H.Shimodaira's Paper

Telepharmacodynamics to predict therapeutic effects of glucocorticoids.

Lancet 1991 Mar 9;337(8741):576-80

Oka K, Shimodaira H

     Sir, Dr Brown and colleagues' report (March 9, p 576) prompts us to propose a new clinicopharmacological concept for gulucocorticoid therapy. Glucocorticoids have various pharmacological effects on many different organs, and in chronic diseases it is difficult to predict individual sensitivity to glucocorticoids unless the patients is recovering satisfactory. A pharmacokinetic approach has not been successful. The resulting overdosing or underdosing can produce side-effects or lead to disease recurrence and the adverse consequences of prolonged therapy.

     The adverse effects of glucocorticoids seem to be more frequent in patients whose peripheral blood lymphocytes show impaired susceptibility to the agent and favorable clinical effects tend to be seen in patients whose lymphocytes are sensitive. Thus glucocorticoids-sensitive patients can be discriminated from resistant patients by in-vitro lymphocyte proliferation test. Unfortunately, these tests are tedious and time-consuming. To overcome these difficulties, a " pharmacological telescope" may be helpful. This permits the pharmacodynamices or therapeutic efficacy of glucocorticoids to be viewed via effects on remote cells on which glucocorticoids produce easily observable pharmacological changes.

     The first example is the glucocorticoid effect on the hypothalamic- pituitary- adrenal axis, resulting in a decrease in circulating cortisol. This reflects the action of steroids on the immune system. In our study half patients with chronic renal failure were steroid resistant - and they showed acute allograft rejection while under high-dose glucocorticoid immuno-suppression. The second example is the cutaneous vasoconstriction response in asthma presented by Brown et al. Glucocorticoid resistance tended to be found in steroid-resistant asthmatic patients treated with 20 - 40 mg prednisolone daily. Measurement of peripheral blood concentrations of endogenous cortisol in the kidney recipients and the study of the intensity of forearm skin blanching in the asthmatic patients both proved to be useful telescopes for discrimination between glucocorticoid sensitive and resistant patients.

     Suppression of endogenous cortisol concentration and peripheral vasoconstriction are well- known effects of systemic and topical glucocorticoids, respectively. The pharmacological mechanisms of these effects and of therapeutic immunosuppression have been thought of as independent of each other. Moreover, glucocorticoid effects on the hypothalamic-pituitary-adrenal axis are seen only as unfavorable, and we cannot be certain that the greater the hormonal suppression, the greater the immunosuppression. Whether or not the different pharmacological effects are indeed independent (could there be some relation between cell susceptibilities towards glucocorticoids via a common receptor / steroid interaction?) the two examples do suggest that the action of glucocorticoids upon different organs, such as the hormonal network and vascular smooth muscle, predicts effects on target organs such as the immune system and bronchial smooth muscle. This concept may be referred to as glucocorticoid "telepharmacodynamics".

PMID: 1677723, UI: 91318874 

Enhancement of anticoagulant action by warfarin-benzbromarone interaction.

J Clin Pharmacol 1996 Feb;36(2):168-74

Shimodaira H, Takahashi K, Kano K, Matsumoto Y, Uchida Y, Kudo T
Pharmacy of Hachioji Pharmaceutical Center, Tokyo, Japan.

To investigate the interaction between warfarin potassium and benzbromarone, administration of benzbromarone to patients receiving long-term treatment with both drugs was discontinued for 1 week and then resumed, and the resulting changes in the coagulation system were examined. Thrombotest value, activity of coagulation factors II and VIII, concentration of protein induced by vitamin K absence or antagonist-II (PIVKA-II), total plasma concentration of warfarin, and free warfarin concentration were measured during the period of concurrent administration of the two drugs, 1 week after discontinuation of benzbromarone, and after resumption of benzbromarone administration. After administration of benzbromarone had been discontinued for 1 week, the thrombotest value and factor II activity rose significantly whereas PIVKA-II activity dropped significantly compared with corresponding levels before discontinuation, but these parameters tended to revert to the previously maintained levels after resumption of benzbromarone treatment. Activity of the vitamin K-independent factor VIII displayed almost no changes, however. Total plasma warfarin concentration also decreased significantly, and free warfarin concentration was nearly unchanged. These results verified that the anticoagulant action of warfarin is enhanced by concurrent administration of benzbromarone. Accordingly, adequate consideration must be devoted to the prevention of grave hemorrhagic tendencies when these two drugs are administered concurrently.

Comparative study of adrenocortical function in renal transplant recipients under different long-term immunosuppressive therapy.

Transplant Proc 1993 Feb;25(1 Pt 2):1359-60

Hirano T,
Shimodaira H, Oka K, Sakurai E, Kozaki K, Tamaki T, Kozaki M
Division of Clinical Pharmacology, Tokyo College of Pharmacy, Japan.
Comparison of adrenal functions in kidney transplant recipients with different long-term immunosuppressive treatments--prednisolone and azathioprine versus prednisolone and cyclosporine.

Transplantation 1993 Sep;56(3):603-9 Related Articles, Books, LinkOut

Oka K,
Shimodaira H, Hirano T, Sakurai E, Tamaki T, Kozaki M
Division of Clinical Pharmacology, Tokyo College of Pharmacy, Japan.

