Efficacy of benzbromarone in hyperuricemic patients associated with chronic kidney disease.

We have retrospectively evaluated the uric acid control status and renal function changes over a period of up to 7 years in 35 patients with renal impairment who had stage 3 or higher chronic kidney disease (CKD; stage 3 in 32 patients, stage 4 in 2 patients, and stage 5 in 1 patient) associated with hyperuricemia and were receiving monotherapy with benzbromarone as an antihyperuricemic drug. Serum uric acid levels significantly decreased from 8.5 ± 0.9 to 6.1 ± 0.8 mg/dL at 6 months and were subsequently controlled at less than 7.0 mg/dL in most patients. Most patients received benzbromarone at a dose of 25-50 mg/day, whereas 150-200 mg/day was used in some patients with stage 4 or 5 CKD. No significant changes in estimated glomerular filtration rate (eGFR) from the baseline value of 46.2 ± 11.5 mL/minute/1.73 m(2) were found after benzbromarone therapy. Although the renal function impairment did not improve by reducing the serum uric acid levels with benzbromarone, the renal function did not deteriorate further on the therapy. These results suggest that benzbromarone is applicable to the management of hyperuricemia associated with renal impairment.

Restoration of menstruation after chemotherapy-induced amenorrhoea in a patient with ovarian immature teratoma.

We described a rare case of a 20-year-old woman with an ovarian immature teratoma who resumed regular spontaneous menses after more than 5 years of chemotherapy-induced amenorrhoea. Efforts to reverse chemotherapy-induced ovarian failure can be continued even after persistent menstrual dysfunction of 5 or more years.

Analysis of microsatellite instability and loss of heterozygosity in uterine endometrial adenocarcinoma.

Microsatellite instability (MSI) and loss of heterozygosity (LOH) were examined in 60 cases of uterine endometrial adenocarcinoma, using 13 microsatellite markers. In non-Smad-related regions, MSI and LOH were noted in 13 of 60 (21.7%) and in 20 of 60 (33.3%) cases, respectively. Genetic alternation of TGF-beta RII was noted in 1 of 60 cases (1.7%). The frequency of MSI and LOH was highest in Stages III and IV, respectively. Cases with G2 carcinoma showed the highest frequency, but LOH frequency did not differ among G1, G2, and G3 carcinoma cases. In Smad-related microsatellite regions, MSI and LOH were noted in 10 of 60 (16.7%) and in 12 of 60 (20.0%) cases, respectively. The frequency of MSI and LOH was highest in Stages III and IV, respectively. LOH was seen only in the Smad2 gene but not in the Smad4 gene. Our results suggest that the alterations in MSI and LOH were associated with middle and late stages of carcinogenesis of endometrial carcinoma. Both MSI and LOH tended to show an association with moderate to severe atypia of carcinoma. Our results also suggest that genetic alteration of the Smad2 gene is more responsible for endometrial carcinogenesis than that of the Smad4 gene. However, the TGF-beta type II receptor gene was considered a minor target of genetic instability in endometrial carcinogenesis.

Two cases of supernumerary ovary: one with large fibroma with Meig's syndrome and the other with endometriosis and cystic change.

Reports of supernumerary ovaries are rare. We describe two such cases, one with fibroma and the other with endometriosis and cystic change. A large fibroma measuring 17.4 x 12.0 x 7.5 cm in size was found in the supernumerary ovary of the omentum in the first case of a 47-year-old married woman with Meig's syndrome. The second case was associated with endometriosis and cystic change, measuring 11 x 5 x 3 cm in size and located in the upper abdominal cavity. It was attached to the uterus of a 28-year-old pregnant woman who had neither fibroma nor Meig's syndrome. Histologically, corpus albicans and a few primordial germ cells were demonstrated, respectively. A fibroma showing a storiform pattern was found in the first case. The second case had endometriosis and a thin-walled cyst with bleeding and necrosis caused by torsion. Immunohistochemically, desmin, alpha-smooth muscle actin, c-kit, CA125, Na+/K+ATPase, overexpression of p53, myc and ras were all negative in the fibroma cells of the first case, and in the endometriosis and cyst wall of the second case. The fibroma cells were positive for vimentin and estrogen receptor, and the proliferating cell nuclear antigen was sporadically demonstrated in their nuclei. The mutation of the p53 gene at exons 5-8 was not detected by sequence analysis. Using RT-PCR, bax, bcl-2 and p16 were not detected either. Clinically, the two cases presented here did not show abnormal hormonal symptoms. They were diagnosed as abdominal tumors or masses. Based on these considerations, one might assume that supernumerary ovaries are probably more frequent than reported at present.

