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Biomedical subjects

K Tojo

Publications and source records attributed to K Tojo.

At least 37 records · Page 2Linked to original sources
PubMed1998

[Delivery of macromolecular drugs to the vitreous and its peripheral tissues].

We evaluated the release behavior of FITC-dextran with an average molecular weight of 4,400(FD4), as a model peptide drug, from poly(DL-lactic acid) (PLA) implant. The drug level in the vitreous and its peripheral tissues were measured following the implantation in the rabbit vitreous. The release profile of FD4 from the PLA implant was biphasic; a fraction of the drug molecules incorporated in the polymer implant was swiftly released; then slowly or even negligibly for a certain period of time and finally complete bursting release probably due to bulk erosion of the polymer. The time-course of drug concentration in the vitreous and aqueous humor after implantation showed a constant level for 14 days and then parabola, where the highest concentration appeared around 28 days. The drug concentrations in the retina/ choroid was maintained a constant level for 28 days. After an injection of FD4 in the rabbit vitreous, the drug concentration in those tissues approximately decreased mono-exponentially. These findings suggest that the present implant could be a useful carrier for delivery of macromolecular drugs to the vitreous and its peripheral tissues.

Animals↗
PubMed1997

Binding of prednisolone and its ester prodrugs in the skin.

PURPOSE: Skin binding of prednisolone and its esters was investigated in the hairless mouse skin in vitro. METHODS: The distribution of the amount of drugs bound in the skin was determined by a skin slicing technique. The model drugs used were prednisolone (PN, M.W. 360) and its esters, senesyonate (PN-C5, M.W. 442), geranate (PN-C10, M.W. 510), farnesylate (PN-C15, M.W. 578), and geranylgeranate (PN-C20, M.W. 646). RESULTS: The distribution of bound drug was nonhomogeneous in the skin; the concentration of PN-C10 and PN-C15 in the skin increased gradually with the distance from the skin surface. The parent drug, PN, however, was hardly bound in the viable skin. CONCLUSIONS: These findings suggest that the prodrugs of prednisolone may prolong the dermal retention of the parent drug and minimize to delivery into the systemic circulation of the prodrug and metabolite.

Animals↗
PubMed1996

Stimulation by corticotropin-releasing factor of atrial natriuretic peptide and brain natriuretic peptide secretions from cultured neonatal rat cardiomyocytes.

The new functional role of corticotropin-releasing factor (CRF) in the regulation of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) release was investigated using cultured neonatal rat cardiomyocytes. Treatment with CRF (10(-10)-10(-6) M) resulted in dose- and time-dependent increase in ANP and BNP secretion, up to 2.5-fold and 1.8-fold above control values, respectively. The effect was significant at 6 hr and persisted for at least 36 hr. The effect of CRF (10(-7) M) was partially blocked by alpha-helical CRF(9-41) (10(-7) M), a specific CRF receptor antagonist. The effect of CRF (10(-7) M) was not only blunted by cAMP-dependent protein kinase A (PKA) inhibitor, H-89 (10(-5) M), but also by protein kinase C inhibitors, H-7 (50 microM) and Calphostin C (10(-6) M). H-7 (50 microM) and Calphostin C (10(-6) M) alone lowered basal ANP and BNP levels. Furthermore, CRF (10(-7) M) stimulates protein synthesis up to 1.2-fold. These results indicate that CRF stimulates ANP and BNP secretions through the CRF receptor and, at least in part, via PKA activation during cardiac hypertrophy.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

Evaluation for intrinsic skin permeation of unstable compounds.

An evaluation method is proposed for the intrinsic skin permeation rate of unstable compounds. Vitamin C and vitamin E were used as the model compounds. The degradation of vitamin C and E in the solutions followed first-order kinetics with degradation constants of 0.26 h-1 and 0.014 h-1, respectively. The apparent skin permeation profiles of vitamin C and E in vitro, approximated by a nonlinear profile of the polynomial regression method, was corrected for intrinsic permeation rate considering first-order degradation in the receptor solution. The intrinsic profiles evaluated agreed well with the ones determined from radio-labelled compounds, indicating the feasibility of the present analysis.

Animals↗
PubMed1996

Unexplained increase in serum corticosteroid-binding globulin levels in a patient with chronic thyroiditis, pituitary adenoma and empty sella.

