Transplacental pharmacokinetics of diclofenac in perfused human placenta.

The aims of this study were to evaluate the transplacental transfer properties of diclofenac and to determine the effect of L-lactic acid on the transplacental transfer of diclofenac. The maternal and fetal vessels of human placenta were perfused in a single-pass mode with a solution containing diclofenac and antipyrine. The transplacental pharmacokinetic model was fitted to the time profiles of the drug concentrations in the effluent and placenta to obtain transplacental pharmacokinetic parameters. In addition, chloride ion in the perfusate was partially replaced with L-lactic acid to see the change in the transplacental transfer properties of diclofenac. The TPT(ss) value (ratio of the rate of amount transferred across the placenta to that infused in the steady state) of diclofenac was 2.22%, which was approximately one-third that of antipyrine and was significantly reduced in the presence of L-lactic acid. The transplacental pharmacokinetic model could adequately explain the transplacental transfer of diclofenac with influx clearances from maternal and fetal perfusates to placental tissue of 0.276 and 0.0345 ml/min/g cotyledon and efflux rate constants from placental tissue to maternal and fetal perfusates of 0.406 and 0.0337 min(-1), respectively. By taking into account protein binding, the placental tissue/plasma concentration ratio in humans for diclofenac was estimated to be 0.108 ml/g of cotyledon and was smaller than that of antipyrine. In conclusion, human placental perfusion and transplacental pharmacokinetic modeling allowed us to determine the transplacental transfer properties of diclofenac quantitatively. Diclofenac may share transplacental transfer system(s) with L-lactic acid.

Kinetic analysis of the transport of salicylic acid, a nonsteroidal anti-inflammatory drug, across human placenta.

The aim of this study was to develop a pharmacokinetic model to describe the transplacental transfer of drugs, based on the human placental perfusion study. The maternal and fetal sides of human placentas were perfused with salicylic acid together with antipyrine, a passive diffusion marker. The drug concentration in the placental tissue was determined at the end of perfusion. A compartment model consisting of maternal space, fetal intravascular space, and placental tissue was fitted to the observed concentration profiles of salicylic acid in the maternal and fetal effluents. The developed model could adequately explain the concentration profiles of salicylic acid in the effluents with influx clearances from maternal and fetal perfusates to placental tissue of 0.0407 and 0.0813 ml/min/g cotyledon and efflux rate constants from placental tissue to maternal and fetal perfusates (k2 and k3) of 0.0238 and 0.176 min(-1), respectively. The kinetics of antipyrine was adequately described by assuming rapid equilibrium between fetal perfusate and placental tissue compartments. The influx plasma clearance from the maternal side (K''1) in humans was estimated by taking into account the protein binding. The K''1/k2 value of salicylic acid was 1.07 ml/g cotyledon and was larger than that of antipyrine (0.642 ml/g cotyledon). We evaluated the transplacental transfer kinetics of salicylic acid by human placental perfusion study with various perfusion protocols. Based on the data obtained, we developed a pharmacokinetic model, which should enable us to estimate the influx profile of drugs into umbilical arterial blood from the maternal plasma concentration profile.

Functional analysis of organic cation transporter 3 expressed in human placenta.

The aim of this study is to investigate the placental transport mechanism of cationic compounds by comparison of the uptake of an organic cation into human placental basal membrane vesicles (BLMVs) with that into organic cation transporter 3 (OCT3)-expressing cells. Reverse transcription-polymerase chain reaction analysis demonstrated that OCT3 is the only OCT isoform expressed in the human placenta. The function of OCT3 was investigated by measuring the uptake of 1-methyl-4-phenylpyridinium (MPP(+)) into human embryonic kidney (HEK)293 cells stably expressing OCT3 (HEK/OCT3 cells). The OCT3-mediated uptake of MPP(+) was sodium- and chloride-independent and saturable, with a Michaelis constant (K(m)) of 82.5 microM. The OCT3-mediated uptake was inhibited by various cationic drugs in a concentration-dependent manner but not by anionic compounds, such as p-aminohippuric acid and captopril, or a zwitterion, carnitine. Western blotting analysis of membrane vesicles prepared from human term placenta revealed that OCT3 is expressed only in BLMVs but not in microvillous membrane vesicles. The uptake of MPP(+) into BLMVs was membrane potential-dependent and saturable, with a K(m) value of 51.8 muM, which is similar to that in HEK293/OCT3 cells. The inhibitory spectrum of various compounds on MPP(+) uptake by BLMVs was also similar to that in HEK293/OCT3 cells. These results suggest that OCT3 is expressed on the basal membrane of human trophoblast cells and plays an important role in the placental transport of cationic compounds.