Palliative radiation therapy for brain metastases from endometrial carcinoma: report of two cases.

Although endometrial carcinoma is a common invasive neoplasm of the female genital tract, brain metastases are extremely rare and few reports exist of their treatment with radiation therapy. We report two patients with manifest clinical signs of brain metastases from endometrial carcinoma on computed tomography (CT) or magnetic resonance imaging (MRI). These two patients had multiple brain metastases, with widespread dissemination late in the course of the disease and received palliative whole-brain radiation therapy to a total dose of 50 Gy in 25 fractions (case 1) and 30 Gy in 10 fractions (case 2). After radiation therapy, improvement of neurological function (NF) was observed in both patients. The duration of improvement of NF was 9 weeks in case 1 and 12 weeks in case 2. The patients died 5 months and 3 months after the diagnosis of brain metastases, respectively. In these two cases, palliative radiation therapy was effective in improving the quality of the remaining lifetime and appears to be the best treatment for brain metastases from endometrial carcinoma as well as those frequently seen from other primaries.

Therapeutic value of neoadjuvant intra-arterial chemotherapy (cisplatin) and irradiation for locally advanced uterine cervical cancer.

We analyzed long-term treatment results in 51 patients with locally advanced uterine cervical carcinoma (IIB, 4; IIIB, 43; IVA, 4) treated with neoadjuvant intra-arterial (I-A) chemotherapy (cisplatin) via the uterine artery and irradiation. Thirty patients (58.8%) developed recurrence. Twelve had pelvic recurrence alone, 8 had distant metastases alone, and 10 had both pelvic and distant failure. The 5-year cumulative pelvic control rate, absolute survival rate, and disease-free survival rate were 55.3, 47.1, and 39.4%, respectively. Eight of 51 patients (15.7%) suffered late complications. These results suggest that our neoadjuvant I-A chemotherapy prior to irradiation has limited additional value for long-term prognosis in patients with locally advanced uterine cervical carcinoma.

[Etoposide (VP-16) in gynecologic malignancy].

Clinical application of etoposide (VP-16) for gynecologic malignancy has been investigated in trophoblastic disease, ovarian, endometrial and cervical cancer. Etoposide has proved to be one of the most effective agents for trophoblastic disease. It is widely used in single or multiple drug regimens in chemotherapy of the disease. Furthermore, this drug is observed to be active in the combination of BLM with CDDP for germ cell tumor of the ovary. It is now playing an important role in chemotherapy of this tumor.

[MR imaging of cerebral palsy].

We evaluated 35 patients with cerebral palsy on the basis of MR imaging findings in the brain. The types of palsy were spastic quadriplegia (n = 11), spastic diplegia (n = 9), spastic hemiplegia (n = 2), double hemiplegia (n = 1), athetosis (n = 10) and mixed (n = 2). Of all patients, 28 (80%) generated abnormal findings. In spastic quadriplegia, although eight cases revealed severe brain damage, two cases showed no abnormal findings in the brain. One of the three had cervical cord compression caused by atlanto-axial subluxation. In spastic diplegia, the findings were divided according to whether the patient was born at term or preterm. If the patient had been born prematurely, the findings showed periventricular leukomalacia and abnormally high intensity in the posterior limbs of the internal capsule on T2-weighted images. MR imaging in spastic hemiplegia revealed cerebral infarction. In the athetoid type, half of all cases showed either no abnormal findings or slight widening of the lateral ventricle. Three cases showed abnormal signals of the basal ganglia. The reason why athetoid-type palsy did not show severe abnormality is unknown. We believe that MR imaging is a useful diagnostic modality to detect damage in the brain in cerebral palsy and plays an important role in the differentiation of cerebral palsy from the spastic palsy disease.

Intra-arterial chemotherapy with cisplatin followed by radical radiotherapy for locally advanced cervical cancer.

