Biomedical subjects
Publications and source records attributed to M Akahane.
The derivatives of 3-[3-oxospiro[benzofuran-2(3H),1'-cyclopropan]-5-yl]acrylic acid were synthesized and tested for antiulcer activities. As a result, 1-[3-[3-oxospiro[benzofuran-2(3H),1'-cyclopropan]-5- yl]acryloyl]piperidine(3t) and 4-[3-[3-oxospiro[benzofuran-2(3H),1'-cyclopropan]-5- yl]acryloyl]morpholine(3u) exhibited potent antiulcer activities.
In the preceding paper, we reported that 1-[3-[3-oxospiro[benzofuran-2(3H),1'-cyclopropan]-5- yl]acryloyl]piperidine(1a) and 4-[3-[3-oxospiro[benzofuran-2(3H),1'-cyclopropan]-5- yl]acryloyl]morpholine(1b) have potent antiulcer activities. In this paper, propionic acid derivatives (2,3) and oxyacetic acid derivatives (4, 5, 10) were prepared by converting the acryloyl moiety into propionyl and oxyacetyl groups, and tested for antiulcer activities. As a result, [3-oxospiro[benzofuran-2(3H),1'-cyclopropan]5-yloxy]-a cetamide(4j) exhibited significant antiulcer activities.
The cardiovascular and metabolic effects of ritodrine hydrochloride on the mother and fetus were investigated during the 28-day and/or longer continuous treatment of threatened premature labor. Concentrations of ritodrine in maternal venous blood during the treatment, and placental transfer of the drug into the fetal circulation and amniotic fluid were also determined to ascertain the effectiveness and safety of the drug. Seventeen volunteer patients at 27-34 weeks of gestation were given a total dose of 2,850-7,350mg of ritodrine intravenously at a mean infusion rate of 72.9 micrograms/min for 28-66 days, when the maternal serum concentration of ritodrine was maintained at approximately 200ng/ml throughout the treatment period. A significant but slight increase in the maternal heart rate and serum glucose, and a slight fall in maternal blood pressure were observed during ritodrine infusion. The fetal heart rate did not change significantly. Although ritodrine also produced decreases in the red blood cell count, hemoglobin and hematocrit, these changes were transient and recovered to the control level thereafter. The ratios of umbilical venous blood and the amniotic fluid concentration of ritodrine to maternal venous concentrations determined at cesarean section were 0.68 and 1.64, respectively, suggesting that a gradual accumulation of placentally transferred ritodrine may occur when long-term continuous infusion is carried out. There were no noticeable drug-related findings in mothers and newborns during and after labor. These results indicate that threatened premature labor may be well effectively controlled by ritodrine without severe side-effects on the mother or fetus in treatment for along period.
Seven healthy pregnant volunteers undergoing elective cesarean section at 39-40 weeks of gestation were studied for transplacental passage of ritodrine hydrochloride, which was administered by intravenous infusion at the rate of 72-149 micrograms/min for 161-335 min. The concentrations of ritodrine in the collected maternal and fetal blood and the amniotic fluid were radioimmunoassayed. The levels of ritodrine in maternal serum were between 22.5 and 51.0 ng/ml one hour after the initiation of infusion, 33.7-66.4 ng/ml after 2 h, 18.2-73.6 ng/ml after 4 h and 45.7-189.6 ng/ml at delivery, respectively. The umbilical blood and amniotic fluid concentrations of ritodrine at delivery were between 15.6 and 35.1 ng/ml in arterial blood, 12.5-29.6 ng/ml in venous blood and 10.0-49.1 ng/ml in amniotic fluid. The ratio of umbilical venous blood concentrations to maternal venous concentrations (CV/MV) ranged from 0.066 to 0.544 with the mean of 0.263 +/- 0.063 (M +/- S.E.). The results obtained substantiate the rapid and appreciable transfer of ritodrine to the fetus and amniotic fluid.
