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Biomedical subjects

Y Yoshikawa

Publications and source records attributed to Y Yoshikawa.

At least 145 records · Page 8Linked to original sources
PubMed1998

Importance of dissolution process on systemic availability of drugs delivered by colon delivery system.

The relationship between in vitro drug release characteristics from colon delivery systems and in vivo drug absorption was investigated using three kinds of delayed-release systems. 5-aminosalicylic acid (5-ASA), tegafur (FT) and carbamazepine (CBZ) were selected as model drugs. Pressure-controlled colon delivery capsules (PCC) for liquid preparations, time-controlled colon delivery capsules (TCC) for liquid and solid preparations and Eudragit S coated tablets for solid preparations were used in this study. At first, in vitro dissolution tests for all preparations were performed. Drug release from solid preparations was delayed compared to that from liquid preparations with all three drugs. Next, these preparations were administered to fasted beagle dogs. For 5-ASA, the mean Cmaxs (peak level) of Eudragit S coated tablets and PCC were 5.52 and 16.89 micrograms ml-1, respectively. The mean Tmaxs (time when drug reached peak level) were 3.0 and 5.3 h. AUCs were 22.57 and 48.09 micrograms.h ml-1, respectively. For FT, Cmaxs of Eudragit S coated tablet and PCC were 0.87 and 1.46 micrograms ml-1, and Tmaxs were 7.0 and 6.7 h, respectively. AUCs were 9.73 and 15.55 micrograms.h ml-1 and bioavailabilities were 43.79 and 70.84%. For CBZ, the mean Cmaxs of liquid preparations and solid preparations were 0.37 and 0.22 micrograms ml-1, respectively. The mean Tmaxs were 4.7 and 4.3 h. AUCs were 0.673 and 0.392 micrograms.h ml-1. With liquid preparations, drug was thought to contact to the colonic membrane easily because of lack of interference by stools, and to be absorbed well as compared with solid preparations. From these findings, drug release from colon delivery systems and drug dissolution in the colonic lumen are very important factors for the systemic availability of drugs from the colon delivery systems.

Animals↗
PubMed1998

Preparation and evaluation of micro-porous ethylcellulose capsule as oral sustained-release preparation of theophylline.

Micro-porous ethylcellulose (EC) membrane capsules were prepared by dissolving polyvinylalcohol (PVA) particles from membranes which were made of a mixture of EC (a water-insoluble polymer). The pore size was approximately 400 microns. Since the dissolution rate of theophylline from the micro-porous EC membrane capsules was fast, gel-forming polymer, poly(acyclic) acid (Carbomer), was incorporated inside the capsule at 10, 20 or 30 mg. Using test capsules containing 100 microns of theophylline, in vitro dissolution studies were performed. By including Carbomer in capsule formulations, the dissolution rate of theophylline was decreased. However, there were not significant differences in dissolution rates between preparations containing the three different amounts of Carbomer. In vivo evaluation studies using beagle dogs showed that AUC, Cmax and Tmax were inversely proportional to the formulated amount of Carbomer. The capsule containing 20 mg of Carbomer gave plasma theophylline concentrations between 5 and 15 micrograms mL-1, which reflect levels within the therapeutic window. The effect of food intake on the pharmacokinetics of theophylline was also studied with the same capsule. Food increased AUC, Cmax and Tmax, although plasma theophylline levels were maintained within the therapeutic range.

Administration, Oral↗
PubMed1998

Comparison of two methods of assisted fertilization in cynomolgus monkeys (Macaca fascicularis): intracytoplasmic sperm injection and partial zona dissection followed by insemination.

