Biomedical subjects

M Hisaoka

Publications and source records attributed to M Hisaoka.

At least 55 records · Page 3Linked to original sources

PubMed1996

Lipid emulsions of palmitoylrhizoxin: effects of composition on lipolysis and biodistribution.

Four types of lipid emulsion for highly lipophilic antitumour agent RS-1541 (13-O-palmitoylrhizoxin) with mean particle diameters of 200-260 nm were prepared using soybean oil (SOY) or dioctanoyldecanoylglycerol (ODO) for the oil phase and lecithin (LEC) or polyoxyethylene-(60)-hydrogenated castor oil (HCO-60) for surfactants. The lipolysis rate of HCO-60-emulsified emulsions by lipoprotein lipase was much slower than that of LEC-emulsified emulsions. Particle sizes of emulsions incubated in plasma with the lipase for six hours were 75%, 79%, 101%, and 93% of initial values for SOY/LEC, ODO/LEC, SOY/HCO-60, and ODO/HCO-60 emulsions, respectively, showing an apparent size decrease for LEC-emulsified emulsions. In rats, uptake clearance values of SOY/LEC and ODO/LEC emulsions of RS-1541 in the reticuloendothelial system (RES) were 81.2 and 135.3 mL h(-1), respectively, and AUC values were 4.0 and 1.3 microg h mL(-1), respectively. In contrast, RES uptake clearances of HCO-60 emulsions of RS-1541 were considerably lower (4.2 mL h(-1) for SOY/HCO-60; 2.2 mL h(-1) for ODO/HCO-60), resulting in high AUC values (35.4 microg h mL(-1) for SOY/ HCO-60; 63.9 microg h mL(-1) for ODO/HCO-60). The concentrations of RS-1541 in tumour tissues after an intravenous administration of ODO/HCO-60 emulsions of RS-1541 to mice bearing solid tumour M5076 sarcoma were about ten times higher than those after the administration of SOY/LEC emulsions. These results indicate that HCO-60 emulsions, compared with conventional LEC emulsions, are more stable to lipoprotein lipase and show low uptakes by RES organs, long circulations in the plasma, and high distributions in tumours. Thus, these sterically stabilized emulsions could show potential as effective carriers for highly lipophilic antitumour agents to enhance the drug delivery in tumours.

Animals↗

PubMed1996

Lipid emulsions of palmitoylrhizoxin: effects of particle size on blood dispositions of emulsion lipid and incorporated compound in rats.

Emulsion formulations of various particle sizes for the highly lipophilic antitumour agent, RS-1541 (13-O-palmitoylrhizoxin), were prepared using dioctanoyldecanoylglycerol (ODO) as lipids and polyoxyethylene-(60)-hydrogenated castor oil (HCO-60) as a surfactant. These emulsions were evaluated as injectable drug carriers and compared with a colloidal solution. Both in vitro and in vivo after i.v. administration, RS-1541 was distributed into lipoproteins from the colloidal solution. When applied as emulsions of various particle sizes (124-419 nm) in vitro, RS-1541 was retained and stabilized within the emulsions. In the in vivo study, however, retention of RS-1541 in the emulsions after i.v. injection depended on their size. The small-particle emulsions (94-112 nm) resulted in long retention, and the large-particle emulsions (415-474 nm) led to short retention. Lipolysis rates of emulsion particles by lipoprotein lipase also depended on their size, indicating rapid lipolysis for small-particle emulsions (133 nm). However, the lipolysis was not such an extensive one, showing 10-30% release of capric acid from ODO within 6 h. Blood dispositions of capric acids approximately paralleled those of RS-1541 after i.v. injection of various particle size emulsions (130-368 nm) to rats, although relatively rapid eliminations of capric acids compared with RS-1541 were observed for the small-particle size emulsions (130 nm). These results suggest that when injected as emulsion formulations, the highly lipophilic antitumour agent, RS-1541, has behaviour similar to that of the emulsion particles in the body, which is dependent on the size of the latter. Thus, by properly selecting the particle size, lipid emulsions consisting of ODO and HCO-60 are expected to be effective and useful DDS carriers for RS-1541.

Animals↗

PubMed1996

Giant degenerative perineurial cell tumor.

We report a case of giant perineurial cell tumor, probably benign, with extensive degenerative changes. The secondary changes were reminiscent of those in giant ancient neurilemomas. To our knowledge, there has been no documentation of the imaging features in perineurioma. The MR findings of the present tumor, especially on T2-weighted images, correlated well with the histologic appearance.

