[The clinical usefulness and transference of cefcapene pivoxil (CFPN-PI) into the maternal cubital blood, umbilical blood and amniotic fluid in premature rupture of the membranes].

We studied the transference of cefcapene pivoxil (CFPN-PI) into the maternal cubital blood, umbilical blood and amniotic fluid as well as its clinical usefulness. 58 pregnant women without complications who had a premature rupture of membranes after day 0 of the 36th week of pregnancy and delivered a child with a normal transvaginal labor were enrolled this study. As a result, we found that the maternal serum level of CFPN-PI reached a detectable level at 1 hr 15 min post dose, reached the maximum (Cmax) at 2 hr 30 min, and was maintained at 0.15-1.14 micrograms/ml until 4 hr 35 min. In the umbilical serum, the drug concentration reached a detectable level at 1 hr 45 min post dose, was maintained at Cmax of 0.40 microgram/ml from 3 hr 3 min until 4 hr 27 min, and showed a level as high as 0.14 microgram/ml at 7 hr 7 min. In the amniotic fluid, the drug concentration reached a detectable level of 0.09 microgram/ml at 2 hr 48 min post dose, reached Cmax at 3 hr 55 min, and was maintained at 0.15-0.61 microgram/ml until 13 hr 37 min. Concerning the prophylactic effects of CFPN-PI against infections, one case of puerperal intrauterine infection in the parent and two cases of neonatal infection were observed, showing an effectiveness of 95%. In terms of adverse events, neither abnormality in maternal laboratory test data suspected as due to CFPN-PI, nor abnormality in subjective and objective findings was observed. In the neonates, no abnormality suspected as due to CFPN-PI was detected, either, including growth retardation until the 3-month medical examination. We think that CFPN-PI can be a first choice drug for prophylaxis of infections in cases of premature rupture of membranes after the 36th week of pregnancy, because of convenience of oral administration, coupled with excellent safety and potent prophylactic effectiveness against infections resulting from a long term maintenance of high levels in the umbilical blood and amniotic fluid.

[A case of peritoneal papillary serous adenocarcinoma successfully treated by intraperitoneal consecutive administration of cisplatin].

The rare case of a 73-year-old woman with peritoneal papillary serous adenocarcinoma (PPSA), which was limited to the retroperitoneum, is described. She was admitted to our hospital because of vaginal bleeding and a pelvic mass. She had a total hysterectomy, double salpingo-oophorectomy, omentectomy, biopsy of the pelvic lymph nodes and subtotal tumorectomy. In immunohistochemical examinations, this tumor was diagnosed as PPSA, which was limited to the retroperitoneum without local or distant metastasis. Thereafter she received chemotherapy using a combination of cisplatin and cyclophosphamide at intervals of three weeks. Cisplatin was intraperitoneally administered in a divided dose of 20 mg from day 1 to day 4, and cyclophosphamide was intravenously infused in a dose of 500 mg on day 1. After three courses of this chemotherapy, a pathological complete response was observed and the only adverse effects were grade 1. In view of these advantages, this chemotherapy should be considered as first-line chemotherapy for aged patients with PPSA.

[Diagnostic usefulness of KL-6 measurements in patients with pulmonary complications after administration of amiodarone].

Amiodarone-induced pulmonary toxicity is one of the major complications in patients receiving administration of amiodarone. KL-6 is a useful indicator to evaluate the activity of interstitial pneumonitis. We studied the clinical utility of KL-6 as a marker for amiodarone-induced pulmonary toxicity. We investigated 6 patients in whom chest radiography revealed abnormal consolidations after administration of amiodarone from 1997 to 1999. All patients were male aged 56 to 76 years (mean 66 +/- 7 years). The indications for amiodarone included sustained ventricular tachycardia in 5 patients and atrial fibrillation in one patient with refractory heart failure. The mean left ventricular ejection fraction was 31 +/- 12% (22-52%). KL-6 levels were measured by a sandwich type enzyme immunoassay using a murine monoclonal antibody (KL-6 antibody), and the cutoff level was determined at 520 U/ml. Complications occurred from 17 days to 45 months after treatment with amiodarone. The KL-6 levels were abnormally high (2,100 and 3,000 U/ml) in 2 patients with amiodarone-induced pneumonitis but under the cutoff level in the non-pneumonitis patients. In one patient with amiodarone-induced pneumonitis, the KL-6 level increased from 695 to 2,100 U/ml concurrently with worsening interstitial changes shown by high resolution computed tomography. We conclude that KL-6 has practical uses as a marker for the detection and evaluation of amiodarone-induced pulmonary toxicity.