Intracytoplasmic sperm injection (ICSI) and partial zona dissection followed by insemination (PZD-I) were used to establish a microinjection system in cynomolgus monkeys (Macaca fascicularis), which are potential models for human reproduction. Two experimental systems were studied, in which either hamster oocytes or cynomolgus monkey oocytes were used as the vehicle. When hamster oocytes were used, 66 out of 81 ICSI-treated oocytes (82%) showed sperm head swelling or pronucleus formation. Following PZD-I of hamster oocytes the rates of spermatozoa penetration (85/114; 75%) and fertilization (71/114; 62%) were relatively high. When cynomolgus monkey oocytes were used, 19 out of 31 (61%) were fertilized by ICSI with cynomolgus monkey spermatozoa and, subsequently, two embryos (7%) developed to the morula stage. In total, 94% (15/16) of the PZD-I treated oocytes were penetrated by spermatozoa and 63% (10/16) were fertilized. These results demonstrate that both micromanipulation techniques can be used in assisted fertilization with cynomolgus monkeys.

Animals↗
PubMed1998

Localization of testosterone and 3beta-hydroxysteroid dehydrogenase/delta5-delta4-isomerase in cynomolgus monkey (Macaca fascicularis) testes.

The enzyme 3beta-hydroxysteroid dehydrogenase/delta5-delta4-isomerase (3beta-HSD) is essential for the biosynthesis of all classes of steroid hormones, including androgens. We localized testosterone and 3beta-HSD by light microscopic immunocytochemistry in the testes of adult cynomolgus monkeys. Immunoreactive testosterone was located as intense deposits in the labeled cytoplasm of Leydig cells, and located weakly in the interstitial tissues, basement membranes, and the regions near tubular walls within tubules. Immunoreactive 3beta-HSD was located in the cytoplasm of all Sertoli cells and was especially intense in the parts near tubular walls and located weakly to intensely in the cytoplasm of some Leydig cells. This is the first immunocytochemical evidence that Sertoli cells of cynomolgus monkeys, as well as Leydig cells, are involved in biosynthesis of androgens.

Animals↗
PubMed1998

Histopathological studies of senile plaques and cerebral amyloidosis in cynomolgus monkeys.

Senile plaques (SPs) and cerebral amyloid angiopathy (CAA), pathological hallmarks of Alzheimer's disease, have not been thoroughly investigated histopathologically in nonhuman primates. To determine the onset age and histopathological characteristics of SPs and CAA, we examined the brains of 64 cynomolgus monkeys (Macaca fascicularis) from 2 to 35 years old. Mature (classical and primitive) plaques appeared in 16 out of 25 monkeys that were >20 years old. Moreover, mature plaques were observed more frequently than diffuse plaques and were located in the temporal cortex of the superior or inferior gyri and amygdala. Diffuse plaques in contrast to mature plaques did not show definite tendencies in onset age and distribution. CAA appeared in more than 22-year-old monkeys in 10 out of 16 animals and was frequently observed in capillaries and often found adjoining mature plaques. During immunohistochemical examination, an antiserum for amyloid beta protein (A beta) 1-40 could detect all SPs, whereas a monoclonal antibody for A beta 8-17 could not detect any diffuse plaques and only one third of the primitive plaques. As for CAA, the polyclonal antiserum was more sensitive than the monoclonal antibody. The present study describes the histopathological features of SPs and CAA in old cynomolgus monkeys.

Aging↗
PubMed1998

Age-related changes in major lymphocyte subsets in cynomolgus monkeys.

Age-related changes in major lymphocyte subsets were analyzed in 195 cynomolgus monkeys (Macaca fascicularis) aged from one month to 31 years. The percentages of CD20+ B cells in peripheral blood lymphocytes (PBL) decreased with age to five years of age, but after that, no significant change was observed. The percentages of CD16+ NK cells gradually increased during the first five years and reached the peak at from four to ten years of age, whereas the percentages of CD3+ T cells in PBL were relatively constant throughout the life. Among the T cells, the CD4+ CD8- T cells decreased, but CD4- CD8+ T cells increased within the first decade of life. We further analyzed the expressions of CD28 and CD29 molecules on T cells to determine the relation between age-related activation and phenotypic changes. Almost all CD4+ CD8- T cells (> 90%) were CD28+ at all ages analyzed, but a clear age-related decrease in CD28 expression was demonstrated in CD4- CD8+ T cells during the first ten years. In the case of CD29 expression, age-related increases in CD29hi cells were apparent in both CD4+ CD8- and CD4- CD8+ T cells during the first ten years. The percentages of CD29hi cells, however, were higher in CD4- CD8+ T cells than in CD4+ CD8- T cells in all ages analyzed. These results indicated that the age-related changes in percentages of major lymphocyte subsets as well as in phenotypes of T cells might be related to the maturation of the immune system including an increase in memory cells in cynomolgus monkeys.

