Z-350, a new chimera compound possessing α1-adrenoceptor antagonistic and steroid 5α-reductase inhibitory actions

The effects of Z-350, (S)-4-[3-(4-{1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]propoxy} benzoyl)indole-1-yl]butyric acid hydrochloride, a newly synthesized compound possessing α₁-adrenoceptor antagonistic and steroid 5α-reductase inhibitory actions, were studied in vitro. In functional experiments, Z-350 shifted the concentration/response curve for the phenylephrine-induced contraction of rabbit prostate, urethra and aorta to the right with pA₂ values of 8.04, 7.57 and 7.13, respectively. The binding affinity of Z-350 for α₁-adrenoceptors in rabbit prostate, urethra and aorta were estimated by the displacement of [³H]prazosin. The pK _i values for this action of Z-350 were 7.53, 7.95 and 7.62 for the prostate, urethra and aorta, respectively. α₁-Adrenoceptor subtype selectivities were studied in the submaxillary gland (α_1A) and liver (α_1B) of rat. Z-350 inhibited the specific binding of [³H]prazosin to α_1A and α_1B-adrenoceptors with pK _i values of 7.82 and 7.29, respectively. Z-350 inhibited rat prostatic steroid 5α-reductase non-competitively with a pIC₅₀ of 8.42. These results indicate that Z-350 is a α₁-adrenoceptor antagonist and is a steroid 5α-reductase inhibitor. It is expected that Z-350 will be a candidate drug for the treatment of benign prostatic hyperplasia. Received: 26 January 1999 / Accepted: 2 March 1999     

Immunolocalization of the components of the plasminogen activating system in breast carcinoma tissue

The plasminogen activating system plays an important role in the progression of carcinomas and the significance of this system in various carcinomas has been thoroughly investigated. To follow up these investigations, we examined the immunolocalization of the components of the plasminogen activating system, namely the urokinase-type plasminogen activator (uPA), its receptor (uPAR), and two inhibitors (PAI-1 and PAI-2), in 72 cases of breast carcinomas. uPA, uPAR and PAI-1 were uniformly expressed in 75.0%, 84.7% and 80.6% of the cases respectively, although their expression was less uniform in T3 or larger carcinomas (p<0.05). Furthermore, the immunoreactivities of these three proteins were often very similar in the lesions. PAI-2 expression was, to the contrary, statistically less extensive (p<0.01)than PAI-1, and only 52.8% of the cases were uniformly positive. The incidence of PAI-2 expression was statistically lower in T3 or larger carcinomas (p<0.01), and in stage III (p<0.01) and grade III carcinomas (p<0.05). Moreover, PAI-1 immunoreactivity was more commonly found in lymph node positive (p<0.05), T3 or larger and stage III carcinomas than PAI-2 immunoreactivity. These findings suggest that uPA, uPAR and PAI-1, whose expression should be regulated by carcinomas once they have grown to a certain degree, work in association with one another, probably promoting carcinoma progression, while PAI-2 might act as the inhibitor in this system. Furthermore, breast carcinomas containing more PAI-I than PAI-2 are more active in respect to both local proliferation and metastasis.     

Stimulatory effect of ipriflavone on formation of bone-like tissue in rat bone marrow stromal cell culture

The effects of ipriflavone (IP) (10^–5 M) on bone formation were studied in stromal cells from the femoral bone marrow of young adult rats cultured for 21 days in the presence of -glycerophosphate and dexamethasone. Stereoscopic microscopy showed nodule formation after 14 days of culturing, and both the number and the size of the nodules increased with time. The alizarin-red-stained calcified area in the nodules in the IP group was nearly 4 times as large as that in the control after 21 days. Light and electron microscopy revealed the presence of many osteoblast-like cells with developed rough endoplasmic reticulum and Golgi apparatus in the nodules in the control group after 14 days, and a collagenous fibril network was seen among the cells. After 21 days, calcification of the dense collagenous fibril network and bone matrix-like tissue were observed in many nodules, resulting in the formation of bone-like tissue containing osteocyte-like cells. In the IP group, the collagenous fibril network area in the nodules was greater than that in the control after 14 days, and a further increase in both the dense collagenous fibril network area and calcified bone-like tissue area was observed after 21 days. These findings indicate that IP stimulates bone-like tissue formation in the rat bone marrow stromal cell culture, suggesting that the promotion of collagen production by osteoblasts is involved in the stimulation of bone-like tissue formation by IP.     

Cerebral arteriovenous malformations: factors influencing the surgical difficulty and outcome.

The outcomes of 151 patients with arteriovenous malformations (AVMs) treated either surgically or conservatively are presented. In terms of long-term survival rate and follow-up results, the patients who underwent total excision had more favorable results than did those treated conservatively. Patient age was the most important clinical factors, with the preoperative level of consciousness being the second most important. A grading system was formulated on the basis of the angiographical factors by using multiregression analysis; the size of the AVM influenced the surgical outcome twice as much as did the location and the pattern of arterial feeding. Thus, a large AVM (greater than or equal to 4 cm) was given 2 points; a small AVM (less than 4 cm) was given 0 points; a deep AVM was given 1 point; a superficial AVM was given 0 points; an AVM supplied by three of more artery systems was given 1 point; and an AVM supplied by one or two artery systems was given 0 points. AVMs were categorized into 5 grades from Grade 0 to 4 by the summation of these points. Predicted Karnofsky scale after surgery was calculated by this grading system and the following equation: predicted Karnofsky scale = 87.2 - 5.6 x Grade. Grade 0 and 1 AVMs showed high rates of total excision (Grade 0, 94%; Grade 1, 82%) and of satisfactory outcome (Grade 0, 90%; Grade 1, 82%) and were classified as "easy" lesions. Grade 2 AVMs are lesions classified as "moderate" and had a total excision rate of 76% and a satisfactory outcome rate of 71%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Single-blood-sample method for the determination of glomerular filtration rate using 99mTc-DTPA in Japanese

