Fuminori Shibuya

Prediction of sleep disorders induced by β-adrenergic receptor blocking agents based on receptor occupancy

Abstractβ-adrenergic receptor blocking agents (β-blocking agents) have been widely used clinically for the treatment of various cardiovascular conditions. However, β-blocking agents are liable to cause sleep disturbance, such as vivid dreams, nightmares, increased waking, and insomnia. The mechanisms of the sleep disorders are not known, but several may conceivably be responsible for these CNS-related side effects. In the present study, we hypothesized that the sleep disorders are induced by the blockade of central or peripheral β2 receptors and/or central serotonin (5-HT) receptors. To verify the hypothesis, we retrospectively analyzed the relationships between the extent of the sleep disorders and the β1, β2, or 5-HT receptor occupancies for four β-blocking agents (atenolol, metoprolol, pindolol, and propranolol). No significant correlations were observed among pharmacokinetic/physicochemical parameters (therapeutic dose, plasma concentration, plasma unbound concentration, cerebrospinal fluid concentration, and lipid solubility) and pharmacodynamic parameters (the scores of the sleep disorders such as the number of dreams). Furthermore, no significant relationship (correlation coefficient: r<0.3) was observed between β1 receptor occupancies of the drugs and the number of dreams. On the other hand, good relationships (r>0.95) were observed between central and peripheral β2 or central 5-HT receptor occupancies and the number of dreams. These findings suggest that β2 and/or 5-HT receptor occupancy is superior to β1 receptor occupancy as an index for the sleep disorders.

A new bleaching protocol for hyperpigmented skin lesions with a high concentration of all-trans retinoic acid aqueous gel.

Abstract. A new bleaching protocol for skin hyperpigmentation with a higher concentration of all-trans retinoic acid (atRA) aqueous gel than those commercially available is introduced. AtRA aqueous gel (0.1%) was applied topically twice a day along with 4% hydroquinone, 7% lactic acid ointment to oriental patients with hyperpigmented lesions such as senile lentigines, melasma, and postinflammatory hyperpigmentation. The clinical results of 39 patients treated with 0.1% atRA aqueous gel were compared to those of 22 patients treated with 0.1% atRA hydrophilic ointment. Better clinical results and subjective satisfaction were obtained through a significantly shorter period of treatment with 0.1% atRA aqueous gel than with 0.1% atRA hydrophilic ointment, although side effects such as erythema and irritation were seen at a higher frequency. It is suggested that our bleaching protocol with a high concentration of atRA aqueous gel in combination with hydroquinone and lactic acid has a strong bleaching ability and a potential as a standard therapy for various kinds of skin lesions with hyperpigmentation.

DECREASED CYCLOSPORINE ABSORPTION AFTER TREATMENT WITH GOLYTELY LAVAGE SOLUTION IN A KIDNEY TRANSPLANT PATIENT

HAJlME KOTAKI, Ph.D. ministration of GoLytely and the blood concentration of cyclosporine returned to the therapeutic range after GoLytely lavage was stopped, we believe that the decrease resulted from poor cyclosporine absorption caused by the GoLytely lavage of the gastrointestinal tract. Proper maintenance of the blood concentration of cyclosporine is important to prevent rejection. With a gastrointestinal dysfunction such as diarrhea or treatment with a laxative such as GoLytely, the whole blood cyclosporine concentration must be monitored carefully, and intravenous administration of cyclosporine may be suitable for providing adequate immunosuppression. Decreased cycIosporine absorption after treatment with GoLytely lavage solution in a kidney transplant patient

Preparation of Local Anesthetic Ointments for Home Care Patients with Post Herpetic Neuralgia. (1). Effects of Lipid Solubility of Local Anesthetics and Ointment Bases on Analgesic Effects.

We prepared ointments containing local anesthetics (LA) with different octanol/water partition coefficient (Pc) (procaine hydrochloride (Pc: 0.02), lidocaine (Pc: 2.9) and bupivacaine hydrochloride (Pc: 27.5)) for home care patients suffering from post herpetic neuralgia. The analgesic effects of these ointments were measured in rats and healthy volunteers. Macrogol ointment (water soluble) or white petrolatum (oil soluble) was used as the ointment base.The analgesic effects of 10% bupivacaine hydrochloride-macrogol ointment in rats were approximately 4 times that of the 2% aspirin ointment (used as a reference ointment) and were almost the same as commercially available indomethacin creams (another reference ointment). Judging from the area under the analgesic effect-time curves by 150 min after the application, the effects of procaine hydrochloride-white petrolatum were approximately 5 times that of the aspirin ointments and 1.2 times that of the indomethacin creams. The results of a test on healthy volunteers with a pain meter were also similar to those in rats. From these findings, it was thus indicated that the ointments in the combinations of LA having a high Pc value and water soluble ointment base, or LA with low Pc and oil soluble ointment base may thus be clinically useful. A good correlation was also observed between the Pc value and the analgesic effect of LA in both rats and in healthy volunteers. Furthermore, the analgesic effects in healthy volunteers also correlated well with those in rats (r=0.796 for macrogol ointment and r=0.953 for white petrolatum).