Biomedical subjects
Publications and source records attributed to A Shishido.
Four cyclic peptides, cyclolinopeptides F-I, were isolated from seeds of Linum usitatissimum. Their structures were elucidated by extensive 2D NMR spectroscopic methods and by chemical degradation. Further, their immunosuppressive activity is examined.
Nilvadipine, a new antihypertensive and antianginal drug, was studied in six healthy male volunteers to evaluate its steady-state pharmacokinetics after oral dosing. The subjects were given a single dose of 4 mg, followed by 4 mg every 12 hours for six days after a washout period of more than 3 days. The pharmacokinetics of nilvadipine were well described by a linear model of triexponential equation with zero-order absorption. The steady state was reached by the fourth day of multiple dosing, with a twofold accumulation of trough plasma concentration and no accumulation of peak concentration. The mean plasma concentration at steady state was 1.0 ng/mL. The optical enantiomers of nilvadipine were also determined in the plasma. The plasma concentration of (+)-nilvadipine was about two and a half times higher than that of (-)-nilvadipine, and this ratio was unaffected by multiple dosing.
The pharmacokinetics of nilvadipine, a new antihypertensive and antianginal drug, were examined in healthy male volunteers. In a Latin square, three-way crossover design with a one-day run-in period, six subjects in three groups of two each were given single 2-, 4-, or 6-mg oral doses of nilvadipine after overnight fasting. Nilvadipine plasma concentrations up to 32 hours after drug treatment were determined by capillary column gas chromatography-negative-ion chemical ionization mass spectrometry (detection limit, 0.01 ng/mL). Nilvadipine urinary concentrations were determined by capillary column gas chromatography with electron capture detector (detection limit, 0.5 ng/mL). Nilvadipine plasma concentrations declined in a bi- or triexponential pattern after reaching the maximum plasma concentrations. The mean +/- standard deviation maximum plasma concentrations of 1.48 +/- 0.47, 3.48 +/- 0.53, and 6.69 +/- 1.54 ng/mL were attained from 1.08 to 1.50 hours after doses of 2, 4, and 6 mg, respectively. The elimination half-life was dose-independent and averaged 11.0 +/- 2.3 hours. The area under the plasma concentration-time curve increased in proportion to the dose. Nilvadipine was not detected in the urine. The pharmacokinetics of nilvadipine were generally linear over the dosage range studied. Besides the above model-independent pharmacokinetic parameters, model-dependent parameters were also obtained by curve-fitting the plasma data to a bi- or triexponential equation with zero-order absorption. Nilvadipine decreased blood pressure slightly and in a dose-dependent fashion.
The effect of two different meals on the bioavailability of nilvadipine, a new antihypertensive and antianginal drug, was examined in 16 healthy male volunteers in two separate studies. In each study of eight subjects in a Latin-square, two-way crossover design, two groups of four subjects each were given a single 6-mg oral dose of nilvadipine after overnight fasting or 30 minutes after a 464- or 748-kcal meal. There were no significant differences in the area under the plasma concentration-time curve or the maximum plasma concentration between the fasting and fed states for either meal. Although the time to reach the maximum plasma concentration was about the same after a 464-kcal meal and after fasting, it increased slightly but significantly after a 748-kcal meal, indicating possible delay in drug absorption after meals. These studies showed that the extent of bioavailability of nilvadipine appears to be little affected in the presence of food. Although a possible delay in the onset of absorption would occur, such a delay may not have any therapeutic importance in chronic therapy.
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Persistent infection of rinderpest virus in Vero cells was established and designated as VRP34. Virus specific antigens were present in nearly 100 per cent of the cells. Cytopathic effect (CPE) consisting of syncytium formation and vacuolation is a unique feature of VRP34. Spontaneously released virus mainly consisted of non-temperature-sensitive virus populations and was able to initiate persistent infection in both normal Vero and RK13 cells. The results indicate that mutation of virus is responsible for the establishment of persistent infection.
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Growth of two measles virus strains, the TYCSA and CAM, was compared in three continuous cell lines derived from the nervous tissues, human neuroblastoma IMR-32, human glioma 118MGC, and rat glioma C-6. The two human neural cells were shown to support the growth of both measles virus strains as efficiently as in the non-neural Vero cells. Different types of cytopathic effect (CPE) between the two virus strains were noticed in IMR-32 cells; the CAM strain induced strand-forming type CPE and the TYCSA strain giant-cell type CPE. As a difference of growth pattern between IMR-32 and 118MGC cells, virus antigen was demonstrated in both the nucleus and cytoplasm of 118MGC cells whereas virus antigen was present only in the cytoplasm of IMR-32 cells. In contrast to the productive infection in human neural cells, growth of both virus strains was restricted in rat glioma C-6 cells without showing CPE although the prolonged presence of virus antigens was demonstrated by the immunofluorescent technique.