[An aged patient with stage IV ovarian cancer successfully treated by intraperitoneal consecutive administration of cisplatin].

The patient was an aged woman with ovarian cancer stage IV that was classified as serous papillary adenocarcinoma. The primary lesion, 60 x 70 x 100 mm in size, was detected in the left ovary and the lymph node metastasis, 54 x 35 mm in the maximum size, expanded from the pelvic lymph node to the left supraclavicular lymph node. The patient underwent three courses of chemotherapy at intervals of three weeks. Cisplatin was intraperitoneally administered in a divided dose of 20 mg from day 1 to day 4, and cyclophosphamide was intravenously infused in a dose of 500 mg on day 1. As a result, histological efficacies of Grade III were recognized not only in the primary lesion but also in the metastatic lesions including lymph nodes. No adverse effects were observed, and the free Pt AUC in cubital blood measured after a course of chemotherapy (3.0 mg.hr/l) was higher than that measured after 2 hour-drip infusion of cisplatin 100 mg/day. The concentration of free Pt in ascites measured one hour after intraperitoneal administration was 2.8 micrograms/ml. These findings show that this method is a highly effective therapy with few adverse effects. In view of these advantages, this therapeutic technique should be considered as first-line chemotherapy for aged patients and those with serous adenocarcinoma who prefer in-home treatment.

[A case of FIGO stage IV A vulvar cancer successfully treated by neoadjuvant chemotherapy with continuous intra-arterial infusion (cisplatin, 5-fluorouracil)].

The subject was a patient who had squamous cell carcinoma in the pudendum and the inguinal region (12.5 x 8.0 cm and 4.5 x 3.0 cm, respectively). A curative operation for FIGO IV A stage (T3N3M0) vulvar cancer is thought to be difficult to perform and is resistant to BOMP therapy, so continuous arterial infusion therapy consisting of cisplatin (CDDP, 10 mg/day, day 2-4, one shot) and 5-fluorouracil (5-FU, 250 mg/day, day 1-4, continuous) was performed weekly via bilateral femoral arteries to the lower end of the branches of bilateral superior gluteal arteries. In consequence, the tumor started to clearly shrink from the first week. After treatment with total doses of 210 mg of CDDP and 7,000 mg of 5-FU, the patient underwent complete resection of the tumor without skin grafting, and a histological efficacy of Grade 1-b or above was obtained. No adverse reactions were found, and the free Pt AUC in the peripheral blood was 0.85 mg.hr/l per course. Pt concentration in the pudendum 2 hours after CDDP therapy was 2.9 micrograms/g. Because of little adverse reaction and high efficacy, this method appeared to be a therapeutic method worth considering from the viewpoint of the quality of life of patients with the progressive vulvar cancer prevalent in elderly persons.

[Pleural fibroma with a cavity-like air space].

A 45-year-old man was admitted to the hospital because of an increase in the size of an abnormal shadow on chest X-ray films over the preceding 5 years. A chest X-ray film on admission revealed a round air space in a mass-like shadow in the right upper lung field. Results of physical examination, sputum cytologic examination, and Ziehl-Neelsen staining were negative. Histopathological examination of a percutaneous lung biopsy specimen revealed a benign fibrous tumor of the pleura. Thoracotomy revealed a pedunculated tumor arising from the visceral pleura at the apical segment of the right upper lobe. A wedge resection was done. Histological examination revealed that the tumor consisted of regularly-shaped spindle cells with densely collagenous tissue. Normal lung tissue was found to be invaginated into the tumor tissue. These findings are consistent with the radiologic findings.

Calcium sensitization in perfused beating guinea pig heart by a positive inotropic agent MCI-154.