Aged↗

PubMed1996

Enhanced tumor delivery and antitumor activity of palmitoyl rhizoxin using stable lipid emulsions in mice.

PURPOSE: A highly lipophilic antitumor agent, 13-O-palmitoyl-rhizoxin (RS-1541), was incorporated into lipid emulsions of various sizes consisting of triglyceride ODO and surfactant HCO-60. Pharmacokinetics, toxicities, and antitumor activities were evaluated after intravenous administration to mice bearing subcutaneously inoculated M5076 sarcoma cells. METHODS: The levels of RS-1541 in the plasma and tissues including tumor, were determined by HPLC. The maximum tolerated dose (MTD) was estimated by toxic death and change in body weight. The decrease in tumor diameter was measured for antitumor activity. RESULTS: There existed large variations in pharmacokinetics of RS-1541, depending on the size of emulsion particles. Compared with a colloidal solution (reference solution), the small (110nm) and medium (230nm) size emulsions showed high concentrations of RS-1541 in the tumor, while the large emulsions (350nm-630nm) exhibited low concentrations. The MTD of RS-1541 was reduced, when incorporated in the emulsions larger than 220nm in size. At MTD, each size of emulsions (70nm-380nm) effectively retarded the tumor growth and increased survival time. The maximum effect was achieved for the 220 nm emulsions. CONCLUSIONS: When particle size is properly selected, these emulsions could be promising and effective as an injectable carrier for lipophilic antitumor agents in order to enhance the tumor delivery and efficacies while reducing toxicities.

Animals↗

PubMed1996

Pharmacokinetics of highly lipophilic antitumor agent palmitoyl rhizoxin incorporated in lipid emulsions in rats.

The effects of i.v. formulations on the pharmacokinetics were examined for two antitumor agents with different lipophilicities: rhizoxin and palmitoyl-rhizoxin (RS-1541). Blood disposition and tissue distributions in rats were evaluated using three formulations: polyethylene glycol 400 (PEG)/dimethylacetamide (DMA) solution, colloidal solution, and lipid emulsions composed of dioctanoyl decanoyl glycerol (ODO) and polyoxyethylene-(60)-hydrogenated castor oil (HCO-60). The effects of emulsion particle size on the pharmacokinetics were also investigated. Rhizoxin rapidly disappeared from the plasma and showed high distribution in the tissues, and in vitro rapidly degraded in the plasma independent of the formulations used. In in vitro plasma, rhizoxin was easily released from the emulsion particles. In contrast to rhizoxin, the pharmacokinetics of RS-1541 with greater lipophilicity changed considerably depending on the formulations. The emulsions showed high and sustained plasma concentrations for RS-1541. RS-1541 was stably incorporated in the emulsion droplets and protected from the degradation when it was applied as an emulsion. Tissue distributions of RS-1541 in rats after an injection as lipid emulsion were strongly affected by the emulsion particle size. Small size emulsions (100-110 nm) showed the highest plasma concentrations of RS-1541, though they were unable to suppress distributions of the drug in peripheral tissues. Emulsions larger than 200 nm (approx.) in size, on the contrary, effectively inhibited the drug from entering the bone marrow, small intestine and other non-reticuloendothelial system (non-RES) organs, where many cytotoxic compounds showed undesired toxicities. These results indicate that the lipid emulsions composed of ODO and HCO-60 could be a promising and effective DDS carrier for RS-1541, which is highly lipophilic and stabilized in the emulsions. This was not the case for rhizoxin, however, which was less lipophilic than palmitoyl analogue RS-1541. The work described herein has demonstrated that by properly selecting the particle size, these lipid emulsions can control the behavior of a drug in the body.

Animals↗

PubMed1995

Mild emphysema: a novel method using formalin-fixed lungs for computed tomography and pathological analyses.

We evaluated a novel method of computed tomography (CT) analysis using formalin-fixed lungs of autopsy cases with mild emphysema. Eight formalin-inflated lungs (FILs) obtained at autopsy were examined using CT after draining off the formalin and air inflation with an air pump, and subjected to pathological study including pathological scoring of emphysema and microscopic image analysis (MIA). Satisfactory CT examination was carried out within 5 h of lung fixation. The mean alveolar area determined by MIA correlated highly with the lung volume (r = 0.845) and CT score (r = 0.722). This method is simple compared with conventional polyethylene glycol fixation for CT and enables CT examination of resected lungs without anxiety about biohazards, Mild emphysema can be detected by MIA.

Aged↗

PubMed1995

DNA flow cytometric and immunohistochemical analysis of proliferative activity in spindle cell haemangioendothelioma.

