A new antibiotic, RK-699a.
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Biomedical subjects
Publications and source records attributed to I Yamaguchi.
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FR900840 [2S)-2-amino-2-carboxyethyl (3R)-2-diazo-3-hydroxybutyrate), a new antibiotic with antitumor activity was isolated from the fermentation broth of Streptomyces sp. No. 8727. Its antitumor activity was examined in three mouse tumor systems and ten human tumor systems. FR900840 had no clear effect on mouse ascitic tumors, P388 and L1210, and the B16 melanoma line, but had prominent antitumor effects on several human solid tumors. Its antitumor activity against A549 human lung adenocarcinoma was stronger than those of vinblastine, doxorubicin and cisplatin. These results suggest that FR900840 may become a useful prototype antitumor drug.
There are various kinds of diagnostic examinations in the field of clinical cardiology. In this field, information concerning cardiac structure, dimensions (hypertrophy and dilatation) and cardiac functions are inevitably important. Noninvasive methods are desirable. Except for radiological examinations, electrocardiography and ultrasonic echocardiography are 2 main examinations in cardiology. Holter monitoring is one of the recent topics in clinical electro-cardiology. It is useful for the detection of rest angina or variant angina. Recently "silent myocardial ischemia" has been studied by using this method. This method is also useful for the study of arrhythmia, which is a major cause of sudden death. Quantitative analysis of arrhythmia in the studies of antiarrhythmic drugs can also be done by Holter monitoring. Late potential is also a topic in electro-cardiology. Ultrasonic echocardiography can detect the changes of cardiac structure and function. Doppler echocardiography, developed recently, has made it possible to estimate intracardiac pressure (especially pulmonary arterial pressure) noninvasively. With esophageal echocardiography findings in left atrium, such as thrombus or myxoma in left atrium can be obtained. The most appropriate tool must be selected from the many kinds of diagnostic examinations for efficient clinical diagnosis and therapy.
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The methods of autoregressive and component-wave analysis were applied to quantitatively assess standing postural sways in humans. In 45 normal persons with the eyes open or closed, sway was divided into the two directions of anteroposterior and lateral movement. The optimum order of autoregressive processes for describing the sway was usually in the eighth to ninth order in each direction with either eye condition. In lateral sway the total power was larger with the eyes closed than with them open. A vector of the swaying was then calculated from the total power of the movement in both directions. The average was 48.2 +/- 15.9 degrees with the eyes open and 40.4 +/- 15.1 degrees with the eyes closed. These were significantly different (p less than 0.05). Most of the component waves were generally in the bands of 0 Hz, 0.5-2.5 Hz, 3.5-5.5 Hz, 7.5-8.5 Hz and 10.0 Hz in the two directions of sway and with either eye condition.
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Age-related changes of the sinus node (SN) function and the autonomic influence on the SN function were evaluated in 65 patients with sick sinus syndrome (range 14 to 84 years). Heart rate (HR), corrected SN recovery time and sinoatrial conduction time were measured before (basic) and after (intrinsic) autonomic blockade (propranolol 0.2 mg/kg plus atropine 0.04 mg/kg intravenously). Percent of autonomic chronotropies of the SN function were calculated by the following formulas: (1)--(intrinsic HR--basic HR/intrinsic HR) X 100; (2) (intrinsic corrected SN recovery time--basic corrected SN recovery time/intrinsic corrected SN recovery time) X 100; (3) (intrinsic sinoatrial conduction time--basic sinoatrial conduction time/intrinsic sinoatrial conduction time) X 100. Basic HR, basic corrected SN recovery time and basic sinoatrial conduction time did not vary with age. Intrinsic HR decreased with age, but this correlation was weak (r = -0.54, p less than 0.001). Intrinsic corrected SN recovery time and intrinsic sinoatrial conduction time tended to increase with age (r = 0.26, p less than 0.05; r = 0.29, p less than 0.05, respectively). Percent chronotropies of HR, corrected SN recovery time and sinoatrial conduction time were negative values in younger patients and positive values in elderly patients; they correlated positively with age (r = 0.59, p less than 0.001; r = 0.60, p less than 0.001; r = 0.43, p less than 0.001, respectively). Thus, the basic SN function did not change with age, while the intrinsic SN function deteriorated with age.(ABSTRACT TRUNCATED AT 250 WORDS)