We investigated the effects of MCI-154, a positive inotropic agent that increases the myofilament response to Ca++, on Ca++ transients, left ventricular (LV) function and phosphodiesterase (PDE) III activity of guinea pig heart, and compared them with the effects of pimobendan and milrinone. In Langendorff guinea pig hearts loaded with a fluorescent Ca++ probe indo-1, LV pressure and Ca++ transient were measured simultaneously. MCI-154 (10(-10)-10(-6) M) increased LV developed pressure, +dP/dt and -dP/dt with a reduction of LV end-diastolic pressure, although it did not affect coronary flow. The positive inotropic activity of MCI-154 was more potent than that of pimobendan and milrinone; EC50 values (concentrations for increasing +dP/dt by 50% from base line) were 4.31, 41.5 and 294 x 10(-9) M, respectively. The positive inotropic effect of MCI-154 was accompanied by the increase in systolic, diastolic and amplitude of indo-1 fluorescence ratio. The relative increase in Ca++ transients against the increase in LV contractility produced by MCI-154, however, was significantly less than that by increasing perfusate [Ca++], pimobendan or milrinone. MCI-154 (3 x 10(-7)-10(-4) M) inhibited the activity of PDE III isolated from guinea pig LV tissues, but the inhibitory effect of MCI-154 was less than pimobendan and milrinone; IC50 values were 10.1, 3.5 and 2.4 x 10(-6) M, respectively. These findings suggest that MCI-154 exerts a positive inotropic effect mainly through Ca(++)-sensitizing action in intact beating whole hearts.

[Three cases of uterine cervical adenocarcinoma successfully treated by neoadjuvant chemotherapy with continuous intra-arterial infusion (cisplatin, 5-fluorouracil)].

Low-dose consecutive intra-arterial infusion therapy with cisplatin and 5-fluorouracil as neoadjuvant chemotherapy was performed on 3 cases of cervical adenocarcinoma (two stage IIb and one stage IIIb). Ten-day infusion of cisplatin 10 mg/day (one shot) and 5-fluorouracil 250 mg/day (continuous) into blood flow-altered bilateral internal iliac arteries, was carried out as one course and 2 times at intervals of 3 weeks. As a result, side effects were slight, and all of these 3 cases showed a tumor diminution rate of above 83.5%, making it possible to perform complete tumorectomy through radical hysterectomy. However, some postoperative additional treatment was thought to be necessary, considering that with the present method, the area under the curve of free Pt of cubital venous blood is 2.4 mg hr/l and that by the present method alone long-term survival cannot be expected in cervical adenocarcinoma.

[Neoadjuvant chemotherapy with continuous intra-arterial infusion (cisplatin, 5-fluorouracil) in the treatment of stage III cervical cancer].

Continuous arterial infusion therapy with a reservoir for neoadjuvant chemotherapy was used in 12 cases of cervical carcinoma, clinically progressive Stage III, to examine its usefulness. Drugs used were cisplatin, 10 mg/day (one shot) and 5-fluorouracil, 250 mg/day (continuous), which were infused from bilateral subhypogastric reservoirs to bilateral internal iliac arteries for 10 days (one course) at a rate of 2 times per 3 weeks. As a result, diminution of main lesion was observed in all cases, and radical hysterectomy could be performed on all but one of 11 patients, who refused the surgery. Histological examination of resected uteri revealed Grade III (3 cases, Grade II (6 cases), Grade I b (1 case) and Grade I a (1 case). The present therapy enabled us to obtain not only AUC of filterable platinum, comparable to 2 hour-drip infusion of cisplatin 100 mg/day, but also therapeutic effects on lymphnodal metastasis. In spite of this excellent effectiveness, slight side effects such as hemotoxicity, Grades 1 and 2, and digestive disorder, were noted. From the above, the present therapy, despite the slight side effects, can be regarded as an effective therapeutic approach which enables us not only to stage down progressive Stage-III cervical carcinoma and to indicate radical hysterectomy, but also expect an improved prognosis.

Effect of a calcium-sensitizing positive inotropic agent MCI-154 and its combined use with enalapril on postischemic contractile dysfunction of dog hearts.

We wished to elucidate the effects of the calcium-sensitizing positive inotropic agent MCI-154 and its combined use with an angiotensin-converting enzyme (ACE) inhibitor enalapril on postischemic contractile dysfunction. Anesthetized dogs underwent a 30-min occlusion of the left anterior descending coronary artery (LAD) followed by 2 h of reperfusion. Regional myocardial segment shortening in the ischemic LAD area was assessed by sonomicrometry. Myocardial segment shortening decreased in response to the LAD occlusion and remained decreased during 2-h reperfusion. The intravenous infusion of MCI-154 (0.1 or 0.3 micrograms/kg/min) initiated 10 min after occlusion and throughout reperfusion significantly improved the recovery of segment shortening. The alleviation of the postischemic contractile dysfunction by MCI-154 was augmented when the animals were treated with a bous injection of enalapril (0.3 mg/kg) 15 min before ischemia followed by an infusion of the drug (0.003 mg/kg/min). The pretreatment with enalapril alone (0.3 mg/kg plus 0.003 mg/kg/min or 1 mg/kg plus 0.01 mg/kg/min) did not alleviate the postichemic dysfunction, however, although it decreased systemic blood pressure (BP). Ischemic bed size, myocardial necrosis (by triphenyltetrazolium chloride staining), and collateral blood flow (by colored microspheres) were similar in all experimental groups. These results indicate that MCI-154 improves the postischemic contractile function of dog heart, whereas enalapril fails to improve it. ACE inhibitors may also augment the efficacy of cardiotonics on postischemic dysfunction.

