Aldosterone antagonists. 4. Synthesis and activities of steroidal 6,6-ethylene-15,16-methylene 17-spirolactones

Several steroidal 6,6-ethylene-15,16-methylene 17-spirolactones were synthesized to find new progestogens that exhibit both progestational and antimineralocorticoidal activities. The influence of substituents in the 10- and 13-position of the steroidal framework on both properties was investigated. It was found that only compound 12, carrying methyl groups at the 10- and 13-positions, possesses high progestational and antimineralocorticoidal activity.     

Increases in oxygen consumption without cerebral blood volume change during visual stimulation under hypotension condition.

The magnitude of the blood oxygenation level-dependent (BOLD) signal depends on cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen (CMRO2). Thus, it is difficult to separate CMRO2 changes from CBF and CBV changes. To detect the BOLD signal changes induced only by CMRO2 responses without significant evoked CBF and CBV changes, BOLD and CBV functional magnetic resonance imaging (fMRI) responses to visual stimulation were measured under normal and hypotension conditions in isoflurane-anesthetized cats at 4.7 T. When the mean arterial blood pressure (MABP) decreased from 89+/-10 to 50+/-1 mm Hg (mean+/-standard deviation, n=5) by infusion of vasodilator sodium nitroprusside, baseline CBV in the visual cortex increased by 28.4%+/-8.3%. The neural activity-evoked CBV increase in the visual cortex was 10.8%+/-3.9% at normal MABP, but was negligible at hypotension. Positive BOLD changes of +1.8%+/-0.5% (gradient echo time=25 ms) at normal MABP condition became prolonged negative changes of -1.2%+/-0.3% at hypotension. The negative BOLD response at hypotension starts approximately 1 sec earlier than positive BOLD response, but similar to CBV change at normal MABP condition. Our finding shows that the negative BOLD signals in an absence of CBV changes are indicative of an increase in CMRO2. The vasodilator-induced hypotension model simplifies the physiological source of the BOLD fMRI signals, providing an insight into spatial and temporal CMRO2 changes.     

New strategies for therapy of breast cancer

New strategies for therapy of breast cancer     

Appearance of numerous lobulated fibers after a protracted course of 18 years in a case of dermatomyositis]

A woman aged 47 first noticed weakness in her proximal muscles of all four limbs at the age of 29. After the initial investigation at our hospital, she was diagnosed as having dermatomyositis associated with primary biliary cirrhosis. In the following 18 years, she was kept on steroids. Although she responded to this treatment, weakness progressed slowly necessitating re-investigation including a second muscle biopsy. It was remarkable that in her first muscle biopsy, no lobulated fiber had been, while they were numerous in the second one. As a result of these studies, possibilities of limb-girdle muscle dystrophy (LGMD) and other myopathies remained but were ultimately ruled out after immunohistochemical/and genetic studies, and the original diagnosis was confirmed. Her weakness responded to an increased dose of steroids. Lobulated fibers were originally described in LGMD, and were reported also in the facioscapulohumeral muscular dytrophy and other hereditary myopathies. They have been rarely described in the inflammatory myopathies. Based on the observation of the present case, we concluded that lobulated fibers have little disease specificity and can newly appear in the course of any chronic myopathies including acquired myopathies like dermatomyositis.     

Effect of clarithromycin on endogenous glucocorticoid levels in mice

The efficacy of erythromycin (EM) and clarithromycin (CAM) is well documented for the management of chronic inflammatory respiratory tract disease. However, the precise mechanism of action of these drugs is still controversial. We previously reported that EM increased serum glucocorticoid (GC) levels and suggested that this increase may be a mechanism of action of the drug. To investigate whether other macrolides had similar activity, we studied the effect of a new macrolide, CAM, on serum GC levels in mice. Intraperitoneal injections of CAM increased the serum GC levels in a dose-dependent manner, with the increase completely suppressed by pretreatment with dexamethasone. These results suggest that CAM increases serum GC levels through activation of the hypothalamo-pituitary adrenocortical axis, and that the antiinflammatory activity of CAM appears to exert its influence via an increase in serum GC levels.     