Aging↗
PubMed1998

Presence of anti-ovalbumin IgE antibody in the sera of laboratory-reared squirrel monkeys (Saimiri sciureus) fed quail eggs.

In this study, we examined serum anti-ovalbumin (OVA) IgE and IgG antibodies in laboratory-reared squirrel monkeys (Saimiri sciureus), that were fed a boiled quail egg everyday. We found that 36 of 95 monkeys (38%) possessed specific IgE and 44% (42/95) had specific IgG against OVA. These antibody titers seemed to increase with age. There was, however, no apparent correlation between the anti-OVA IgE and IgG antibody titers.

Animals↗
PubMed1998

Comparative analysis of human and macaque monkey CD4: differences in formaldehyde lability and conformation.

Here we characterized macaque monkey CD4 by flow cytometry. The results showed that relatively lower fluorescence intensity was observed depending on the monoclonal antibodies (mAbs) used for staining; Leu-3a exhibited four-fold lower intensity than Nu-Th/i, and that formaldehyde fixation dramatically reduced fluorescence intensity of macaque CD4+ cells stained with Leu-3a but not of human cells. Nu-Th/i is therefore preferable for the analysis of macaque CD4. Pretreatment of either mAb inhibited the other mAb binding to human CD4. On the contrary, Nu-Th/i inhibited Leu-3a binding but Leu-3a poorly blocked Nu-Th/i binding to the macaque CD4. These results indicate that Leu-3a and Nu-Th/i epitopes are conserved in macaque CD4 but Leu-3a epitope is conformationally cryptic and/or fragile, resulting in the lower affinity. Amino acid sequence alignment of CD4 domain 1 shows that the substitutions outside the linear Leu-3a epitope may determine these characteristics of macaque CD4.

Amino Acid Sequence↗
PubMed1998

Effects of single and multiple injections of ketamine hydrochloride on serum hormone concentrations in male cynomolgus monkeys.

Using simulated short- and long-term effect studies, we evaluated the effect of ketamine anesthesia on serum cortisol, testosterone, and immunoreactive luteinizing hormone (ILH) and bioactive LH (BioLH) concentrations in adult male cynomolgus monkeys. Cortisol, testosterone, and ILH were measured by use of radioimmunoassay, and BioLH was measured by use of a radioreceptor assay method. For the acute effect, the first group (eight monkeys) was given four successive intramuscular injections of ketamine (10, 5, 5, and 5 mg/kg of body weight at 0, 30, 60, and 110 min respectively). Blood samples were taken at 0, 15, 30, 45, 60, and 120 min. For the long-term effect, the second group (10 monkeys) was given a single injection of ketamine (10 mg/kg) once a week for 4 consecutive weeks. Blood samples were taken 5 to 10 min after each injection, then were used to determine the variation in hormone concentrations among the monkeys (inter-individual variation) and within each monkey (intra-individual variation). There were no statistically significant differences in serum cortisol, testosterone, ILH, and BioLH values between the first blood sample (before the ketamine injection) and sequential blood samples in monkeys of the first group. Although intra-individual variation in the hormones (i.e., hormonal change within each monkey) was not statistically significant, inter-individual variation (among the monkeys) was significantly (0.00001 < P < 0.033) different in monkeys of the second group. These results indicate that an adequate number of animals must be used to minimize animal-to-animal variability. Our results confirm that ketamine is a suitable anesthetic agent to immobilize male cynomolgus monkeys in experimental studies (short- and long-term studies) aimed at elucidating hormonal changes.

