Nagoya Journal of Medical Science

We reviewed papers written about autoregulation of cochlear blood flow (CBF). In animals, autoregulation of CBF has been recognized not only by variations of systemic blood pressure (BP) but also by manipulations to the blood vessels, such as occlusion of the anterior inferior cerebellar artery, occlusion of the draining veins from the cochlea, and variations of the inner ear pressure. Recent reports have shown that autoregulation of CBF is not so different from that of cerebral blood flow in its strength, but it is disturbed in endolymphatic hydrops or aged animals. Since it became possible to measure CBF in humans, clinical investigation about autoregulation of CBF needs to be done in various inner ear diseases.

Bacterial endotoxin (lipopolysaccharide) has a variety of biological and immunological activities. Endotoxin-induced physiological changes in several organs might modify the pharmacokinetic behavior, including the biliary and urinary excretions and hepatic metabolism, of various drugs. We have conducted a series of studies as part of a program for the development of guidelines for the safe use of various drugs in patients with Gram-negative bacterial infections. We have found that endotoxin isolated from Klebsiella pneumoniae dramatically reduces renal and biliary excretion of organic anionic drugs actively secreted into the urine and bile, respectively. More recently, we found that K. pneumoniae endotoxin decreases the activity of cytochrome P450-mediated drug-metabolizing enzymes in a time-dependent manner. This article reviews recent progress in the description of pharmacokinetic properties of drugs during conditions of endotoxemia, focusing especially upon the effects of K. pneumoniae endotoxin on the hepatic metabolism and biliary excretion of drugs, and the relationship between pharmacokinetic changes and various endotoxin-induced mediators.

Circadian variations in chemotherapy toxicity and antitumor effects were investigated in experimental and clinical studies. In the experimental study, Balb/c mice bearing murine colon carcinoma Colon 26 were treated with 4 injections of 5-fluorouracil (5-FU) (80 mg/kg) at 0000 Hours After Light On (HALO), 0600 HALO, 1200 HALO and 1800 HALO. The antitumor effect of treatment at 0000 HALO (early resting phase) group was significantly better with lower toxicity than the 1200 HALO (early activity phase) group, resulting in significantly longer survival (p < 0.05). In the clinical study, the effect of circadian rhythm-modulated 5-FU plus leucovorin therapy was evaluated in an end-stage patient with recurrent gastric carcinoma. After continuous weekly infusion of 5-FU (1000 mg/m2/day x 2) was stopped because of its gastrointestinal toxicity, circadian rhythm-modulated chemotherapy (CRMC) was performed changing the dose of 5-FU to 666 mg/m2/day during the daytime (0500 to 1700) and to 1333 mg/m2/day from evening to night (1700 to 0500). The patient persevered with the 23 CRMC course without any signs of severe side effects and survived for nearly a year, suggesting the potential effect of CRMC in minimizing toxicity and prolonging survival.

Voltage-dependent calcium currents (ICa), which developed in cultured human neuroblastoma cells (NB-I), were studied using a whole-cell recording technique. Three types (T-, N- and L-type) of ICa were identified based on their biological and pharmacological properties. The T-type ICa was observed in about 60% of the cells from day 2 to day 12 and in about 20% after day 14. Likewise, the amplitude gradually decreased from -61.7 +/- 10.1 pA on day 2 to -18.3 +/- 9.1 pA on day 18. The N-type ICa appeared on day 6, with the number of cells exhibiting this current increasing up to 90.9% (-73.4 +/- 16.0 pA) on day 14 and immediately decreasing thereafter. The L-type ICa was observed in 50.0% of the cells on day 2, increasing to 84.6% of the cells on day 6 and remaining thereafter, while the amplitude gradually increased from -37.8 +/- 14.0 pA on day 2 to -158.8 +/- 22.8 pA on day 18, and decreased thereafter. These findings indicate that the expression of the voltage-dependent Ca2+ channels is strongly regulated by the developmental stage of the cell.

The clinical and radiographic results of vascularized pedicle iliac bone grafting (PBG) and Sugioka's transtrochanteric anterior rotational osteotomy of the femoral head (ARO) for idiopathic osteonecrosis of the femoral head were compared. Four male patients with bilateral osteonecrosis of the femoral head were treated with PBG in the first hip and with ARO in the second. All patients had stage 2 or 3 involvement according to Ficat's classification. Average age at the time of PBG and ARO was 42 and 43 years, respectively. Average follow-up of PBG and ARO was 7.5 and 5.7 years. At final follow-up, the average Harris hip scores of PBG and ARO were 73 and 85, respectively. Collapse was observed in 3 PBG hips and in 1 ARO hip. Three patients were more satisfied with the ARO procedure than with the PBG treatment, and one patient was undecided. ARO was considered better surgical treatment than PBG from both a clinical and radiological perspective.

The effect of the menstrual cycle on oro-cecal transit time (OCTT) has been controversial. Since poor reproducibility of OCTT measurements by lactulose might be responsible for this controversy, we measured OCTT with either milk or a solid test meal during the luteal and follicular phases of the menstrual cycle. Nine healthy young women (21.9 +/- 0.42 years old) with regular menstruation were studied for 4 consecutive menstrual cycles. Control (37 degrees C) or cold (10 degrees C) milk was used as a liquid meal, and the OCTT measurements were taken 3 times at each milk temperature during each of the 2 phases for 3 consecutive menstrual cycles. OCTT after a solid test meal (cooked rice, miso soup, a boiled egg, and cooked soybeans with mixed vegetables) was studied twice in 1 menstrual cycle. Breath hydrogen was determined every 15 min for 6 h. OCTT was defined as the time when breath hydrogen showed a sustained rise of 3 ppm or more from baseline. OCTT was not different between the luteal and follicular phases when the test meal was control milk or the solid meal. When cold milk was used as the test meal, OCTT was significantly shorter during the luteal phase (134 +/- 15 min) than during the follicular phase (165 +/- 21 min). In conclusion, cold milk accelerates OCTT during the luteal phase but not the follicular phase of the menstrual cycle in women.