuclidinyl benzilate) combined with the single cells, the Scatchard plot yielding a straight line. The dissociation constant of QNB was similar to values estimated in other membrane preparations. The apparent dissociation constants of cholinergic drugs estimated from inhibition of the specific binding of [3H]QNB (0.20 nM) to the single cells by the cholinergic drugs were also in agreement with the values in other membrane preparations. The results indicate that the single smooth muscle cells are useful for the study of drug-receptor interactions.
The cleavage of arachidonate from pituitary phospholipids may contribute to the process that regulates the release of prolactin. To test this hypothesis, primary cultures of anterior pituitary cells from female rats were preincubated with [3H]arachidonate to label their phospholipid-containing components. The cells were then washed and incubated with vehicle or test agents and the release into the medium of prolactin and [3H]arachidonate cleaved from the phospholipids was measured. Thyrotropin-releasing hormone (TRH) and neurotensin significantly increased the release of both [3H]arachidonate and prolactin. Although basal [3H]arachidonate release was not affected by dopamine or somatostatin, both of these agents reduced [3H]arachidonate release induced by TRH. The relationship between calcium mobilization and arachidonate release was investigated by exposing the cells to agents that modify calcium balance. Maitotoxin, a calcium channel activator, stimulated prolactin and arachidonate release. In contrast cobalt, a calcium channel blocker, penfluridol, a calcium-binding protein inhibitor, and low-calcium medium decreased basal and TRH-induced prolactin release and diminished the TRH-induced release of arachidonate. RHC 80267, an inhibitor of diacylglycerol lipase, decreased TRH-induced prolactin and arachidonate release. BW755c, an inhibitor of the conversion of arachidonate to its metabolites, decreased TRH-induced prolactin release but predictably increased arachidonate release. These findings support the hypothesis that arachidonate metabolites may be involved in the process regulating prolactin release.
We investigated the intrathoracic contributions to the caudal mediastinal lymph node (CMN) efferent lymph in 12 anesthetized sheep after removing possible systemic contributions from below the diaphragm. We interrupted various pathways that may send lymph to the CMN (chest wall, esophagus, lung). Because the experiment is destructive, we did the resections in various combinations and waited 1 h between steps. Base-line CMN efferent lymph flow averaged 0.90 +/- 0.52 g/15 min (mean +/- SD). Cutting the pulmonary ligaments bilaterally caused lymph flow to decrease by an average of 58%. In five sheep, cauterizing around the lung hila reduced lymph flow by 16% of base line, cauterizing along the esophagus reduced lymph flow by 18% of base line, and cauterizing along the chest wall increased lymph flow by 6% of base line. After complete isolation of the node, except for the bronchoesophageal artery, dorsal mediastinal vein, and CMN efferent duct, 14% of base-line flow remained. The lymph-to-plasma total protein concentration ratios did not change significantly with any procedure. Under the conditions of our experiments, approximately 74% of base-line intrathoracic CMN efferent flow comes from the lung.