Biomedical subjects

Fumiaki Takahashi

Publications and source records attributed to Fumiaki Takahashi.

11 recordsLinked to original sources

PubMed2007

Synthesis and biological evaluation of a 3-positon epimer of 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71).

1alpha,25-Dihydroxy-2beta-(3-hydroxypropoxy)vitamin D(3) (ED-71), an analog of active vitamin D(3), 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], possesses a hydroxypropoxy substituent at the 2beta-position of 1,25(OH)(2)D(3). ED-71 has potent biological effects on bone and is currently under phase III clinical studies for bone fracture prevention. It is well-known that the synthesis and secretion of parathyroid hormone (PTH) is regulated by 1,25(OH)(2)D(3). Interestingly, during clinical development of ED-71, serum intact PTH in osteoporotic patients did not change significantly upon treatment with ED-71. The reason remains unclear, however. Brown et al. reported that 3-epi-1,25(OH)(2)D(3), an epimer of 1,25(OH)(2)D(3) at the 3-position, shows equipotent and prolonged activity compared to 1,25(OH)(2)D(3) at suppressing PTH secretion. Since ED-71 has a bulky hydroxypropoxy substituent at the 2-position, epimerization at the adjacent and sterically hindered 3-position might be prevented, which may account for its weak potency in PTH suppression observed in clinical studies. We have significant interest in ED-71 epimerization at the 3-position and the biological potency of 3-epi-ED-71 in suppressing PTH secretion. In the present studies, synthesis of 3-epi-ED-71 and investigations of in vitro suppression of PTH using bovine parathyroid cells are described. The inhibitory potency of vitamin D(3) analogs were found to be 1,25(OH)(2)D(3)>ED-71> or =3-epi-1,25(OH)(2)D(3)>>3-epi-ED-71. ED-71 and 3-epi-ED-71 showed weak activity towards PTH suppression in our assays.

Animals↗

PubMed2007

[Therapeutic agents for disorders of bone and calcium metabolism: ED-71].

ED-71 is a new vitamin D receptor ligand, bearing a hydroxypropoxy substituent at the 2beta-position of 1alpha, 25 (OH) (2)D(3). In ovariectomized rats, ED-71 increased lumbar vertebral bone mass and bone strength by inhibiting bone resorption and maintaining bone formation without causing hypercalcemia. In a randomized, placebo-controlled, double-blinded clinical trial for osteoporotic subjects with sufficient vitamin D supply, ED-71 treatment for 12 months can effectively increase lumbar and hip bone mineral density in a dose-dependent manner without causing sustained hypercalcemia. Serum calcium (Ca) and urinary Ca excretion was increased dose-dependently by ED-71 treatment, but it was in normal range. These results demonstrate that ED-71 can effectively increase bone mass without causing hypercalcemia, and suggest that ED-71 can be a promising candidate for the treatment of osteoporosis.

Animals↗

PubMed2006

Synthesis and evaluation of a 3-position diastereomer of 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71).

A 3-position diastereomer of 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71, 2), 3-epi-ED-71 (4), was synthesized by the convergent method coupling the A-ring fragment (5) with the C/D-ring fragment (6). As the results of preliminary in vitro biological evaluation of 3-epi-ED-71 (4), the inhibition of parathyroid hormone secretion in bovine parathyroid cells and binding affinity to human recombinant vitamin D receptor and to human vitamin D binding protein in comparison with ED-71 (2), 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3, 1), and 3-epi-1,25(OH)2D3 (3) are described.

Animals↗

PubMed2004

Expression of insulin-like growth factor 1 receptor in primary breast cancer: immunohistochemical analysis.

Insulin-like growth factor-1 receptor (IGF-1R) has been implicated in regulation in tumor growth. The results of previous studies performed by radioimmunoassay are conflicting, and the prognostic significance of IGF-1R expression in primary breast cancer is still controversial. IGF-1R expression was evaluated in formalin-fixed, paraffin-embedded tissue of 210 primary breast cancer patients by using anti-IGF-1R antibody. The clinicopathologic variables and 5-year disease-free survival were studied, and their correlations between IGF-1R expressions were investigated. IGF-1R overexpression was observed in 43.8% of tumors. IGF-1R overexpression had no correlation with prognosis or with other clinicopathologic parameters, such as age, tumor size, nodal status, histologic grade, hormone receptor status, and human epidermal growth factor 2 status. Though its prognostic value in breast cancer is limited, immunohistochemical evaluation of IGF-1R by using this monoclonal antibody may be useful in translational research using archived material.