Cynomolgus monkeys with or without measles antibody were intracerebrally inoculated with measles or canine distemper viruses, and antibody responses in the cerebrospinal fluid (CSF) were investigated. In measles antibody-free monkeys, natural infection with wild measles virus or intracerebral inoculations with two attenuated measles vaccines evoked primary antibody responses to measles virus in the sera but not in the CSF. In measles-immune monkeys, intracerebral inoculation with the TYCSA strain of measles virus produced a significantly high titer of measles antibody in the CSF with a minimal rise in the serum antibody and resulted in a significant decrease in serum/CSF antibody ratios. Intracerebral inoculation of a neurotropic canine distemper virus, the Onderstepoort strain, into measles-immune monkeys caused production of both measles and distemper antibodies in the CSF. Inoculation of measles-immune monkeys intravenously with measles virus or intracerebrally with rubella virus, which has no antigenic relation to measles virus, failed to evoke a measles antibody response in the CSF. These results indicated that local production of measles antibody in the CSF was caused by a stimulus within the central nervous system of measles virus antigen or canine distemper virus antigen that partially cross-reacted with measles virus antigen as a secondary antibody response.
This is apparently the first attempt to elucidate the relationship between drug dependence and the osmotic fragility of erythrocyte membrane. The osmotic fragility was measured using a coil planet centrifuge (CPC) system. Utilizing the drug-admixed food (DAF) method, rats were made drug-dependent. The osmotic fragility of morphine-dependent rats was significantly enhanced, compared with that of naive rats. By withdrawing or treating the rats with levallorphan, the osmotic fragility was enhanced more than in the morphine-dependent state. When the morphine-withdrawal rats were again given the morphine-admixed food, the osmotic fragility recovered to the morphine-dependent level. The osmotic fragility of phenobarbital-dependent rats was significantly decreased, compared with that of naive rats. On the contrary, in the phenobarbital-withdrawal rats, the osmotic fragility was significantly enhanced, compared with that of the phenobarbital-dependent rats. With re-treatment of phenobarbital-admixed food, the osmotic fragility was recovered to the levels seen in the phenobarbital-dependent rats. Abstinence signs including weight loss, decrease in food and water intake, adrenal hypertrophy etc., were observed during morphine or phenobarbital withdrawal. The effects of food or water deprivation and application of ACTH on the osmotic fragility were then studied and we found that the osmotic fragility was enhanced with these treatments. These results suggest that enhancement of osmotic fragility during withdrawal of these drugs is partly influenced by these treatments.
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A highly sensitive procedure of solid-phase radioimmunoassay (RIA) was developed for the detection of measles IgG antibody. HeLa cells persistently infected with measles virus were used as a solid-phase antigen. This technique was applied to the detection of measles IgG antibody in patients with subacute sclerosing panencephalitis (SSPE) and multiple sclerosis. Normal subjects having experienced natural measles or measles vaccination and patients with various neurological diseases of non-virus nature were also examined as control groups. Measles antibody was detected at high titers in both the sera and cerebrospinal fluid of SSPE patients. Moreover, RIA/HI ratios of SSPE patients were significantly higher than those of normal subjects, suggesting the presence in the formers of antibodies to nucleocapsids at high titers as well as to viral envelopes. On the other hand, no significant difference was found in both RIA and HI titers between the sera of multiple sclerosis and those of various neurological diseases.
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Decrease in the susceptibility of embryonic chick neural retina cultures to the multiplication of various viruses was observed with increasing age of the embryo. In contrast the retinal cells supported the multiplication of Sindbis virus irrespective of the age when they were infected with the viral RNA. These results suggest that the restricted multiplication of the viruses observed is due to the modulated inability of the cell to process the adsorbed viruses for subsequent replication.
A long-term surveillance system using a computer system was established for the follow-up study on the protective effect of measles vaccination. More than 3,000 children, 3 to 6 years of age, who were immunized with measles vaccines by various methods have been registered in the system since 1971, and their outcomes with regard to measles have been followed up every year. The subjects were divided into three groups by the vaccination method: live vaccine alone (L), further attenuated live vaccine alone (FL), and the combined use of live and killed vaccines (KL). From comparative studies with these groups, the following results were obtained: (1) Annual measles incidence rates were found to be the lowest in L group followed by FL and KL. (2) Accumulated incidence rates of measles for 10 years in L, FL and KL groups calculated were 1.90, 2.49 and 17.84%, respectively. A linear regression was observed only from 0 to 3 years after vaccination in L and FL groups, and from 0 to 9 years in KL group. KL group showed a significantly larger regression coefficient than did the former two groups. (3) Protection rates against close contact with measles in families calculated were 97% in L and FL and 80% in KL group, respectively. (4) Low but detectable levels of antibody titers were observed in the sera for at least 4--6 years after vaccination.
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A strain of canine distemper virus was shown to be highly neuro-virulent in non-human primates. Intracerebral inoculation induced in monkeys histological lesions of encephalomyelitis, i.e., degenerative changes consisting mainly of neuronal damage and inflammatory changes such as perivascular cuffings and glial proliferation, in wide areas in the brain and spinal cord. In one monkey observed for 70 days, lesions with a tendency of subacute sclerosing were also noticed. Immunosuppression with cyclophosphamide or antithymocyte serum was found to aggravate the clinical course and to modify the histological lesions in the central nervous system as well as the level of antibody response to the virus in cerebrospinal fluid. Possible application of distemper encephalomyelitis in monkeys as a primate model for analysis of the immune mechanism involved in paramyxovirus-induced encephalomyelitis was discussed.