Adverse effects of cyclosporine on the adrenal cortex have been documented in animal experiments, but nothing has been reported in human subjects. Endogenous cortisol in peripheral blood was monitored for three years after transplantation, with 30 kidney recipients on two different immunosuppressive treatments. In the azathioprine group, 16 patients were treated with coadministration of prednisolone at an initial dose of 120 mg/day. In the cyclosporine group, 14 patients were also treated with prednisolone, using an initial dose of 60 mg per day. Short ACTH stimulation tests were performed to reconfirm the results obtained by basal cortisol monitoring. During the first year following transplant, cortisol concentrations in the cyclosporine group were higher, though not significantly so, than those in the azathioprine group, in accordance with cumulative amounts of prednisolone administered. At three years, however, the mean cortisol concentrations in the azathioprine group were 2-3 times higher than those in the cyclosporine group (P < 0.05). All patients in the azathioprine group responded well to ACTH, whereas 4 patients out of 14 in the cyclosporine group showed continuous severe suppression without considerable response to ACTH (P < 0.01). In conclusion, we would like to suggest that adrenocortical toxicity of long-term cyclosporine use may appear one year after transplant, resulting in chronic suppression of the adrenal cortex, and, accordingly, difficulty in further reduction of prednisolone use.

PMID: 8212155, UI: 94025065
Suppression of endogenous cortisol for evaluating pharmacodynamics of prednisolone in early allograft rejection in renal transplantation.

Clin Chem 1990 Mar;36(3):481-6 Related Articles, Books, LinkOut
Oka K, Hirano T,
Shimodaira H, Homma M, Sakurai E, Tamaki T, Kozaki M.
Division of Clinical Pharmacology, Tokyo College of Pharmacy, Japan.


Concentrations of endogenous cortisol were examined in 34 kidney-transplant recipients by improved "high-performance" liquid chromatography. Ten recipients were treated with prednisolone and azathioprine, the others with prednisolone and cyclosporine. Peripheral serum samples were collected just before transplantation, daily for two weeks after the transplant, weekly until discharge for about two months, and then monthly or occasionally. Mean (+/- SD) cortisol concentrations, initially 145 +/- 87 micrograms/L, decreased immediately to 5.93 +/- 5.11 micrograms/L after transplant, remained at almost these same values for two months, and then swiftly increased to 51 +/- 59 micrograms/L by 1000 days. Cortisol concentrations within the period characterized by a cumulative dose of prednisolone at 300-700 mg were correlated significantly with the presence or absence of acute allograft rejection; patients with cortisol greater than 4 micrograms/L had a higher risk of rejection. The majority of stable patients showed cortisol concentrations between 1 and 4 micrograms/L throughout the cumulative prednisolone period characterized above. Concentrations less than 1 microgram/L after high-dose administration of methylprednisolone were accompanied by severe lung infection. We conclude that suppressed concentrations of endogenous cortisol, as assessed by highly specific HPLC, might provide a basis for predicting the therapeutic efficacy and adverse effects of prednisolone.

PMID: 2311218
Effects of phosphorus-containing calcium preparation (bone meal powder) and calcium carbonate on serum calcium and phosphorus in young and old healthy volunteers: a double-blinded crossover study.

J Bone Miner Metab. 2000;18(6):321-7.

Tsuboi M, Shiraki M, Hamada M,
Shimodaira H.
New Medical Research System Clinic, Tokyo, Japan.

To evaluate the effects of bone meal powder (BEC) on calcium and phosphorus metabolism, a calcium absorption test was conducted using a preparation of calcium carbonate (CAC) as the control drug. A total of 12 healthy volunteers, consisting of 6 younger (aged 20-29 years, 3 men and 3 women) and 6 older (aged 60-69 years, 3 men and 3 women) persons, were subjected to a double-blinded crossover study. Serum calcium (s-Ca) level significantly increased to 105.3% +/- 1.9% (P < 0.01 vs the basal value; mean +/- SD) from the basal value in the BEC group and to 104.4% +/- 2.7% (P < 0.01) in the CAC group at 3h post load. Urinary excretions of calcium (u-Ca/glomerular filtration rate, u-Ca/GF) after BEC and CAC load rose to 226.6% +/- 154.5% (P < 0.05) and 211.1% +/- 148.0% (P < 0.05), respectively. Serum phosphorus (s-P) levels after BEC load increased to 110.0% +/- 15.1% (P < 0.05), whereas that after CAC load showed no significant change (99.3% +/- 7.9%). On the other hand, urinary excretion of phosphorus (u-P/GF) after CAC load decreased to 60.0% +/- 32.4% (P < 0.01) and that in the BEC group showed no significant change (92.5% +/- 49.5%). The increase in s-Ca led to decrease in serum intact parathyroid hormone (i-PTH) level [77.3% +/- 33.4% (P < 0.05) for BEC and 69.5% +/- 20.3% (P < 0.01) for CAC] although s-P was increased by the BEC load. The responses to BEC and CAC administration were compared in the younger and the older groups. The responses in the younger and the older group showed fundamentally the same trends and to the same extent. However, the changes in serum ionized calcium (i-Ca) and i-PTH levels at 1.5 h post load were significantly smaller in the older group than in the younger group (P < 0.01; P < 0.05). The increment in s-P level after BEC load in the older group was larger than that in the younger group. In conclusion, BEC can modulate not only calcium but also phosphorus metabolism in both younger and older subjects. Further investigations are required to evaluate the effects of BEC on bone density and safety for renal function in long-term observations.

Publication Types: Clinical Trial 
Controlled Clinical Trial 

PMID: 11052464