Unexplained high serum corticosteroid-binding globulin (CBG) concentrations (mean +/- SD, 74.1 +/- 12.1 micrograms/dl; normal women, 32.5 +/- 5.6 micrograms/dl) were found in an unmarried women who was not pregnant or taking exogenous estrogens. She was also found to suffer from subclinical chronic thyroiditis, pituitary adenoma and empty sella. The increased serum CBG concentrations in this patient were not due to any of the factors known to increase CBG. Consistently high basal serum GH levels and unusual GH responses to GH-releasing factor (GRF) and L-dopa were also noted.

Adenoma↗
PubMed1996

A rare case of idiopathic hypoparathyroidism with varied neurological manifestations.

A 47-year-old man was admitted for evaluation of unsteady gait, postural instability, and dysarthria. On admission, neurological examinations revealed cerebellar ataxia, extrapyramidal signs including parkinsonism and positive Trousseau's sign. Laboratory findings revealed severe hypocalcemia and hyperphosphatemia, and serum intact parathyroid hormone was not detectable. Brain computed tomography revealed severe calcification of basal ganglia and dentate nuclei. He was diagnosed as idiopathic hypoparathyroidism; treatment with 1 alpha (OH) vitamin D3 brought marked improvement of neurological manifestations. We report a rare case of idiopathic hypoparathyroidism presenting with extrapyramidal and cerebellar dysfunction with a review of literature.

Basal Ganglia↗
PubMed1996

47 XXY/46 XY mosaic Klinefelter's syndrome presenting with multiple endocrine abnormalities.

We report here a rare case of 47 XXY/46 XY mosaic Klinefelter's syndrome associated with multiple endocrine disorders. A 35-year-old male admitted for the evaluation of renal dysfunction and recurrent bone fractures was diagnosed as having Klinefelter's syndrome by endocrinological examinations and sex chromosome analysis. He has suffered from diabetes mellitus for more than ten years. The serum FSH and LH levels were high together with low free testosterone and estradiol levels. There was a discrepancy between basal serum GH and somatomedin-C levels. On admission, thyroid function revealed thyrotoxicosis with low radioactive iodine uptake and negative thyroid autoantibodies. During hospitalization, serum FT3 and FT4 levels were gradually decreased and serum TSH levels became elevated, leading to the diagnosis of subacute thyroiditis. Serum ACTH levels showed high basal levels with delayed, exaggerated responses to insulin-induced hypoglycemia. Rapid ACTH test (1-24ACTH 0.25 mg) showed low cortisol responses and many of the adrenocortical steroids in plasma and urine were low or low normal. Furthermore, bone mineral density (BMD) by DEXA showed marked osteoporosis. Possible mechanisms underlying these varied endocrine disorders remain to be elucidated.

Adult↗
PubMed1996

Williams syndrome associated with chronic renal failure and various endocrinological abnormalities.

A 31-year-old man who had been under regular hemodialysis for 6 months was diagnosed as Williams syndrome (WS) by fluorescence in situ hybridization (FISH) chromosomal analysis. The association of WS and chronic renal failure (CRF) is only rarely encountered. Endocrinological examinations revealed hypergonadotropic hypogonadism. Prolonged and exaggerated responses of adrenocorticotropin (ACTH) to insulin-induced hypoglycemia and corticotropin releasing hormone (CRH) were also noted. While most of the endocrinological abnormalities observed in this patient could be attributed to altered endocrine circumstances in CRF, some findings stand in contrast. Furthermore, the testicular biopsy specimen showed severe hypospermatogenesis. Endocrine disorders observed in this patient may be at least in part, responsible for various clinical features underlying WS.

Adult↗
PubMed1995

A new family of Boucher-Neuhäuser syndrome: coexistence of Holmes type cerebellar atrophy, hypogonadotropic hypogonadism and retinochoroidal degeneration: case reports and review of literature.