Analysis of multiple primary cancers in patients with urologic cancer

Background The study of the clinical features of multiple primary cancers (MPC) may provide insight into the pathogenesis of specific cancers, as well as the issue of treatment-related induction of second tumors. Methods Between 1972 and 1995, 94 of 765 patients with urologic cancer treated at our hospital had MPC. We retrospectively analyzed the clinical features of these patients, and compared them with those of the 671 patients with single primary cancers (SPC). Results The frequency of MPC among all 765 patients was 12.3%. The average age at diagnosis of urologic cancer in the male patients was significantly higher in the MPC group than in the SPC group. In the MPC group, the organs most commonly involved were the bladder and prostate (urologic cancers), and the stomach and lung (nonurologic cancers). Adenocarcinoma was the most common tumor in the MPC group. The interval between the first and second cancer diagnoses was significantly longer in female patients with MPC than in male patients. No significant difference between the MPC and SPC groups was observed in the distribution of ABO blood groups or in the frequency of history of tobacco or alcohol use. Four MPC patients had second cancers considered to have been induced by the treatment for the first cancer. The prognoses were significantly poorer for the patients with MPC. The rate of death due to urologic cancer was much lower in the patients with MPC than in those with SPC. Conclusions We found that more than 10% of the 765 patients with urologic cancer whose cases we reviewed had another primary cancer. Because the number of cases of MPC is increasing, it is important to be aware of the possibility of the development of MPC and to therefore carefully follow up cancer patients.     

Angiotensin II type 1 receptor antagonist and angiotensin-converting enzyme inhibitor altered the activation of Cu/Zn-containing superoxide dismutase in the heart of stroke-prone spontaneously hypertensive rats.

Although angiotensin II type 1 (AT1) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors are known to reduce both reactive oxygen species (ROS) generated by activated NAD(P)H oxidase and vascular remodeling in hypertension, the effects of AT1 receptor antagonists or ACE inhibitors on ROS-scavenging enzymes remain unclear. We hypothesized that AT1 receptor antagonists or ACE inhibitors may modulate vascular remodeling via superoxide dismutase (SOD) in hypertension. Male stroke-prone spontaneously hypertensive rats (SHRSP) were treated for 6 weeks with a vehicle, an AT1 receptor antagonist (E4177; 30 mg/kg/day), or an ACE inhibitor (cilazapril; 10 mg/kg/day). We evaluated protein expression using immunoblots, determined SOD activities with a spectrophotometric assay, and measured NAD(P)H oxidase activity by a luminescence assay. The two drugs showed equipotent effects on blood pressure, left ventricular hypertrophy and fibrosis, and endothelial NO synthase in the SHRSP hearts. The wall-to-lumen ratio of the intramyocardial arteries and the NAD(P)H oxidase essential subunit p22(phox) and its activity were significantly reduced, whereas Cu/Zu-containing SOD (Cu/ZnSOD) expression and activity were significantly increased in the SHRSP hearts. Furthermore, E4177 reduced vascular remodeling more than did cilazapril not only by reducing p22(phox) expression and NAD(P)H oxidase activity but also by upregulating the Cu/ ZnSOD expression and its activity in the SHRSP hearts. Thus, both the AT1 receptor antagonist and the ACE inhibitor inhibited vascular remodeling and reduced ROS in SHRSP via not only a reduction in NAD(P)H oxidase but also an upregulation of Cu/ZnSOD.     

A case of spontaneous dissection of the cervical carotid artery with pseudoaneurysm]

We experienced the case of a dissecting carotid artery presenting with a pulsatile neck mass. This 60-year-old man was admitted to our department due to a progressive, painful left neck mass. The lesion was diagnosed as a dissecting left internal carotid artery with the subsequent formation of a giant pseudoaneurysm. First, the patient underwent an endovascular treatment using self-expandable stent and Guglielmi detachable coils (GDCs). However, four months after the treatment, recurrence of the pseudoaneurysm happened to him, and he was readmitted to our department. Angiographies revealed an enlargement of the pseudoaneurysm. Then, proximal occlusion of the left internal carotid artery was performed using a balloon and GDCs. Ten months after the second endovascular treatment, since symptoms of the central retinal artery embolism and progression of the mass effect occurred, surgical treatment with trapping and resection of the pseudoaneurysm was performed. We investigated pathologically the surgical specimen and could observe a partial thrombosed wall of the pseudoaneurysm. The multiple neovascular channels in the intima and media layers of the aneurysmal wall could be found, and the vasa vasorum in the adventitia was also noted. We thus suggest that mechanism of the enlargement of the pseudoaneurysm may be due to the retrograde neovascular supplies from the vasa vasorum. As a consequence, repeated bleeding and thrombosis in the dissecting arterial wall may result in the formation of partial thrombosed giant aneurysms.     

Prognostic significance of laminin in adenocarcinoma of the lung

The distribution of laminin in tumor-associated basement membrane was immunohistochemically investigated in 115 cases of adenocarcinoma of the lung. The distribution of laminin was classified into continuous and discontinuous staining patterns. The incidence of the discontinuous pattern was less in early-stage disease than that in advanced stages (P less than 0.01). In patients with stage I, the incidence of discontinuous patterns was greater in short-term survivors than in long-term survivors (P less than 0.05). By contrast, in patients with stage III, the discontinuous pattern of laminin was frequently seen in both long-term survivors and short-term survivors, with no difference between the two groups. These data suggest that the discontinuous pattern of laminin in tumor-associated basement membrane reflects the spread and dissemination of tumor, hence a close relationship to the prognosis.