Adenocarcinoma↗

PubMed2004

Development of neutron-monitor detector using liquid organic scintillator coupled with 6Li + ZnS(Ag) Sheet.

A phoswitch-type detector has been developed for monitoring neutron doses in high-energy accelerator facilities. The detector is composed of a liquid organic scintillator (BC501A) coupled with ZnS(Ag) sheets doped with 6Li. The dose from neutrons with energies above 1 MeV is evaluated from the light output spectrum of the BC501A by applying the G-function, which relates the spectrum to the neutron dose directly. The dose from lower energy neutrons, on the other hand, is estimated from the number of scintillations emitted from the ZnS(Ag) sheets. Characteristics of the phoswitch-type detector were studied experimentally in some neutron fields. It was found from the experiments that the detector has an excellent property of pulse-shape discrimination between the scintillations of BC501A and the ZnS(Ag) sheets. The experimental results also indicate that the detector is capable of reproducing doses from thermal neutrons as well as neutrons with energies from one to several tens of megaelectronvolts (MeV).

Environmental Exposure↗

PubMed2004

[ED-71].

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Animals↗

PubMed2002

Hyperplasia of the parathyroid gland without secondary hyperparathyroidism.

BACKGROUND: Low dietary phosphorus (P) prevents parathyroid gland (PTG) hyperplasia and the development of secondary hyperparathyroidism (SH) in uremic rats. The present study explores the effects of P restriction on parathyroid hormone (PTH) synthesis and secretion and PT cell growth in rats with established SH and PTG hyperplasia. METHODS: Normal and 5/6 nephrectomized rats were fed a high P (0.8%) diet. After two weeks, the normal rats and half of the uremic rats were sacrificed (U-HP) while the remaining uremic rats were switched to a low P (0.2%) diet (U-HP-LP). RESULTS: High dietary P induced a significant increase in serum P, PTH, and PTG weight, but not ionized calcium compared to normal animals fed the same diet (N-HP). P restriction returned serum P and PTH to normal levels by one week. In contrast, PTG size did not regress and glands remained enlarged for up to eight weeks with no evidence of apoptosis. Ribonuclease protection assay and metabolic labeling studies demonstrated similar PTH/actin mRNA ratios and 35S-labeled PTH among the three groups. Intracellular intact PTH was higher in U-HP and U-HP-LP rats compared to N-HP animals with no differences between the two uremic groups. PTG-PTH content correlated only with PTG weight, and serum PTH only with serum P. The PTG secretory response to calcium remained intact. CONCLUSIONS: In established chief-cell hyperplasia, P restriction restores normal serum PTH levels without affecting PTG hyperplasia, PTH synthesis, PTG cytosolic PTH or the PTH secretory response to calcium, suggesting an impaired exocytosis of PTH.

Animals↗

PubMed2002

Effects of i.v. and oral 1,25-dihydroxy-22-oxavitamin D(3) on secondary hyperparathyroidism in dogs with chronic renal failure.

BACKGROUND: 1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3), calcitriol) has been used for the treatment of secondary hyperparathyroidism (2HPT) associated with chronic renal failure (CRF). However, hypercalcaemia frequently precludes the administration of ideal doses of 1,25(OH)(2)D(3). 1,25-Dihydroxy-22-oxavitamin D(3) (22-oxacalcitriol, OCT) is an analogue of 1,25(OH)(2)D(3) with less calcaemic activity. Several investigators have reported the effect of this analogue on suppressing parathyroid hormone (PTH) in vitro and in vivo in rats and dogs. METHODS AND RESULTS: The first experiments were designed to compare the relative potency of an i.v. injection of OCT and 1,25(OH)(2)D(3) (i.v. OCT vs i.v. 1,25(OH)(2)D(3)) on serum PTH and ionized calcium (ICa). A single dose of OCT (5 microg/kg) to uraemic dogs suppressed PTH by 81% without a statistical significant change in serum ICa. On the other hand, any of the effective doses of 1,25(OH)(2)D(3) on PTH suppression were hypercalcaemic. The intermittent administration of OCT (0.1 microg/kg) or 1,25(OH)(2)D(3) (0.025 microg/kg), three times per week i.v. suppressed serum PTH by 89 or 77%, respectively without hypercalcaemia. To evaluate OCT as an oral drug, it was given intermittently (three times per week) to a group of six dogs for a period of 4 weeks. Subsequently, it was changed to a daily administration (0.05 microg/kg) for a period of 2 weeks. Finally the dose was reduced to 0.025 microg/kg. Daily OCT 0.05 microg/kg suppressed serum PTH by 67%. Subsequently, 0.025 microg/kg maintained serum PTH within the normal range without hypercalcaemia for 4 weeks. The time course of serum OCT concentrations following a single i.v. or oral OCT dose to uraemic dogs showed that oral OCT was rapidly absorbed and reached maximum plasma concentration and its disappearance from blood was similar to that of i.v. injection. CONCLUSIONS: In conclusion, our results suggest that OCT is a useful vitamin D(3) analogue, with a potentially larger therapeutic window than that of i.v. 1,25(OH)(2)D(3) and which is available for i.v./oral, in the management of 2HPT.