Efficacy and safety of ceftazidime (CAZ) in women during the perinatal period and their neonates were evaluated by a perinatal co-research group, and the results obtained were summarized as follows. Following an intravenous bolus injection or a drip infusion of CAZ from 1 g to 2 g, CAZ was transferred to maternal serum, umbilical cord serum and amniotic fluid rapidly and effectively. In 31 cases of perinatal infections, clinical efficacy was excellent in 10 cases, good in 18 and poor in 3, with an efficacy rate of 90.3%. In 85 cases given CAZ for prophylaxis of infections accompanying premature rupture of the membrane or following cesarean section, prophylactic effects were noted in 81 cases (efficacy rate: 95.3%). Neither adverse effects, nor abnormal laboratory findings were observed in any case. Also, no abnormalities in total serum bilirubin were observed in any neonates. From the above results, CAZ is considered to be a safe and useful drug for infections in women in perinatal period, usually in a unit dose of 1 g twice daily, or if necessary, 2 g twice daily.
Ceftazidime (CAZ), a newly developed cephalosporin with very high stability to beta-lactamase, was evaluated for its transfer into fetus and amniotic fluid in the third trimester pregnancy, following a single bolus intravenous injection at a dose of 1 g. In subjects with various conditions (background factors) standardized, concentrations of CAZ in maternal venous blood, venous and arterial blood in umbilical cord, and amniotic fluid were determined. High concentration of CAZ (10 micrograms/ml or higher) was found to be maintained in fetal blood and amniotic fluid for ca. 4 hours and ca. 8 hours, respectively, after intravenous injection, showing good placental transfer of CAZ. In view of MICs of CAZ, satisfactory clinical efficacy is expected in perinatal infections.
The transplacental passage of single intravenous doses of aztreonam (AZT), 1 g or 2 g, was examined in 7 sheep and 14 women in late pregnancy, respectively and the obtained data were analyzed by a two-compartment model. The obtained results were summarized as follows. After single 2 g intravenous doses were given to pregnant sheep, the mean peak level of AZT in maternal blood was 83.79 micrograms/ml and the half-life of the beta-phase was 1.525 hours. After single 1 g intravenous doses were administered to pregnant women, the mean peak level of AZT in blood was 102.62 micrograms/ml and the half-life of beta-phase was 2.128 hours. The peak levels in umbilical venous blood and amniotic fluid were 14.43 micrograms/ml and 11.86 micrograms/ml, respectively.
The materno-fetal transfer of aztreonam by a single intravenous dose of 1 g was examined in 7 volunteer women undergoing induced abortion in early pregnancy and the following results were obtained. After administration of the drug, maternal blood levels at 15, 30, 60 and 120 minutes were 77.24 +/- 6.09 micrograms/ml (Mean +/- S.E.), 37.84 +/- 5.85 micrograms/ml, 25.62 +/- 3.15 micrograms/ml and 18.10 +/- 2.22 micrograms/ml, respectively. Amniotic fluid level of the drug was low in 3 cases, of which amniotic fluid levels were determined; 0.74 microgram/ml after 229 minutes, 0.83 microgram/ml after 280 minutes and 0.74 microgram/ml after 328 minutes. Fetal tissue concentration of the drug was below our detection limit at 120 minutes. Tissue levels of villus and decidua in 6 cases were also too low to be detectable between 89 and 328 minutes after injection.
The purpose of this study was to examine the placental passage of ritodrine hydrochloride in relation to the drug's effects on the fetal circulation. Studies were carried out on nine nulliparous pregnant (120-140 days) ewes with chronically implanted cannulae for measurements of maternal and fetal arterial pressures and for blood sampling. One group of animals received sequential infusions of doses ranging from 0.1 to 30 micrograms/kg per min for 30 min (group 1). A second group was given a constant infusion of the drug at a dose of 3.0 micrograms/kg per min for 4 h (group 2). The peak concentrations of ritodrine in maternal and fetal blood were determined by radioimmunoassay. In group 1 they were 313.4 +/- 24.1 ng/ml (mean +/- S.E.) and 12.6 +/- 3.7 ng/ml at the finish of 30.0 micrograms/kg per min infusion for maternal and fetal blood, respectively. In group 2, maternal drug levels were 81.3 +/- 20.4 ng/ml after 30 min and 95.9 +/- 17.1 ng/ml after 4 h of the infusion. Fetal plasma concentrations increased slowly from trace levels at 30 min to 3.3 +/- 0.7 ng/ml at 4 h. Fetal blood pressure and heart rate did not show any significant changes during and after the infusion of ritodrine in both treatment groups. Our findings demonstrate the maternal administration of ritodrine produces no significant effects on the circulatory system of the fetal lamb because of the low transplacental passage of this drug.