Short-term combinational therapy of low-dose estrogen with selective serotonin re-uptake inhibitor (fluvoxamine) for oophorectomized women with hot flashes and depressive tendencies.

AIM: To examine whether low-dose and short-term estrogen-replacement therapy (ERT) plus selective serotonin re-uptake inhibitor (SSRI) treatment is effective or not in the treatment of climacteric disorders, hot flashes and depressive symptoms, in oophorectomized women. METHOD: Forty-two oophorectomized women with hot flashes and depressive symptoms were assigned randomly to two groups. We examined the efficacy rates of climacteric disorders, particularly hot flashes and depressive symptoms in 21 women on low-dose ERT (conjugated equine estrogens [CEE] 0.3125 mg/day) and 21 women on low-dose ERT (CEE 0.3125 mg/day) plus SSRI (fluvoxamine 50 mg/day) treated for 8 weeks. We used questionnaires to evaluate the efficacy for depression, namely the Self-rating Depression Scale (SDS) and the Self-rating Questionnaire for Depression (SRQ-D), and for anxiety with the State-Trait Anxiety Inventory (STAI). In the statistical analysis, in the mixed-effect model, for the score against time and adjusted with age, treatment and treatment as the fixed effects. RESULTS: The average scores on the SDS in both groups were decreased by the treatment (P < 0.001). But the efficacy of the ERT + SSRI group in the time x treatment SDS and SRQ-D scores was significantly higher compared with those of ERT (P = 0.0025, 0.0162) and there was a significant difference in the decrease in the frequency of hot flashes by 8 weeks between the two groups (P = 0.036). CONCLUSIONS: A combination of low-dose and short-term ERT + SSRI is more effective than low-dose estrogen alone in relieving the depressive symptoms and hot flashes of oophorectomized women.

Hormone replacement therapy and breast cancer risk in Kyushu University Hospital: supporting the Women's Health Initiative study.

AIM: The influence of hormone replacement therapy (HRT) on breast cancer has not been clarified in Japan, however the Women's Health Initiative (WHI) trial recently showed breast cancer risk according to use of estrogen plus progestin. We assessed retrospectively the incidence of breast cancer in postmenopausal women who received HRT at our outpatients clinic. METHODS: Among the patients registered at the postmenopausal clinic in Kyushu University Hospital from 1990 to 2003, 917 women who received HRT (estrogen plus progestin, 507 patients; estrogen only, 410 patients) after informed consent were examined by mammography or breast ultrasound tomography. RESULTS: Breast cancer occurred in nine patients: five patients who received estrogen plus progestin and four who received estrogen only. Four of five the patients who used estrogen plus progestin received HRT for more than 5 years. CONCLUSION: Breast cancer risk in patients who used estrogen plus progestin for more than 5 years seemed to be higher than those who used it for less than 5 years. This tendency is similar to the results of the WHI. In addition, breast cancer incidence in patients treated with HRT in our clinic seemed to be higher than the incidence in average Japanese women. Therefore, patients need to be given sufficient information before undergoing HRT.

Prenatal diagnosis of slow-rate ventricular tachycardia using fetal electrocardiography.