Anesthetics, Dissociative↗
PubMed1998

[Improvement of drug bioavailability using protease inhibitors].

Although many proteins and peptides were produced by gene-technology, their administration routes are limited to be i.v. route. To increase the clinical use of these products, oral dosage form is required. However, in the case of oral administration, proteins are degraded by digestive fluid having strong protease activity. To decrease the protease activity, protease inhibitors are administered concomitantly with proteins. Aprotinin, soybean trypsin inhibitors and gel-forming polymer such as Polycarbophil are representative protease inhibitors. Gel-forming polymers have both protease inhibiting activity and absorption enhancing effect on protein/peptides. The usefulness of these protease inhibitors have been suggested as an additive for the oral delivery of G-CSF and vasopressin derivatives.

Acrylic Resins↗
PubMed1998

[Design and application of oral sustained-release anticancer drug--a new oral dosage form of cisplatin].

As compared to the conventional standard chemotherapy of solid cancer such as lung, biochemical modulation (BCM) therapy has been proven to have a good therapeutic efficiency. BCM therapy uses the low dose and low infusion rate of anti-cancer drug. To increase of the QOL of cancer patients, oral BCM therapy is needed. For this purpose, two kinds of new oral sustained-release cisplatin preparations were developed, micro-porous CDDP capsule made of ethylcellulose(EC) and CDDP-EC-stearic acid solid dispersion. After oral administrations of these preparations, serum CDDP levels were maintained over 0.2 microgram/ml for 24h. Experimental therapy using P815 tumor cells transplanted mice suggested the usefulness of CDDP solid dispersion preparation.

Administration, Oral↗
PubMed1998

Fibrillar crystal structure in essential monoclonal IgM kappa cryoglobulinemia.

In monoclonal IgG cryoglobulinemia, two types of crystallization have been demonstrated with electron microscopy at high magnification. In contrast, little information is available on well-defined crystallization in cases of monoclonal IgM cryoglobulinemia. We present a case of pure monoclonal IgM kappa cryoglobulinemia and rapidly progressive glomerulonephritis occurring in a 75-year-old woman. We detected unequivocal formation of fibrillar crystal structure within intraglomerular macrophages on electron microscopy: the structure accords with that in a case of monoclonal IgG cyroglobulinemia described in the literature.

Aged↗
PubMed1998

Prevalence of herpes B virus antibody in nonhuman primates reared at the National University of Japan.

A serological investigation by means of an enzyme immuno assay test for herpes B virus (cercopithecine herpesvirus 1) was performed on 961 sera of healthy nonhuman primates reared in laboratory animal facilities which belong to the Association of Laboratory Animal Facilities of the National University of Japan. An antibody prevalence of 40% (384/ 961) was demonstrated. The antibody titer was shown to be higher among macaques (60% of cynomolgus monkeys, 53% of rhesus monkeys, and 34% of Japanese monkeys) than among non-macaque species (21%). These data indicate that nonhuman primates reared in animal facilities may present an occupational health problem and a potential zoonotic biohazard as demonstrated in limited cases in the United States.

Animals↗
PubMed1998

Antiviral effects of 6-chloro-2',3'-dideoxyguanosine in rhesus monkeys acutely infected with simian immunodeficiency virus.

A lipophilic dideoxynucleoside analogue, 6-chloro-2',3'-dideoxyguanosine (6-Cl-ddG), was expected to be effective against AIDS-related dementia. In this study, we tested the effect of 6-Cl-ddG on simian immunodeficiency virus (SIVmac239) replication in vitro and on acute infection of six rhesus monkeys (Macaca mulatta) with SIVmac239. This compound inhibited SIV-induced cytopathic effect in CEM x 174 cells and SIV replication in vitro with an ED50 value of 2.5 microM. A dose of 25 mg/kg 6-Cl-ddG was administered to three monkeys every 8 h for 10 days and an untreated group of three monkeys was injected with the solvent without drug. Although 6-Cl-ddG was not detected in the plasma, the metabolite ddG was maintained at a concentration of more than 3 microM for 8 h after administration. In the cerebrospinal fluid, the ddG concentration was 2 microM at 2 h after administration. SIV antigen (p27) and antibody appearance in the plasma were delayed for 5-8 days compared with the mock-treated group. The occurrence of lymphadenopathy in treated monkeys was delayed for 6 days compared with the mock-treated group. Signs of 6-Cl-ddG toxicity were minimal after the treatment. The results of this study provide further evidence that 6-Cl-ddG may act as a potent anti-human immunodeficiency virus agent in vivo.