Although spindle cell haemangioendothelioma was initially described as a low-grade angiosarcoma, recent reports have suggested that it is a reactive or benign vascular proliferation. In order to assess the proliferative activity in spindle cell haemangioendothelioma, 12 cases, one of which was associated with Maffucci's syndrome, were immunohistochemically analysed with antibodies against proliferating cell nuclear antigen (PCNA), Ki-67 and p53. DNA flow cytometry was performed on six of the 12 cases. Seven of the 12 patients had multiple nodules or papules. Although two cases recurred once and twice, respectively, after surgery, there was no evidence of metastasis. Immunohistochemically, the percentages of PCNA, Ki-67 and p53 positive tumour cells ranged from 0.1% to 6.4% (mean 3.3%), 0.1% to 14.9% (3.5%) and 0.1% to 2.8% (1.1%), respectively, indicating a low proliferative activity and a low p53 expression in this tumour. All seven lesions from the six cases examined flow cytometrically were DNA diploid with proliferative indices (S + G2/M-phase fractions) ranging from 4.9% to 19.5% (mean, 10.9%). These findings are compatible with a bland-looking histological picture and an indolent clinical course of spindle cell haemangioendothelioma.

Adolescent↗

PubMed1995

Intramuscular myxoma with fibrous dysplasia: a report of two cases with a review of the literature.

Two cases are reported of a rare association of intramuscular myxoma with fibrous dysplasia in a 70 and 40 year old Japanese woman, respectively. One of them had a solitary intramuscular myxoma, and the other patient suffered from two intramuscular tumors that had been initially misdiagnosed as myxoid liposarcoma. Only 24 cases of this kind of association have been recorded in the literature. This association should be taken into consideration to avoid inappropriate treatment, when cases of myxoid soft tissue tumor with a bone lesion are encountered.

Adult↗

PubMed1995

Angiomyofibroblastoma of the vulva: a clinicopathologic study of seven cases.

A clinicopathologic and immunohistochemical review was made of seven cases of angiomyofibroblastoma. The patients were middle-aged women who had a slowly growing mass, measuring 1.5-6 cm in maximum dimension, located subcutaneously in the vulva. The tumors were well-demarcated and characterized by well-vascularized, alternating hypercellular and hypocellular edematous areas composed of bland, plump spindle- or oval-shaped stromal cells frequently aggregated around small blood vessels. An epithelioid appearance of the stromal cells was seen in two cases. Immunohistochemically, the stromal cells were consistently positive for vimentin and desmin, but negative for muscle specific actin, alpha-smooth muscle actin, myosin, cytokeratins, S-100 protein or von Willebrand factor. Ultrastructurally, the plump stromal cells had a small amount of peripherally located rough endoplasmic reticulum, numerous pinocytotic vesicles and abundant intermediate filaments, on which immunogold probes for desmin were localized, whereas fine filaments were few and there were no electron dense plaques. Thus, while the proliferating stromal cells expressed an immunohistochemical profile of peculiar myoid differentiation, ultrastructural findings differed from those of smooth muscle cells or those seen in typical myofibroblasts. At 1-4 years after surgery, there was no evidence of recurrence.

Adult↗

PubMed1994

Small bile duct abnormalities and chronic intrahepatic cholestasis in Behçet's syndrome.

A 42-year-old man with Behçet's disease of the intestinal type and a chronic cholestatic profile is presented. He had oral aphthea, genital ulcer, erythema nodosum, thrombophlebitis and central retinitis during the clinical course. Deep ileal ulcers recurred with massive bleeding and perforation. Cholestatic laboratory findings were also noted in the clinical course. A biopsied liver specimen, taken at the second operation for the ileal ulcer, showed chronic portal inflammation associated with ductopenia and epithelial degeneration of the small interlobular bile ducts, but periductal concentric fibrosis was not found. The patient died of sepsis 7 months after the last laparotomy. Although there was no significant abnormality in the large biliary tract at autopsy, pericholangitis in the small portal tracts and cholestasis were pronounced. Sclerosing cholangitis is one of well-known complications of ulcerative colitis or Crohn's disease. We report herein another rare association of small bile duct damage resembling sclerosing cholangitis with enteritis in Behçet's disease.

Adult↗

PubMed1993

Sclerosing fibrous tumor of the cauda equina: a fibroblastic variant of peripheral nerve tumors?