Effect of MCI-154, a cardiotonic agent, on regional contractile function and myocardial oxygen consumption in the presence and absence of coronary artery stenosis in dogs.

The effects of MCI-154 (6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)- pyridazinone hydrochloride.3H2O), a cardiotonic agent with calcium sensitizing actions, on regional contractile function and myocardial oxygen consumption (MVO2) were studied in the dog hearts with and without partial occlusion of the left anterior descending coronary artery and compared with those of dobutamine. Segment shortening by sonomicrometry, regional myocardial blood flow by microspheres and the oxygen content of coronary venous blood drawn from the ischemic left anterior descending coronary artery area were simultaneously measured. The ischemic zone segment shortening and left ventricular (LV) dP/dtmax were decreased after partial occlusion. The infusion of MCI-154 starting 20 min after ischemia improved the depressed segment shortening and LV dP/dtmax without increasing the ischemic zone MVO2 and regional myocardial blood flow. In the nonischemic hearts, MCI-154 did not increase MVO2 and coronary blood flow despite the augmentation of myocardial contractility. MCI-154 decreased LV end-diastolic pressure and systemic blood pressure. On the other hand, dobutamine failed to increase the ischemic zone segment shortening, but the drug increased MVO2, coronary blood flow and LV dP/dtmax in both ischemic and nonischemic hearts. These results indicate that MCI-154 alleviates the ischemic contractile failure without increasing myocardial oxygen demand. Thus, MCI-154 may be useful in the management of heart failure with reduced coronary reserve.

The affinity of betaxolol, a beta 1-adrenoceptor-selective blocking agent, for beta-adrenoceptors in the bovine trachea and heart.

1. The specificity of betaxolol, a beta-adrenoceptor antagonist, for beta 1- and beta 2-adrenoceptors was compared with that of other beta-antagonists, atenolol, ICI-118551, butoxamine and (+/-)-propranolol, in the bovine trachea and heart by competitive interaction with [3H]-CGP12177 as a radioligand. 2. The radioligand Kd values were 0.75 +/- 0.12 and 1.60 +/- 0.11 nM in the trachea and heart, respectively, and the Bmax values were 34.00 +/- 4.41 and 21.54 +/- 2.94 fmol mg-1 protein, respectively. 3. Using ICI-118551, we determined the ratio of beta 1:beta 2-adrenoceptors in the trachea and heart to be approximately 29:71 and 56:44, respectively. 4. In the trachea, a beta 2-predominant tissue, betaxolol and atenolol were more selective for beta 1-adrenoceptor binding sites than beta 2-adrenoceptor binding sites, whereas ICI-118551 and butoxamine were more selective for beta 2-adrenoceptor binding sites. 5. The beta 1-selectivity of betaxolol was 2.2 and 2.7 fold higher than that of atenolol in the bovine trachea and heart. These findings suggest that betaxolol may be useful in the treatment of hypertension, cardiac arrhythmia and angina pectoris.

Anomalous left brachiocephalic vein: CT findings.

Eight cases of anomalous position of the left brachiocephalic vein were demonstrated by CT. Six coursed downward lateral to and below the aortic arch to enter the superior vena cava (SVC). Two cases were double left brachiocephalic veins. The superior branch was in the normal position, but the inferior vessel coursed below the aortic arch. Most of these subaortic left brachiocephalic veins enter the SVC at the same level or caudal to the azygous arch. Only two cases were associated with congenital heart disease. This anomalously positioned vessel is asymptomatic but must be distinguished from the pulmonary artery and persistent left SVC, especially when open heart surgery for cardiac malformations is being considered.

Beneficial effect of MCI-154, a cardiotonic agent, on ischemic contractile failure and myocardial acidosis of dog hearts: comparison with dobutamine, milrinone and pimobendan.