Nilvadipine and other calcium antagonists were studied for their effect on 1-alpha-hydroxyvitamin D3 (1 - alpha (OH)D3)-induced aortic calcium deposition in rats. The animals were treated orally with 1-alpha (OH)D3 (10 micrograms/kg) for 2 weeks. Calcium antagonists were given orally twice a day during the same period. The aortic calcium content in 1-alpha (OH)D3-treated rats increased to about 100 times that in the control. Nilvadipine reduced the aortic calcium deposition dose-dependently, with percent inhibition of 6, 43, 72 and 92%, at doses of 0.1, 1, 10 and 100 mg/kg, respectively. Similar activities were obtained for the other calcium antagonists except diltiazem which had no effect even at the largest dose of 100 mg/kg. According to the ED50 values, nilvadipine (2.2 mg/kg) was more potent than nifedipine (23.2 mg/kg), nicardipine (12.4 mg/kg) and verapamil (32.0 mg/kg). Scanning and transmission electron microscopy showed clear-cut degenerative changes in the endothelial cells after 1-alpha (OH)D3 treatment. Nilvadipine exerted a protective effect against these degenerative changes but not against 1-alpha (OH)D3-induced hypercalcemia. Furthermore, the drug had only minimal effect on in vitro calcification of the aorta. Our findings suggest that nilvadipine inhibits aortic calcification by protecting the aortic wall cells.
The chemotactic activities of inflammatory cell products for rat aortic smooth muscle cells (SMC) were examined in modified Boyden chambers. A checker board analysis revealed that interleukin-1 (IL-1), leukotriene B4 (LTB4), platelet-derived growth factor (PDGF) and inflammatory exudate from zymosan-activated air pouches stimulated chemotaxis of SMC. The chemotaxis, irrespective of the attractants used, was strongly inhibited by nilvadipine, a potent calcium antagonist, and the IC50 values were around 1 x 10(-10) M. Removal of extracellular calcium abolished the chemotactic activities of the attractants. These results suggest that inflammatory cells such as macrophages and polymorphonuclear leukocytes (PMN) have an important role in the migration of SMC into the intima during atherogenesis, and that nilvadipine might be useful for preventing and treating atherosclerosis.
FK506, a new immunosuppressive agent, was given intramuscularly to rats for 12 days, starting on the day of type II collagen immunization. FK506 in doses of 0.32 mg/kg or more suppressed arthritis and also suppressed humoral and skin test response to type II collagen. FK506 suppressed arthritis only when given during the afferent limbs of immune response (0-4 days), whereas the drug was only marginally effective when treatment was started during the efferent limbs of immune response (7-11 days). FK506-induced immunosuppression continued and/or was maintained throughout the experiments (50 days). These rats immunized with type II collagen and treated with FK506 failed to develop arthritis even following a secondary immunization 50 days later but were fully capable of developing experimental allergic encephalomyelitis. This result suggest that FK506-treated rats develop specific unresponsiveness toward the type II collagen. It is concluded that FK506 is a strong immunosuppressive drug on collagen-induced arthritis.
We investigated the effect of a new immunosuppressant, FK506, on the development of experimental allergic encephalomyelitis (EAE) in rats. EAE developed in 100% of rats immunized with myelin basic protein (MBP) in complete Freund's adjuvant. FK506 in doses of 1.0 mg/kg/day or more prevented the clinical signs of EAE for at least 50 days, when administered intramuscularly 5 days a week for 2 weeks starting on the day of immunization (days 0-4 and days 7-11), and a similar result was obtained, when the compound was given for 5 days (days 0-4). FK506, however, showed a significant but weak effectiveness when started from 7 days after immunization. Delayed-type hypersensitivity (DTH) to MBP developed before EAE, and anti-MBP antibody levels increased. Both humoral and cellular immune response to MBP were completely suppressed in rats treated with FK506. From these results, it is presumed that immunosuppression of cell-mediated immunity and/or humoral immunity by the treatment of FK506 actually causes the decreased incidence noted in the experiment for the development of EAE.