The case of a 43-year-old man with an unusual mesenchymal tumor of the cauda equina is presented. A well-circumscribed firm tumor was found in the lower spinal canal at L1 level. Although a nerve root was involved, the adjacent dura mater or filum terminale was unrelated to the tumor. Microscopically, the tumor was rich in collagen and made up of irregularly intertwining fascicles of fibroblastic spindle cells lacking in nuclear atypia or mitotic activity. Partial broad hyalinization of collagen was another histological feature of the tumor. Histological and immunohistochemical studies failed to reveal any findings that suggested known fibrous neoplasms, such as schwannoma, neurofibroma and meningioma, originating in the nervous system. Ultrastructural features of the tumor cells were consistent with those of fibroblasts. Hence, the present tumor is regarded as a unique pure fibroblastic tumor (fibroma) derived from the interstitium of a nerve root in the cauda equina.

Adult↗

PubMed1993

Pancreatic morphogenesis and extracellular matrix organization during rat development.

We investigated the rat pancreatic morphology at various developmental stages ranging from 12 days of gestation to the neonatal stage, with special emphasis on alterations in extracellular matrix organization in vivo. The rat pancreatic development in utero could be divided into four representative stages as follows: (1) initial epithelial buds (12 days of gestation), (2) elongated and branching epithelium (13-14 days), (3) tubular structure (15-16 days), and (4) acinar structure (17 days or more). Ultrastructurally, the fetal and neonatal pancreata were almost constantly encompassed by continuous basal lamina, except for the earliest stage, in which minute disruptions of basal lamina were observed. Through the disruption, the direct epithelial-mesenchymal contact was formed between an endocrine cell and an adjacent mesenchymal cell, which implied epithelial-mesenchymal interactions in processes of endocrine cell differentiation. Collagen fibrils were frequently accumulated at the cleft (branchpoint) of the branching epithelium during the second and third stages mentioned above. Immunohistochemically, fibronectin and collagen type-I were localized particularly beside the neck (narrow part) or cleft of the pancreatic epithelium at these stages, although continuous linear localization of these matrices was noted around the initial pancreatic bud. This was in contrast to invariable linear localization of laminin and collagen type-IV at the epithelial/mesenchymal interface throughout the pancreatic development. Diffuse fibrillar localization of fibronectin and collagen type-I in the mesenchyme was pronounced at the later stages and after birth. Collagen type-III was only focally detectable around the pancreatic epithelium from the second stage, and its distinct localization was noted in the interlobular connective tissue after birth. Thus, chronological changes in extracellular matrix organization seemed to be closely related to morphogenetic processes of the rat pancreas, especially in the branching epithelial morphogenesis, and the major alterations appeared prior to distinct acinar cell differentiation.

Animals↗

PubMed1993

A unique case of apocrine carcinoma on the male pubic skin: histopathologic and ultrastructural observations.

We report a case of cutaneous adenocarcinoma on the pubic region of a 56-year-old male. The exophytic tumor showed solid, ductal, and glandular patterns with decapitation secretion and mucinous carcinoma-like nests. Despite the exophytic nature of the lesion, an invasive growth pattern into the deep dermis and subcutaneous fat was seen. An additional characteristic of this tumor was the presence of Paget's phenomenon. From these findings, we conclude that this tumor is an apocrine adenocarcinoma having an unusual clinical appearance and unique histopathological features which have some similarities to apocrine carcinoma of the breast and some to syringocystadenoma papilliferum and nipple adenomatosis.

Adenocarcinoma↗

PubMed1992

Morphological development of the rat fetal pancreas.

Rat fetal pancreata of days 12 to 19 of gestation and those of neonates were examined with light and electron microscopes. The pancreas arose from the primitive epithelium of the foregut as two primordia (dorsal and ventral pancreatic primordia) of epithelial cell nests surrounded with abundant fetal mesenchymal tissue between days 11 and 12. Primitive pancreatic islets, which mainly consisted of the endocrine cells with A cell type secretory granules, also appeared in the primordia at this age. The epithelial cell nests elongated gradually and had a branching cord-like arrangement. Two pancreatic primordia fused together on day 15, and an apparent ductular structure was observed on days 15 to 17. An acinar configuration of exocrine cells with zymogen granules gradually formed between days 17, 18 and 19. After birth, the volume of pancreatic parenchyma markedly increased and that of mesenchymal tissue prominently decreased. Ultrastructurally, the pancreatic primordia in the early stage showed immature epithelial features with the surrounding basement membrane and inconspicuous intercellular junctions. This might imply a plasticity in cellular differentiation of protodifferentiated pancreatic epithelial cells toward a ductular structure of immature exocrine pancreas which appeared later. In addition to the basement membrane, abundant fetal mesenchymal tissue was considered to play a possible role in the early morphogenesis in pancreatic development.