The association of familial hypogonadism with progressive cerebellar ataxia is only rarely encountered, and the exact link between the symptoms remains unknown. We report here two sisters presenting with Holmes type cerebellar ataxia, hypogonadotropic hypogonadism and retinochoroidal degeneration recently diagnosed as Boucher-Neuhäuser syndrome. There was consanguinity between the parents of the affected individuals and the condition seemed to be inherited as an autosomal recessive defect. On endocrinological examinations, in both cases, the responses of LH and FSH to LH-RH (100 micrograms) were impaired even after repetitive stimulation with LH-RH (400 micrograms, 7 days), suggesting that the hypogonadism was due to a primary pituitary disturbance. Impaired GH responses to GRF (100 micrograms) and insulin-induced hypoglycemia (0.1 U/kg) were also noted. The two sisters shared an almost identical clinical and endocrinological picture. Their karyotypes were 46, XX. They had been treated for primary and secondary amenorrhea at the age of 20 years and neurological problems had started at the age of 30 years. This unique family displays clinical evidence of a possible common mechanism responsible for a progressive hypothalamo-pituitary and cerebellar impairment of late onset.

Atrophy↗
PubMed1995

Boucher-Neuhauser syndrome associated with hypocalciuric hypercalcemia.

A 52-year-old woman was diagnosed as having cerebellar ataxia, hypogonadotropic hypogonadism and retinochoroidal degeneration, the so-called, "Boucher-Neuhauser" syndrome proposed by Limber et al (Am J Med Genet 33:409, 1989). In addition, laboratory findings showed the elevation of serum calcium (Ca) levels, low urinary Ca excretion, and exaggerated reabsorption of filtrated Ca (FECa:0.14%), suggesting complication of hypocalciuric hypercalcemia. This is a very rare case of Boucher-Neuhauser syndrome associated with hypocalciuric hypercalcemia.

Calcium↗
PubMed1995

Familial thyroxine-binding globulin deficiency associated with hyperthyroidism.

A 24-year-old woman with familial thyroxine-binding globulin (TBG) deficiency associated with hyperthyroidism is reported. Thyroid-stimulating hormone (TSH)-binding inhibitor immunoglobulin (TBII) was negative, whereas thyroid-stimulating antibody (TSAb) was positive. Serum thyroxine-binding globulin (TBG) levels were extremely low, and remained low even after the normalization of thyroid function with methimazole (MMI) treatment. The serum TBG level of the mother of patient was also below the normal lower limit. Genetic analysis revealed single nucleotide deletion, common among Japanese with complete TBG deficiency (TBG-CD), from the allele-specific amplification of the TBG genes of the patient.

Adult↗
PubMed1994

Diffusion and metabolism of prednisolone farnesylate in viable skin of the hairless mouse.

The diffusion and metabolism of prednisolone 21-farnesylate were investigated in viable skin of the hairless mouse in vitro. The prodrug ester was extensively metabolized in viable skin, while it was stable in the donor and receptor solutions. The rate of appearance of the prodrug and its metabolite prednisolone was markedly influenced by the direction of the skin placed between the in vitro diffusion half-cells. The rate of bioconversion of the prodrug was determined as a function of the distance from the surface of the skin. The prodrug was increasingly metabolized with the distance from the surface of the skin, indicating that the responsible enzymes are enriched in the lower layers of the viable skin. A model with linearly increasing enzyme activity in the viable skin accounts for the in vitro profiles of the diffusion/metabolism of the prodrug in the viable skin of hairless mouse.

Animals↗
PubMed1994

In vivo/in vitro correlation of intravitreal delivery of drugs with the help of computer simulation.

The elimination of dexamethasone sodium m-sulfobenzoate, DMSB, following intravitreal injection, was measured in rabbit vitreous body under in vivo and in vitro conditions. The rate of elimination in vivo was appreciably greater than that in vitro, indicating that the in vivo data include not only the elimination due to metabolism/degradation in the vitreous humor, but also the elimination through the surrounding tissues such as the posterior aqueous humor, the retina/choroid/sclera membrane, and the lens. A general mathematical model based on Fick's second law of diffusion was developed for describing the pharmacokinetics of the intravitreal injection of DMSB. The model parameters were independently determined from a set of in vitro experiments. The in vivo data of elimination of DMSB following intravitreal injection agreed with the profiles calculated from the mathematical model, together with the model parameters determined from the in vitro experiments. The present in vivo/in vitro correlation, with the help of computer simulation, can be used for optimizing the therapeutic systems of intravitreal drug delivery.

Animals↗
PubMed1994

Possible thyroidal involvement in a case of Fabry disease.