Animals↗
PubMed1997

Efficacy of 6-chloro-2',3'-dideoxyguanosine (6-Cl-ddG) on rhesus macaque monkeys chronically infected with simian immunodeficiency virus (SIVmac239).

To assess the therapeutic effects of 6-chloro-2',3'-dideoxyguanosine (6-Cl-ddG), a lipophilic dideoxynucleoside analogue, three rhesus macaques chronically infected with simian immunodeficiency virus (SIVmac239) were subcutaneously administered 25 mg/kg of the drug every 8 hours for 2 weeks. In two of three animals, the viral RNA in plasma and the cell-associated viral load from peripheral blood mononuclear cells were markedly decreased and the number of CD4+ and CD8+ lymphocytes were increased after 6-Cl-ddG administration. The decrease of the virus copies was associated with a reciprocal increase in the number of CD4+ lymphocytes. Additionally, a limiting dilution assay revealed a marked decrease in the lymph node cell-associated virus titer during the treatment. However, in the third monkey, the baseline of the number of CD4+ and CD8+ lymphocytes was higher than that of the other monkeys; these numbers changed very little during the treatment. In this monkey, the plasma SIV RNA level was decreased at the first week and was the same as the pretreatment level at the second week of the 6-Cl-ddG administration. In all three treated monkeys, the number of SIV RNA copies in the cerebrospinal fluid also tended to decrease during the 6-Cl-ddG treatment.

Animals↗
PubMed1997

Evidence that absence of Wnt-3a signaling promotes neuralization instead of paraxial mesoderm development in the mouse.

Wnt-3a mutant embryos show defects caudal to the forelimb level; somites are absent, the notochord is disrupted, and the central nervous system has a pronounced dysmorphology. Previous studies revealed that the primary defects of the mutant embryos are likely to be in the process of paraxial mesoderm formation. In this study, we analyzed the phenotype of Wnt-3a mutant embryos at early somite stages (8.0 days post coitum), when somite formation is initiated. In Wnt-3a mutants, cells which have ingressed through the primitive streak do not migrate laterally but remain under the streak and form an ectopic tubular structure. Several neural-specific molecular markers, but no paraxial mesoderm markers, are expressed in this structure, suggesting that the ectopic tube is an additional neural tube. In normal embryos, Wnt-3a is expressed in the primitive ectoderm, including the cells which are fated to give rise to the paraxial mesoderm and neurectoderm, but expression is absent in migrating mesoderm cells. These results suggest that Wnt-3a signaling may play a role in regulating paraxial mesodermal fates, at the expense of neurectodermal fates, within the primitive ectoderm of the gastrulating mouse embryo.

Animals↗
PubMed1997

In vitro fertilization and preimplantation embryo development of African green monkeys (Cercopithecus aethiops).

Ovaries of five adult female African green monkeys were stimulated by repeated administrations of equine chorionic gonadotrophin (eCG), followed by a single administration of human chorionic gonadotrophin (hCG). Oocytes were collected from enlarged follicles 28 h after hCG administration and incubated in vitro for 288 h. Oocytes that had extruded the first polar body were inseminated with spermatozoa that had been incubated for 4 to 6 h in medium with caffeine and dibutyryl cyclic AMP. Of these oocytes, 66% were fertilized and the incidence of polyspermy was 37%. Eighty-two percent of the fertilized eggs cleaved, with some developing into expanded blastocysts.

Animals↗