Nocardia rubra cell wall skeleton (N-CWS) was shown to augment interleukin 1 (IL-1) production from peritoneal resident and exudate macrophages in C3H/HeN mice. The mol. wt of the N-CWS-induced IL-1 product was about 17,000 daltons, which is a similar weight to that obtained by lipopolysaccharide stimulation. The stimulation of IL-1 production by N-CWS was seen as early as 8 h after the start of incubation and peak production was observed at 48 h. Profound effects were seen with 10 micrograms/ml or more of N-CWS. Experiments on the regulation of the N-CWS-augmented IL-1 production showed that prostaglandin E2 inhibited the augmentation, and indomethacin (cyclo-oxygenase inhibitor) further augmented it. Leukotriene B4 and AA861 (lipoxygenase inhibitor) had no effect. Our findings suggest that the previously reported adjuvant effect of N-CWS may, in part, be mediated via its ability to stimulate IL-1 production; and that such a stimulation may be blocked by prostaglandins.
FK506, an immunosuppresant, was isolated from Streptomyces tsukubaensis. Intramuscular administration of FK506 (0.32 mg/kg or more) 5 days a week for two weeks after grafting prolonged the acceptance time of F344 skin allograft to WKA rats. Similar results were obtained with cyclosporine at 32 mg/kg or more, but other immunosuppressives (i.e., prednisolone, azathioprine, and bredinin) gave only a marginal prolongation. The prolonging effect of FK506 was obtained in various donor-recipient combinations across a major or minor histocompatibility barrier. The agent also prolonged the acceptance time of mouse skin xenografts to rats. Furthermore, maintenance doses of 3.2 or 0.32 mg/kg twice a week after an initial 14-day treatment with the agent at 3.2 mg/kg gave graft survival as long as the treatment was continued for more than 120 days. Our findings show that FK506 has a potent immunosuppressive effect in rats and suggest that the agent merits further investigation.
To investigate the response of locally sympathectomized myocardium to sympathetic stimulation, 90% phenol solution was painted on the left ventricular anterior wall surface in 13 open chest anesthetized dogs. Two pairs of ultrasonic crystals were implanted into the mid-myocardium and the left ansa subclavia was stimulated (LSS) at a frequency of 4 Hz. Heart rate, left ventricular systolic pressure and peak dP/dt increased following LSS before and after phenol application. After phenol application, the increase in peak dP/dt was significantly lower than before phenol application (p less than 0.01) despite similar increases in both heart rate and left ventricular systolic pressure. Before phenol application, norepinephrine (NE) overflow was observed following LSS (1.60 ng/ml) but after phenol application NE overflow decreased to 0.45 ng/ml, indicating that phenol interrupted sympathetic nerve conduction. During LSS, in both anterior and posterior walls, %shortening (%dL) increased from 13 +/- 1 (mean +/- SE) to 22 +/- 3% and 12 +/- 1 to 20 +/- 2%, respectively. After phenol application, LSS caused an increase of %dL in the posterior wall from 10 +/- 1 to 17 +/- 2%, while in the anterior wall it decreased from 15 +/- 2 to 8 +/- 3%. At the end of the experiment, when NE was infused to maintain the left ventricular systolic pressure similar to that obtained during LSS, %dL increased from 15 +/- 2 to 21 +/- 3% in the anterior wall. Pressure-length loop during LSS showed an early systolic expansion in the phenol treated anterior wall which disappeared during NE infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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To evaluate the relationship between aging and electrocardiographic abnormalities and arrhythmias, conventional surface 12 leads ECG findings were analyzed. The study group consisted of a total of 3,174 cases (1,778 men and 1,396 women, 17-87 years) without apparent organic heart diseases. The proportion of normal ECG progressively decreased with advancing age; it reached to the minimum of 20.0% in male and 22.7% in female after the age of 75. Frequency of supraventricular and ventricular premature complexes increased with advancing age as well as atrial fibrillation, left and right bundle branch block and left anterior hemiblock. Sinus bradycardia (less than 50/min) and the WPW syndrome did not follow this general trend but the former increased with advancing age after 55. Second and third-degree AV blocks were very rare in this study population. Right bundle branch block with left anterior hemiblock was not observed before age of 35, which may be regarded as a possible consequence of advanced age. Supraventricular and ventricular premature beats, and atrial fibrillation were more frequent in men than in women, but only in the older age stratum. Intraventricular conduction disorders were generally more common in men than in women. However, left bundle branch block was more frequently observed in female than in male in the older age stratum. The prolongation of QTc by oral IA antiarrhythmic drugs was observed after the age of 65. Thus, it was confirmed that aging might be important factor in abnormal findings and appearance of arrhythmias in conventional surface 12 lead ECGs.