Endocrinological evaluations of a 48-year-old man with Fabry disease revealed low levels of serum thyroid hormones and high levels of serum thyrotropin (TSH), indicating that the patient had primary hypothyroidism. Also, an exaggerated growth hormone (GH) response to hypoglycemic stimuli was observed. Thin layer chromatography of the lipid extract of the thyroid gland obtained by biopsy demonstrated marked accumulation of ceramide trihexoside (CTH) and ceramide dihexoside (CDH). These findings strongly suggest that thyroid hypofunction and hypothalamic dysfunction could be involved in Fabry disease.

Fabry Disease↗
PubMed1993

Corticotropin-releasing factor (CRF) stimulates 45Ca2+ uptake in the mouse corticotroph cell line AtT-20.

Corticotropin-releasing factor (CRF) stimulates adrenocorticotropin (ACTH) release via the adenylate cyclase/cAMP-dependent protein kinase system. Because calcium is necessary for receptor-mediated release of ACTH, we have examined the effect of CRF on 45Ca2+ uptake in a corticotroph cell line model, AtT-20. Treatment of AtT-20 cells with CRF (10(-9)-10(-6) M) resulted in dose- and time-dependent increases in 45Ca2+ uptake, up to 2.2-fold above control values. The effect was statistically significant at 1 min and persisted for at least 10 min. Treatment with forskolin (1-30 microM), 8-Br-cAMP (0.5 mM), cholera toxin (CT, 100 ng/ml) and K+ (20 mM) also increased cell-associated 45Ca2+. The effect of K+ was completely blocked by nifedipine (100 microM), whereas the effects of CRF (10(-8) M) were only partially inhibited by this calcium channel antagonist. These data suggested a role of voltage-dependent calcium channels in 45Ca2+ uptake. Short term pretreatment (1-2 h) of AtT-20 cells with CRF (10(-8) M) significantly desensitized both CRF-stimulated cAMP accumulation and ACTH release, but did not attenuate CRF-stimulated 45Ca2+ uptake. Pretreatment with CRF (10(-8) M) for 4 h did not alter CT- or forskolin-stimulated cAMP accumulation and ACTH release. This suggests that the molecular mechanisms of desensitization are proximal to adenylate cyclase. Conversely, long term pretreatment (24 h) of AtT-20 cells with CRF (10(-8) M) induced significant desensitization of CRF-stimulated 45Ca2+ uptake. These results indicate that CRF stimulates calcium uptake in AtT-20 cells via cAMP-dependent and cAMP-independent mechanisms, and that the cellular mechanisms involved in desensitization of cAMP accumulation and ACTH release and those involved in desensitization of calcium uptake are qualitatively different.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1991

Water loading tests both in supine and upright positions in three cases of idiopathic edema.

Three cases of idiopathic edema are reported with the results of water loading tests. Free water clearance and fractional sodium excretion revealed that three cases were different in water and sodium retention both in supine and upright positions. Aldosterone, plasma renin activity and antidiuretic hormone seemed to little to correspond to water and sodium retention; whereas atrial natriuretic peptide markedly increased in the upright position in all the cases. These data suggest that three cases cannot be explained by a single factor, but that enhanced reduction of venous return to the heart in the upright position may be a common feature in all three cases.

Adult↗
PubMed1990

A numerical approach to study the effect of binding on the iontophoretic transport of a series of amino acids.

The objective of this investigation was to quantitate the effect of binding on the iontophoretic transport of a series of amino acids. The diffusivity and concentration in the stratum corneum and viable skin were estimated from the passive permeation profiles through whole and stripped skin. Using these parameters and the Langmuir binding parameters from equilibrium binding studies, the passive permeation and desorption profiles were simulated using a bilayer skin permeation model. The parameters were adjusted until convergence with experimental data was achieved. Then the iontophoretic profiles were simulated, using the parameters from the simulated passive permeation studies, an estimate of convective flow from the flux of tritiated water, and measurement of the potential across the skin. The overall effect of binding on the iontophoretic profiles was found to dampen the effect of the iontophoresis treatment; the profiles appear flatter, and the transition to passive diffusion less distinct compared to profiles which do not include the binding parameters. It also appear that the degree of skin hydration has a substantial effect on the shape of the iontophoretic profile, such that approximately 50% of the enhancement in the iontophoretic profile of freshly excised skin continues after treatment.

Amino Acids↗