Locally advanced cervical cancer has a dismal prognosis, with a high local failure rate and a poor survival rate. To improve the cure rate for advanced carcinoma of the cervix, we initiated a study of intra-arterial (I-A) chemotherapy with cisplatin via the uterine artery prior to definitive radiotherapy. I-A chemotherapy via the internal iliac artery has been used to treat advanced cervical cancer; however, access by way of the uterine artery has not been tested for this purpose. Thirty-four patients with central tumor > or = 5 cm in anteroposterior diameter observed on CT scans were treated with I-A chemotherapy. I-A chemotherapy consisted of unilateral catheterization of the uterine artery using 120 mg/m2 cisplatin. After assessment of I-A chemotherapy, all but 3 patients were treated with a combination of whole-pelvis external irradiation and intracavitary irradiation. The 3 patients underwent external radiotherapy alone. Twenty-seven of 34 patients treated were evaluable for response to I-A chemotherapy. Eleven patients (41%) experienced a partial response. Seventy-six percent of the 34 patients treated with I-A chemotherapy followed by radiotherapy exhibited a complete response by the end of treatment. Toxicity was well tolerated and no death due to treatment occurred. The 2- and 5-year actuarial survival rates were 64 and 55%, respectively. The crude incidences of pelvic recurrence and distant metastasis observed at a median follow-up of 54 months were both 47%. This study for locally advanced cervical cancer suggests there is benefit to be derived from our I-A chemotherapy followed by radical radiotherapy.

Prevention of diabetes by thymic hormone in alloxan-treated rats.

We investigated the effects of facteur thymique sérique (FTS), a thymic peptide hormone, on alloxan- and streptozotocin-induced diabetes in rats. Pretreatment with intravenous injection of FTS significantly suppressed both alloxan- and streptozotocin-induced hyperglycemia. The effects of FTS were time dependent. FTS suppressed hyperglycemia in a dose range of 1-6600 micrograms/kg. Alloxan-induced hyperglycemia was completely prevented when FTS was injected in doses of 40-50 micrograms/kg 1 min before injection of alloxan. Histological examination of islet areas showed that alloxan-induced destruction of beta-cells was inhibited by FTS. FTS had no significant effects on lymphocyte subsets and immunity-related cells or on plasma superoxide dismutase activity and total glutathione level. The blood half-life time of exogenously injected FTS was short (2-3 min), indicating acute internalization of FTS into pancreatic beta-cells. Our results suggested that FTS acutely and directly blocks some initial effect of alloxan, preventing the destruction of beta-cells.

Estimation of plasma glucose fluctuation with a combination test of hemoglobin A1c and 1,5-anhydroglucitol.

We investigated the effect of plasma glucose fluctuation on hemoglobin A1c (HbA1c) and plasma 1,5-anhydroglucitol (AG) levels, especially in insulin-dependent diabetes mellitus (IDDM). Plasma AG is a new marker that provides sensitive and analytical information on glycemic control. The basic mechanisms underlying both the reduction and recovery of the plasma AG level, ie, the excretion into urine with glucosuria and the amount supplied to the body, were presumed to be similar in IDDM and non-insulin-dependent diabetes mellitus (NIDDM) patients. The correlation coefficient for mean plasma glucose and AG was -.591, and it was .578 for mean plasma glucose and HbA1c in IDDM patients. In NIDDM, the correlation between mean plasma glucose and AG was -.869, and between mean plasma glucose and HbA1c, .875. The plasma AG levels in the IDDM group showed a lower range than in the NIDDM group, even with similar HbA1c levels. All the cases showing lower plasma AG levels among those with similar HbA1c levels manifested greater fluctuation of plasma glucose and a larger amount of urinary glucose. The lower AG level in IDDM patients was reversible to the level in NIDDM patients when the greater fluctuation of plasma glucose was corrected. Thus, it was suggested that because urinary glucose excretion is intermittently high in IDDM patients, plasma AG is frequently low, even though the mean plasma glucose and HbA1c levels suggest good control.(ABSTRACT TRUNCATED AT 250 WORDS)

Origin and disposal of 1,5-anhydroglucitol, a major polyol in the human body.

The origin and disposal of 1,5-anhydro-D-glucitol (AG), one of the main polyols found in the human body, was studied in normal subjects and diabetic patients. AG was detected in various kinds of foods. The mean AG supplement through foods was estimated to be approximately 4.38 mg/day, which was compatible with that calculated in a food analysis (average 0.22 mg AG/100 kcal in Japanese foods) on eight healthy subjects. The mean AG excretion in urine was approximately 4.76 mg/day in these subjects. Excretion into stools was negligible. From observations on the patients without oral supplement of AG, 0.4 mg of daily de novo synthesis of AG was strongly suggested. It was also implied that urinary AG excretion occurred soon after food ingestion and that its amount was closely correlated with daily supplement through foods. Thus the fundamental kinetics of AG were recognized as follows: 1) AG in the body originates mainly from foods and is well absorbed in the intestine, 2) AG is little degraded and metabolized in the body, and 3) an equilibrium exists between oral supplement plus a small but steady amount of de novo synthesis and excretion in urine.