The study was aimed to evaluate glomerular filtration rate with 99mTc-DTPA by means of a single-plasma-sample method in Japanese. Three were 50 patients (29 males and 21 females, age range being 25 to 91 years) with diabetes mellitus of various degree of the renal function. 99mTc-DTPA of 300 MBq/2 ml that was prepared in our hospital was injected. Dynamic renal scintigraphy was carried out and 10 blood samples were taken after the injection. Blood clearance (true GFR) of 99mTc-DTPA was determined from plasma concentration which was fitted to the biexponential curve by a non-linear least squares method. Plasma concentration (ml/min/1.73 m2) after 75 min-post injection showed very higher linear regression and linear correlation with true GFR than 0.900. The best linear regression and linear correlation was observed with 180 min-sample (r = 0.989). As general, the following equation was obtained; Y = A + Bln(X), A = 436.1217 - 3.45817t + 0.01205t2 - 0.000015t3, B = -212.601 + 1.42518t - 0.04834t2 + 0.0000062t3, X = plasma concentration at sampling time t (%ID/L/1.73 m2), t = sampling time from 75 to 300 min (r > 0.900). This is the new equation of single-plasma-sample method for the determination of GFR using 99mTc-DTPA for Japanese. The clinical feasibility should be accessed in a field of a nuclear medicine practice.     

Cerebral oximetry for the detection of cerebral ischemia during temporary carotid artery occlusion

The near-infrared spectroscopy cerebral oximeter was assessed as a monitoring device for detecting and/or predicting cerebral ischemia during carotid endarterectomy (CEA) and the balloon occlusion test in 24 patients, 12 males and 12 females aged 28 to 77 years (mean 59.9 years). Tolerance testing of complete internal carotid artery (ICA) occlusion by balloon inflation for 20 minutes was performed in nine patients (cerebral aneurysm 6, neck tumor 3) and CEA was performed in 15 patients. The probe of the cerebral oximeter was placed on the forehead of the affected side and regional cerebral oxygen saturation (rSO2) was monitored continuously during all procedures. Stump pressure was measured just after ICA occlusion. Collateral circulation detected by digital subtraction angiography was classified into three groups: good, moderate, or poor. Stump pressure was 41-90 mmHg (mean 61.3 mmHg) in the good collateral circulation group, 40-43 mmHg (41.5 mmHg) in the moderate group, and 14-30 mmHg (23.8 mmHg) in the poor group. Change in rSO2 after ICA occlusion was +3.5(-)-4.2% (mean -1.6%) in the good collateral circulation group, -1.2(-)-6.6% (-3.2%) in the moderate group, and -2.4(-)-10.2% (-6.6%) in the poor group. Changes in rSO2 were significantly different between the good and poor collateral circulation groups (p < 0.01). A greater than 5% fall in rSO2 was observed in 0 of 15 patients in the good collateral circulation group, one of five in the moderate group, and three of four in the poor group. The cerebral oximeter is a useful, real-time, non-invasive method to measure brain oxygenation during CEA, skull base surgery, or other procedures which need to evaluate brain ischemia. A fall of greater than 10% from the rSO2 baseline value is dangerous, but less than 5% is safe.     

Percutaneous endoscopic gastrostomy (PEG) for the management of dysphagia: experiences in the neurosurgical care unit

This report concerns percutaneous endoscopic gastrostomy (PEG) administered in the neurosurgical care unit to a patient with dysphasia. This reliable nutrition route has the major advantage of minimal surgical invasion and can be expected to become a standard nutritional method. Since patients with neurological disorders account for the majority of those who need PEG, neurosurgeons need to be aware of the importance of PEG.     

An experimental approach to spinal fusion using sintered bovine bone in a pig model

Sintered bovine bone is a biomaterial based on calcium phosphate, an organized crystal of bone mineral that possesses a natural trabecular structure. The authors considered whether sintered bovine bone can integrate with recipient bone and adjust to the strength of recipient bone for anterior spinal fusion in an animal model. Either autologous iliac bone or sintered bovine bone was implanted for a spinal body fusion. Some pigs underwent exposure of the spinal bodies without implantation. Based on radiographic evaluation, manual palpation, biomechanical testing, and histologic examination, spinal fusion with sintered bovine bone resulted in a composition and structure similar to that of the autograft (or of no implantation). The sintered bovine bone with its moderate strength tended to adjust to the bone stiffness of the host bone in the specimens as new bone grew.     

Regression of a presumed meningioma with the antiestrogen agent mepitiostane. Case report

This 68-year-old woman underwent a distal gastrectomy for gastric cancer in August 1994. A presumed meningioma of the falx was found incidentally on a staging examination of the gastric cancer, but the meningioma was not treated with surgery. Instead, after gastrectomy the patient received tegafur as adjuvant chemotherapy until February 1996, when she was readmitted to the hospital because of loss of appetite and emaciation but with no recurrence of the gastric cancer. A computerized tomography scan obtained during this second admission showed no change in the meningioma. To improve her general condition, tegafur was discontinued and she was started on a course of the antiestrogen agent mepitiostane. Administration of mepitiostane for approximately 2 years resulted in a marked regression (73%) of the meningioma. This is the first reported case of a presumed meningioma that regressed as a result of use of the antiestrogen agent mepitiostane.