Administration, Oral↗

PubMed2002

Dental ESR dosimetry of a medical physicist who received occupational radiation exposure for almost 40 Y.

Dose distribution in the oral region of a medical physicist who received occupational radiation exposure for almost 40 y was determined retrospectively by electron spin resonance measurements of 24 tooth enamel samples using a calibration curve method. The result is considered to agree well with the value estimated from the record of his occupational exposure, including the measured values of personnel monitors. Doses to twelve of the above samples were determined by the additive re-irradiation method. The measured values obtained by the two methods agreed with the exception of one sample.

Aged↗

PubMed2002

[Effects of intravenous and oral OCT on secondary hyperparathyroidism in dogs with chronic renal failure].

In this study, we compare the relative potency of single intravenous OCT (IV OCT) and 1,25 (OH) (2)D(3) [IV 1,25 (OH) (2)D(3)] on serum PTH and ionized calcium (ICa) in dogs with chronic renal failure (CRF). In addition, we examine the efficacy of intermittent IV OCT. A single dose of OCT (5 microg/kg) to uremic dogs suppressed PTH by 81% without a statistical significant change in serum I Ca. On the other hand, any of the effective doses of 1,25 (OH) (2)D(3) on PTH suppression were hypercalcemic. The intermittent administration of OCT (0.1 microg/kg) or 1,25 (OH) (2)D(3) (0.025 microg/kg), 3 times per week IV suppressed serum PTH by 83% or 77%, relatively without hypercalcemia. To evaluate OCT as an oral drag, it was given intermittently (3 times per week) to a group of 6 uremic dogs for a period of 4 weeks. Subsequently it was changed to a daily administration (0.05 microg/kg) for a period of 2 weeks. Finally the dose was reducted to 0.025 microg/kg. Daily OCT 0.05 microg/kg suppressed serum PTH by 67%. Subsequently 0.025 micro/kg maintained serum PTH within the normal range without hypercalcemia for 4 weeks. OCT seems to be promising as a useful agent not only for hemodialysis patients but also for predialysis and CAPD patients. In conclusion, our results suggest that OCT is a useful vitamin D(3) analogue, which has a potentially larger therapeutic window than that of 1,25 (OH) (2)D(3) and which is available for IV/oral, for the management of secondary hyperparathyroidism.

English Abstract↗

PubMed2000

Calcemic activity of 19-Nor-1,25(OH)(2)D(2) decreases with duration of treatment.

19-Nor-1,25(OH)(2)D(2) (19-norD(2)) has been shown to suppress parathyroid hormone effectively, but with lower calcemic activity than 1,25(OH)(2)D(3). The present study investigated potential mechanisms to explain the reduced calcemic response to 19-norD(2). Tissue localization of [(3)H]19-norD(2) or[(3)H]1,25(OH)(2)D(3) after a single injection was not different. Intestinal calcium absorption and bone mobilization, measured in vitamin D-deficient rats 24 h after single injections of 60 or 600 pmol of 19-norD(2) or 1,25(OH)(2)D(3), were enhanced to a similar degree by the two compounds. However, when normal rats were treated every other day with 240 pmol of 19-norD(2) or 1,25(OH)(2)D(3), increases in serum calcium were identical 24 h after the first injection but diverged thereafter with significantly lower serum calcium in the 19-norD(2)-treated rats by 5 d. Intestinal calcium absorption and bone calcium mobilization were reassessed in vitamin D-deficient rats after seven daily injections of 600 pmol of 19-norD(2) or 1, 25(OH)(2)D(3), and both parameters were significantly lower in the 19-norD(2)-treated rats. Pharmacokinetic analysis after seven daily injections of 600 pmol of 19-norD(2) or 1,25(OH)(2)D(3) showed similar localization to the intestine and bone. In addition, intestinal vitamin D receptor levels were not different after 1 wk of treatment with 19-norD(2) or 1,25(OH)(2)D(3). In conclusion, the low calcemic activity of 19-norD(2) seems to be due to an acquired, postreceptor resistance of the intestine and bone to chronic treatment with the analog.

Animals↗