Effects of ouabain on contractile response to norepinephrine in isolated rat aorta.

1. Inhibition of sodium(Na+), potassium(K+)-ATPase activity was dependent on the concentration of ouabain and inverse to the concentration of potassium ([K+]) in the reaction mixture. 2. Contractility of isolated rat aorta preparation in response to norepinephrine was augmented by ouabain and low [K+]. 3. Results suggest that inhibition of Na+,K(+)-ATPase activity will be correlated with augmentation of vascular contractility maybe through activation of Na(+)-calcium exchange system.

Enhancement of vascular contractility by plasma substances obtained from pregnancy-induced hypertension.

1. Augmentation of norepinephrine (NE)-induced contraction of isolated dog mesenteric arteries by ouabain was significantly enhanced under 4 mM potassium ([K+]) medium condition compared with usual medium condition at 6 mM [K+]. 2. Vascular contractility to NE was significantly enhanced by plasma substances obtained from pregnancy-induced hypertension (PIH) patients compared with that from normotensive pregnant women under 4 mM [K+] medium condition despite of no difference between them under 6 mM [K+] medium condition. 3. These results suggest the possible involvement of the ouabain-like substance in development of hypertension in PIH patients.

Ouabain-like Na+,K(+)-ATPase inhibitory activity of a plasma extract in normal pregnancy and pregnancy induced hypertension.

To estimate the participation of a Na+,K(+)-ATPase-inhibiting plasma factor in pregnancy induced hypertension (PIH), the inhibitory activity and the characteristics of plasma extract eluted with ethanol through a C8 column were examined in normotensive non-pregnant women (N) and women with normal pregnancy (NP) and PIH. There were no differences among the 3 groups in the Na+,K(+)-ATPase activity of erythrocyte ghosts. The heat- and acid-stable plasma extract dose-dependently inhibited Na+,K(+)-ATPase activity with a pattern similar to that of ouabain, but different from that of vanadate. The inhibitory activity of plasma extract was not influenced by polyclonal digoxin antibody which almost completely prevented digoxin-induced inhibition and slightly but significantly reduced the ouabain-induced one. The results indicate that the plasma extract has ouabain-like inhibitory activity on Na+,K(+)-ATPase and that it is not endogenously synthesized digoxin itself, but a substance differing in structure from digoxin. Furthermore, the ouabain-like Na+,K(+)-ATPase inhibitory activity in NP plasma was significantly lower than that in PIH plasma, which was similar to that in N plasma. There were significant relationships between the ouabain-like Na+,K(+)-ATPase inhibitory activities in plasma and the diastolic and systolic blood pressures in NP and PIH groups. The results suggest that the lower ouabain-like Na+,K(+)-ATPase inhibitory activity in plasma probably participates in maintaining the blood pressure within the normal range during pregnancy and its failure may be involved in the genesis of PIH.

Cardiac effects of beta-2 adrenoceptor stimulation with intracoronary procaterol in the absence and presence of regional myocardial ischemia in dogs.

To evaluate consequences of cardiac beta-2 adrenoceptor stimulation on coronary hemodynamics and regional myocardial function assessed by sonomicrometry in the normal and regionally ischemic heart, the effects of administration of procaterol, a selective beta-2 adrenoceptor agonist, into the left circumflex coronary artery (LCX) were examined in the absence and presence of a stenosis of the LCX in anesthetized open-chest dogs. The stenosis of the LCX was made sufficient to decrease percent segment shortening in the LCX-perfused region to around 2 to 3%. When coronary stenosis was absent, intracoronary infusion of procaterol (6.7 ng/min for 15 min) produced significant increases in LCX flow and myocardial segment shortening in the infused region without changes in global hemodynamics. During coronary stenosis, on the contrary, intracoronary procaterol at the same dose significantly deteriorated regional myocardial dysfunction without changing LCX flow, global hemodynamics and cardiac lactate metabolism. These changes induced by procaterol were not observed in the dogs treated with a selective beta-2 antagonist, erythro-(+/-)-1-(7-methylindan-4-yloxy)-3-isopropylaminob utan-2-ol. These results suggest the presence of functional beta-2 adrenoceptors in the canine heart both with and without myocardial ischemia.

Regional vasodilating effects of spirapril diacid and enalapril diacid in anesthetized dogs.