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Ritodrine hydrochloride (ritodrine) is a beta 2-adrenoceptor stimulant which has been effectively prescribed for the prevention of premature labor. The present studies were carried out to investigate the effects of ritodrine on uterine motility in rats and rabbits during gestation, as compared with those of isoproterenol and isoxsuprine. The results were as follows: 1) Spontaneous movements and evoked contractile responses of isolated rat uterus (19-20th days of gestation) were suppressed by 10(-9) - 10(-6) M ritodrine. The potency of ritodrine was approximately 10 times more than that of isoxsuprine and 100 - 1,000 times less than that of isoproterenol. 2) When these drugs were administered to pregnant rats or rabbits intravenously, the tocolytic potency was in the following order: isoproterenol greater than ritodrine greater than isoxsuprine. 3) Ritodrine induced hypotension and tachycardia, but these effects were less than those of isoproterenol and isoxsuprine. 4) The effects of isoproterenol and ritodrine were almost prevented by pretreatment with propranolol, but those of isoxsuprine were only partially or not affected. These results suggest that ritodrine is effective in preventing the uterine contractions in rats and rabbits and that it has less effect on the circulatory system than isoproterenol and isoxsuprine. It is also concluded that ritodrine produces these effects through activation of beta-adrenoceptors.
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Ritodrine hydrochloride (ritodrine) is a beta 2-adrenoceptor agonist and has been effectively prescribed for the prevention of premature labor. The present study was carried out to investigate the effect of ritodrine on uterine motility, cardiovascular system, fetal heart rate and placental blood flow in late pregnant rabbits, in comparison with the effects of isoproterenol and isoxsuprine. Furthermore, we investigated the effect of ritodrine on the damage to utero-placental circulation evoked by drugs. Ritodrine (10-1,000 micrograms/kg) suppressed the spontaneous motility of pregnant rabbit uterus (27-29th days of gestation) in a dose-dependent manner. Maternal blood pressure and heart rate were little affected by ritodrine. Isoxsuprine induced hypotension and isoproterenol increased the heart rate. Ritodrine and isoproterenol had little effect on the fetal heart rate. On the other hand, isoxsuprine induced marked fetal bradycardia. Ritodrine, isoxsuprine and isoproterenol showed a tendency to decrease the placental blood flow. Isoxsuprine was more potent than the other two drugs and needed a long time for restoration. Ritodrine restored the changes in placental blood flow or fetal heart rate evoked by drugs. These results suggest that ritodrine effectively suppresses uterine motility and has little effect on the maternal land fetal cardiovascular system.
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Gastric motility of stressed rats was studied to determine its role in producing stress-induced gastric lesions. Restraint and water immersion resulted in an increase in gastric motility which consisted of an increase in frequency and amplitude of contractions and a rise in gastric tone. This increase reached maximal levels 2 to 4 hr after stress, and persisted thereafter. Formation of gastric lesions was markedly accelerated after occurrence of the increased gastric motility. In contrast, restraint alone neither produced such a vigorous increase in gastric motility, nor were the gastric lesions severe. A continuous infusion of papaverine during restraint and water immersion inhibited increase in frequency and amplitude of gastric contractions and prevented formation of gastric lesions. It is concluded that increased gastric motility is closely associated with marked formation of gastric lesions under conditions of restraint and water immersion stress and is probably a main cause for their vigorous formation, although formation of lesions occurs to a small degree without involvement of gastric motility.
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Multiple malignant gliomas are relatively uncommon, but are sometimes difficult to differentiate from multiple metastatic brain tumors. We analyzed the MR findings of four cases of multiple gliomas, comparing them with 12 cases of multiple metastatic brain tumors. All tumors were pathologically proven by surgical operation or autopsy. Gliomas were located in the deep white matter of the cerebrum, with none found in the posterior fossa. Tumors were relatively large, and irregular, thick, ring-like enhancement was noted after the administration of Gd-DTPA. Intratumoral hemorrhage was noted in only one case. High signal intensity on T2WI around the tumor suggested that edema was greater and more extensive than in metastatic tumors and was seen even in the corpus callosum. One autopsied case that showed this high intensity presented not only edema but also tumor infiltration. Metastatic tumors were located mainly in the corticomedullary junction of the brain. They were relatively small, and eight of 12 tumors showed, nodular or smooth ring-like enhancement. Intratumoral hemorrhage was noted in four cases. Edema was noted mainly around the tumor. We conclude that differential diagnosis between gliomas and metastases is possible to some extent by MRI.