OBJECTIVES: We report a case in which fetal ventricular tachycardia (VT) could be diagnosed, in utero, using a transabdominal fetal electrocardiogram (fECG) with motion-mode (M-mode) echocardiography. METHODS: The fetus was referred at 32 weeks' gestation due to tricuspid atresia. The fetal cardiotocogram demonstrated paroxysmal tachycardia with a ventricular rate of 155 to 160 bpm within the confines of normal sinus rhythm. RESULTS: M-mode echocardiography showed atrioventricular dissociation with a rather slow ventricular rate. To identify the level of the ectopic focus for tachyarrhythmias, we attempted to detect the electrical signals of the fetal heart and succeeded in recording the fECG. Morphological assessment of the fECG allowed for the extraction of both the normal QRS complex and apparently dissimilar ectopic QRS beat, which has a different polarity despite a relatively similar width. CONCLUSION: Consequently, the case proved to have VT at a slow rate, probably originating from the focus near the atrioventricular junction inside the ventricle.

Significance of human neutrophil antigen-2a (NB1) expression and neutrophil number in pregnancy.

BACKGROUND: Expression of human neutrophil antigen-2a (HNA-2a) is greater in women than in men. The size of the HNA-2a-positive neutrophil population increases with pregnancy. STUDY DESIGN AND METHODS: T he relationship between HNA-2a expression on neutrophils and monocytes, and their relative numbers, was investigated. HNA-2a expression shown as the size of the HNA-2a-positive cell population and the fluorescence intensity on the cells was analyzed using flow cytometry. This investigation was done among 165 pregnant women during pregnancy and postpartum. RESULTS: In normal pregnancy, numbers of neutrophils and monocytes changed in relation to HNA-2a expression. HNA-2a was also expressed intensively on monocytes from some pregnant women in the first and second trimesters. HNA-2a expression and the number of cells markedly decreased postpartum. In threatened premature labor, the number of neutrophils decreased earlier than in normal pregnancy. CONCLUSION: HNA-2a expression may increase soon after fertilization. In this study, the results indicate that the change in the number of neutrophils and monocytes is related to HNA-2a expression.

Predicting the effects of estrogen replacement therapy on lumbar bone mineral density in oophorectomized women: analysis of a 10-year longitudinal study.

The purpose of this study was to investigate whether it is possible to predict the long-term effects of estrogen replacement therapy (ERT) on lumbar bone mineral density (BMD) of oophorectomized women based on changes in BMD. In this study, we retrospectively investigated the changes in lumbar BMD of 70 oophorectomized women under ERT for more than 10 years, and examined whether it was possible in the early stage of ERT to predict the amount of lumbar BMD based on various parameters. Seventy oophorectomized Japanese women (56.8+/-3.9 years old) treated with conjugated equine estrogen (oral) at a dosage of 0.625 mg/day for 10 years were enrolled. Lumbar (L2-L4) BMD was measured annually by dual-energy X-ray absorptiometry (DXA; CV<1.0%). The correlation between changes in BMD after 10 years on ERT (DeltaBMD10) and several clinical factors was examined using a stepwise multiple regression model. The change in BMD after 1 year on ERT (%DeltaBMD1) was the only independent factor that correlated with changes in BMD after 10 years on ERT; the coefficient of correlation was R(2)=0.557 ( R=0.750, P<0.001). Based on the %DeltaBMD1, the 70 women were divided into two groups: women with a positive change in the 1st year (%DeltaBMD1 >or=0%) in group A ( n=40) and those with a negative value in the first year ( %DeltaBMD1<0%) in group B ( n=30). We investigated the sensitivity and specificity in the coincidence of %DeltaBMD1 changes in BMD after 10 years on ERT. The %DeltaBMD1 coincided with changes in BMD after 10 years on ERT; the sensitivity was 92.5% and specificity was 70.0%. In conclusion, changes in lumbar BMD on ERT can be predicted from the changes in lumbar BMD at the end of the 1st year.

Determination of precise gamma-ray emission probabilities for 88Rb.

Precise gamma-ray emission probabilities of 88Rb have been measured by 4pi beta-gamma coincidence using a live-timed two-dimensional data-acquisition system. The absolute emission probabilities of the 898.1, 1836.1 and 2677.9 keV gamma rays were determined from the absolute gamma-ray intensities and the disintegration rates to be 14.68+/-0.13%, 22.73+/-0.15% and 2.123+/-0.021%, respectively. The relative intensities were measured for the weak gamma rays by a gamma-ray spectrometer, and the 88Rb decay scheme was determined from these results.