Animals↗

PubMed1992

Pancreatic islet abnormalities in sudden infant death syndrome. Qualitative and quantitative analyses of 15 cases.

The pancreata of 15 autopsy cases of sudden infant death syndrome (SIDS) and those of 14 age-matched controls were examined qualitatively and quantitatively to re-evaluate the relationship between pancreatic islet abnormalities and sudden death in infancy. Histopathologically, a diffuse or focal form of nesidioblastosis and septal islets were frequently observed in the pancreata of both groups. Endocrine cell dysplasia was found only in 2 infants who had died of SIDS. Quantitatively, there was little difference of islet cell composition between the SIDS cases and the controls. A relatively high proportion of islet cell area to total pancreatic tissue area was demonstrated in the SIDS group (8.46 +/- 4.90% in the pancreatic head; 8.66 +/- 4.23% in the pancreatic body to tail) in comparison with the controls (5.32 +/- 1.77%; 5.63 +/- 1.60%). Although nesidioblastosis and septal islets were considered to be within the limits of normal variation during pancreatic development, endocrine cell dysplasia and quantitatively unusual proliferation of the pancreatic endocrine tissue suggest the possibility that abnormalities in the endocrine pancreas may be causally related to sudden death in infancy.

Humans↗

PubMed1992

Prediction of human pharmacokinetics of panipenem-betamipron, a new carbapenem, from animal data.

The pharmacokinetic behavior of panipenem (PAPM)-betamipron (BP), a new carbapenem, in humans was successfully predicted from data collected from six animal species. PAPM and BP were biphasically eliminated from plasma after intravenous (i.v.) administration of PAPM-BP to mice, guinea pigs, rats, rabbits, monkeys, and dogs. Elimination rates of PAPM and BP were correlated with animal size: the larger the animal was, the slower the elimination was. As for PAPM and BP, log-log plots of total plasma clearance (CLtot) versus body weight and log-log plots of distribution volume at steady state (VSS) versus body weight for six animal species were linear, with high correlation coefficients. These allometric equations were extrapolated to predict CLtot and VSS for PAPM and BP in humans. In addition, concentration in plasma-time profiles for humans were predicted by using two-exponent equations fitted to the complex Dedrick plot of animal data. Predicted values for CLtot and VSS for PAPM and BP in humans agreed well with observed values in humans given 750/750 mg of PAPM-BP as an i.v. drip infusion for 30 min. Predicted concentration in plasma-time profiles for humans approximated observed profiles. Thus, the pharmacokinetics of PAPM-BP extrapolated well from animal species to humans when allometric equations and the complex Dedrick plot were used.

Animals↗

PubMed1992

Neurotoxicity of panipenem/betamipron, a new carbapenem, in rabbits: correlation to concentration in central nervous system.

The neurotoxic potential of panipenem/betamipron (PAPM/BP), a new carbapenem antibiotic, was compared with that of imipenem/cilastatin (IPM/CS). The drug concentration in cerebrospinal fluid (CSF) at the onset of epileptogenic electroencephalographic (EEG)-activity and the drug distribution into the central nervous system (CNS) were evaluated. Epileptogenic reactions correlated well with drug levels in CSF, but not with drug levels in circulating plasma. The concentration of PAPM in CSF at the onset of epileptogenic EEG-activity was almost twice that of IPM, suggesting that neurotoxic activity of PAPM is about half that of IPM. In addition, in terms of incidence percent for the epileptogenic EEG-activity, PAPM/BP was found to be less toxic than IPM/CS within the dose of 1.0-1.2 g/kg. Concentrations of PAPM in CSF and brain extracellular fluid after PAPM/BP i.v. infusion were comparable with those of IPM after IPM/CS infusion, indicating the similar characteristics of distribution into the CNS for the two antibiotics. From these results of pharmacologic effects and drug distributions, it is suggested that the neurotoxicity of PAPM/BP is less than half that of IPM/CS.

Alanine↗

PubMed1992

Prediction of human pharmacokinetics of panipenem, a new carbapenem antibiotic, from animal data.

The prediction of human pharmacokinetics of Panipenem (PAPM), which is a new carbapenem antibiotic, was investigated using animal data. The plasma concentration-time curve after intravenous administration of PAPM in each animal showed biexponential elimination. There were good allometric correlations between pharmacokinetic parameters (CLtotal and Vd,ss) calculated from the plasma concentration in animal species and body weight of experimental animals. Predicted human pharmacokinetic parameters calculated by these allometric equations agreed with the values observed in humans.

Adult↗