The acute regional hemodynamic effects of spirapril diacid, a novel nonsulfhydryl angiotensin-converting enzyme inhibitor, and enalapril diacid at an equidepressor dose were examined in anesthetized dogs by simultaneously measuring renal, coronary, vertebral arterial and aortic blood flow. Spirapril diacid (30 micrograms/kg, i.v.) lowered aortic pressure and increased aortic and renal blood flow associated with no marked change in heart rate, myocardial contractility, vertebral and coronary blood flow in a similar manner to enalapril diacid (30 micrograms/kg, i.v.). Both inhibitors thus produced an increase in stroke volume and a decrease of the rate-pressure product. The decrease of renal vascular resistance after administration of both agents was greater than that in vertebral and coronary vascular beds. A relatively more prolonged renal vasodilatation and a shortened coronary vasodilatation were seen with spirapril diacid as compared with enalapril diacid, despite practically identical reductions in total peripheral resistance. Each of the drugs markedly inhibited the pressor and renal vasoconstrictor responses to angiotensin I. These results indicate that the two inhibitors exhibit a similar profile of regional differences in vasodilatory effects, although they might display different durations of regional vasodilatation.

Effect of polyoxyethylene-modified superoxide dismutase on recovery of myocardial dysfunction after coronary stenosis in dogs.

The effects of superoxide dismutase modified with polyoxyethylene (SOD-POE) on impairment of myocardial segment shortening (SS) during coronary stenosis plus pacing-induced tachycardia (CSPT) and the recovery after reperfusion was examined in anesthetized dogs. SOD-POE or saline was administered i.v. 30 min before reperfusion. Changes in hemodynamic variables and SS by CSPT were similar in both groups. However, the SOD-POE group showed improved recovery of SS compared with the control group. Results indicate that oxygen-derived free radicals may partially be involved in the genesis of myocardial dysfunction after CSPT-induced regional ischemia.

Comparative effects of arotinolol, labetalol and propranolol on regional myocardial dysfunction induced by flow-limiting coronary stenosis in anesthetized dogs.

Effects of arotinolol, a combined alpha- and beta-adrenoceptor blocking agent, on regional myocardial dysfunction produced by severe coronary stenosis in anesthetized dogs were examined and compared with those of labetalol and propranolol. Doses of these three antagonists were selected to produce a comparable degree of the negative chrono- and inotropic effect but a different potency of alpha-adrenoceptor blockade (labetalol greater than arotinolol). Regional myocardial function measured as segment shortening (%SS) was decreased to around 2-3% by constriction of the left circumflex coronary artery (LCX), and then drug or saline was administered i.v. The stenosis of LCX was released 30 min after the administration. No significant alteration in hemodynamic and contractility parameters was seen as compared to the predrug value up to at least 30 min after saline i.v. Arotinolol and propranolol both reduced heart rate and peak positive left ventricular dP/dt (LVdP/dt) without a significant change in LCX flow. Concomitantly, %SS distal to a coronary stenosis was significantly improved by arotinolol and propranolol. On the other hand, labetalol significantly reduced LCX flow probably due to systemic hypotension and failed to improve %SS in the ischemic area, although the agent markedly decreased heart rate and LVdP/dt. These results indicate that arotinolol improves impaired regional myocardial function distal to a coronary stenosis in a similar manner with propranolol.

Investigation on the effect of dipyridamole and papaverine on regional blood flow and cardiac hemodynamics in anesthetized dogs.

Vasodilating effects of dipyridamole were compared with those of papaverine in anesthetized open-chest dogs. Dipyridamole i.v. produced a significant fall in aortic blood pressure and significant increases in aortic and coronary blood flows. Vertebral blood flow did not alter, but renal blood flow was transiently decreased. Left ventricular dP/dt, heart rate and left ventricular enddiastolic pressure were hardly affected by dipyridamole. Papaverine i.v. significantly increased aortic, vertebral and coronary blood flows, left ventricular dP/dt and heart rate and significantly decreased aortic blood pressure and left ventricular enddiastolic pressure. Renal blood flow was instantly decreased by papaverine. Percent change in each vascular resistance showed decreases in total peripheral, vertebral and coronary vascular resistances in response to both drugs, and the decrease in coronary vascular resistance was the most remarkable. Renal vascular resistance was increased by dipyridamole, while it was decreased by papaverine. Percent change in double product (heart rate x systolic arterial blood pressure) showed a monophasic decrease pattern with dipyridamole and a biphasic pattern with an initial, transient decrease followed by an increase with papaverine. The present results indicate that dipyridamole and papaverine produce marked coronary vasodilatation, and that papaverine is different from dipyridamole in cardiotonic properties.