The effects of MCI-154, a cardiotonic agent with Ca++ sensitizing actions, on the ischemic contractile failure and myocardial acidosis were studied in the dog heart, in which the left anterior descending coronary artery (LAD) was partially occluded for 90 min, and compared with those of dobutamine, milrinone, pimobendan and isosorbide dinitrate (ISDN). Partial occlusion of LAD decreased segment shortening (measured by sonomicrometry) and myocardial pH (assessed by a micro glass pH electrode) in the ischemic myocardium. MCI-154, when administered i.v. 30 min after ischemia, improved the segment shortening in the ischemic zone, whereas dobutamine, milrinone and pimobendan failed to improve it when the drugs increased peak positive left ventricular dP/dt. Among the cardiotonic agents tested only MCI-154 attenuated myocardial acidosis during ischemia. The degree of the attenuation of acidosis by MCI-154 was equivalent with that by ISDN. However, the improvement of the ischemic zone segment shortening by MCI-154 was more pronounced than that by ISDN. These results suggest that in addition to the attenuation of myocardial acidosis the positive inotropic action of MCI-154, presumably increasing the responses of myofilaments to Ca++, may be possibly responsible for the improvement of regional contractile function in the ischemic myocardium. Thus, MCI-154 may be useful in the management of ischemic heart failure.

[A case report of anomalous left brachiocephalic vein].

An anomalous case of a left brachiocephalic vein passing behind the ascending aorta was observed in a 49-year Japanese man. This is known as anomalous left brachiocephalic vein. The anomalous left brachiocephalic vein descended along the left mediastinum in a position identical to that of a persistent left superior vena cava, so the diagnosis of this venous abnormally require carefully considered. Many cases of anomalous left brachiocephalic vein have been reported based on autopsy findings, but this venous anomaly was recently demonstrated by ultrasonography, CT, and MRI.

MCI-154, a novel cardiotonic agent, reverses the acidic pH-induced decrease in responses of cardiac myofilaments to Ca++: comparison with sulmazole and pimobendan.

In the present study, we have examined the effects of decreasing pH from 7.0 to 6.6 on the tension developed by direct activation of the myofilaments in chemically skinned fibers from guinea pig papillary muscles. We then compared the effects of the novel inotropic agents MCI-154, pimobendan and sulmazole, which have direct action on cardiac myofilaments, on the acidic pH-induced changes in responses of the contractile system to Ca++. The reduction of pH from 7.0 to 6.8 shifted the pCa (-log[Ca++] M)-tension relation curve to the right with no change in maximum tension. However, the reduction of pH from 7.0 to 6.6 shifted the pCa tension relation curve to the right and also depressed maximum force development. These effects were reversible by returning to neutral pH (pH 7.0), but were not overcome by increasing the free [Ca++] (decreasing pCa from 4.4 to 4.0). The amplitude of pMg-ATP (-log[MgATP]M)-tension curve in the absence of free Ca++ (Ca++ less than 1 nM, bell-shaped curve) was shifted downward by reducing pH from 7.0 to 6.6. MCI-154 (1-100 microM) reversed the acidic pH-induced decrease of tension development which was activated by pCa 5.8 in a concentration-dependent manner. Moreover, the acidosis induced reductions of maximum tension (pCa, 4.4) and pMgATP 6.0-activated tension (Ca++ less than 1 nM) were also reversed by MCI-154 (1-100 microM) in a concentration-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Improvement of postischemic contractile dysfunction of dog heart by MCI-154, a novel cardiotonic agent.

The effects of MCI-154, a cardiotonic agent which has direct effects on cardiac myofilaments, on postischemic contractile dysfunction were studied in dog heart subjected to a 30-min occlusion of the left anterior descending coronary artery followed by reperfusion, and compared with the effects of milrinone and dobutamine, that have largely cyclic AMP-dependent mechanisms of action. Regional myocardial contractility (segment shortening) and tissue ATP levels were severely depressed in reperfused myocardium. MCI-154 (0.3 and 1 microgram/kg per min) improved the regional function of postischemic myocardium and decreased left ventricular end-diastolic pressure and systemic aortic pressure when infused i.v. from 30 min after reperfusion. The improvement of regional function caused by MCI-154 (1 microgram/kg per min) was more pronounced than that caused by milrinone (1 microgram/kg per min) or dobutamine (1 microgram/kg per min), although the drugs produced an equal increase in cardiac performance (peak positive left ventricular dP/dt). These results suggest that MCI-154 produces a more pronounced improvement of regional myocardial function than milrinone and dobutamine, presumably by increasing the responses of the contractile protein system to Ca2+. In this respect, MCI-154 would be of much benefit for the treatment of postischemic left ventricular dysfunction.