Surgical management in rerupture of internal carotid aneurysm after recanalization treated-coil: a case report

Introduction: Little is known about incidence, anatomical and clinical characteristics and results of endovascular treatment of the internal carotid artery (ICA) aneurysms. This type of the aneurysms can be approached by surgical with low morbidity and mortality. Clinical presentation: a 48-year-old woman submitted an endovascular embolization treatment in 2005, and in 2009 presents a new bleeding. The angiography shows that the same aneurysm was ruptured and a surgical repair was proposed. The surgical management shows detachable coils in the brain parenchyma. Conclusion: Some endovascular surgeons preferred the less invasive procedure (endovascular treatment) for intracranial aneurysms, but the surgical repair still remains the best choice for definitive treatment for intracranial aneurysms.

Discovery and functional characterization of a novel small molecule inhibitor of the intracellular phosphatase, SHIP2.

BACKGROUND AND PURPOSE: The lipid phosphatase known as SH2 domain-containing inositol 5'-phosphatase 2 (SHIP2) plays an important role in the regulation of the intracellular insulin signalling pathway. Recent studies have suggested that inhibition of SHIP2 could produce significant benefits in treatment of type 2 diabetes. However, there were no small molecule SHIP2 inhibitors and we, therefore, aimed to identify this type of compound. EXPERIMENTAL APPROACH: The phosphatase assay with malachite green was used for high-throughput screening. The pharmacological profiles of suitable compounds were further characterized in phosphatase assays, cellular assays and oral administration in normal and diabetic (db/db) mice. KEY RESULTS: During high-throughput screening, AS1949490 was identified as a potent SHIP2 inhibitor (IC(50)= 0.62 microM for SHIP2). This compound was also selective for SHIP2 relative to other intracellular phosphatases. In L6 myotubes, AS1949490 increased the phosphorylation of Akt, glucose consumption and glucose uptake. In FAO hepatocytes, AS1949490 suppressed gluconeogenesis. Acute administration of AS1949490 inhibited the expression of gluconeogenic genes in the livers of normal mice. Chronic treatment of diabetic db/db mice with AS1949490 significantly lowered the plasma glucose level and improved glucose intolerance. These in vivo effects were based in part on the activation of intracellular insulin signalling pathways in the liver. CONCLUSIONS AND IMPLICATIONS: This is the first report of a small molecule inhibitor of SHIP2. This compound will help to elucidate the physiological functions of SHIP2 and its involvement in various diseases, such as type 2 diabetes.

Efficacy and safety of PTCA using brachial approach and low-dose heparin.

Percutaneous transluminal coronary angioplasty (PTCA) is routinely performed using the femoral approach. However, recent reports suggest the usefulness of the brachial approaches for patients for whom the femoral approach is impossible due to peripheral vessel disease or to shortened postoperative rest times. However, some reports have revealed that the incidence of vascular complications undergoing brachial-approach PTCA may be higher than those with the femoral approach, possibly due to relatively higher dose of heparin. Accordingly, in this study we evaluated the efficacy and safety of PTCA using the brachial approach and low-dose heparin, hypothesizing that lowering the heparin dose might result in reduced vascular complications. The study population of patients admitted for angina pectoris consisted of 217 subjects (221 lesions) who underwent brachial-approach PTCA and 102 subjects (115 lesions) who underwent PTCA via the femoral approach. Both groups were monitored for complications. There were no significant differences in patient or lesion characteristics between the groups. Incidence of vascular complications tended to be lower in the brachial group than in the femoral group (1.8% vs. 3.5%), although the difference did not reach statistical significance. Use of anodynes was also significantly lower in the brachial group (3.6% vs. 33%). PTCA from the brachial approach with low-dose heparin is as safe and effective a strategy as compared with the femoral approach with standard dose of heparin.

Effects of YM471, a nonpeptide AVP V(1A) and V(2) receptor antagonist, on human AVP receptor subtypes expressed in CHO cells and oxytocin receptors in human uterine smooth muscle cells.

YM471, (Z)-4'-[4,4-difluoro-5-[2-(4-dimethylaminopiperidino)-2-oxoethylidene]-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl]-2-phenylbenzanilide monohydrochloride, is a newly synthesized potent vasopressin (AVP) receptor antagonist. Its effects on binding to and signal transduction by cloned human AVP receptors (V(1A), V(1B) and V(2)) stably expressed in Chinese hamster ovary (CHO) cells, and oxytocin receptors in human uterine smooth muscle cells (USMC) were studied. YM471 potently inhibited specific [(3)H]-AVP binding to V(1A) and V(2) receptors with K(i) values of 0.62 nM and 1.19 nM, respectively. In contrast, YM471 exhibited much lower affinity for V(1B) and oxytocin receptors with K(i) values of 16.4 microM and 31.6 nM, respectively. In CHO cells expressing V(1A) receptors, YM471 potently inhibited AVP-induced intracellular Ca(2+) concentration ([Ca(2+)](i)) increase, exhibiting an IC(50) value of 0.56 nM. However, in human USMC expressing oxytocin receptors, YM471 exhibited much lower potency in inhibiting oxytocin-induced [Ca(2+)](i) increase (IC(50)=193 nM), and did not affect AVP-induced [Ca(2+)](i) increase in CHO cells expressing V(1B) receptors. Furthermore, in CHO cells expressing V(2) receptors, YM471 potently inhibited the production of cyclic AMP stimulated by AVP with an IC(50) value of 1.88 nM. In all assays, YM471 showed no agonistic activity. These results demonstrate that YM471 is a potent, nonpeptide human V(1A) and V(2) receptor antagonist which will be a valuable tool in defining the physiologic and pharmacologic actions of AVP.

Vasopressin increases vascular endothelial growth factor secretion from human vascular smooth muscle cells.

Vascular endothelial growth factor (VEGF) is a potent and specific mitogen of vascular endothelial cells which promotes neovascularization in vitro. To determine whether vasopressin induces VEGF secretion in human vascular smooth muscle cells, we performed enzyme-linked immunosorbent assays. Vasopressin potently induced a time-dependent and concentration-dependent (maximal, 10(-7) M) increase in VEGF secretion by human vascular smooth muscle cells that was maximal after 24 h. Furthermore, vasopressin also concentration-dependently caused mitogenic effect, as reflected by total protein content of cells per culture well. These vasopressin-induced VEGF secretion increase and mitogenic effect of these cells were potently inhibited by vasopressin V1A receptor antagonists, confirming this is a vasopressin V1A receptor-mediated event. These results indicate that vasopressin increases VEGF secretion in human vascular smooth muscle cells, the magnitude of VEGF secretion being temporally related to the mitogenic effect of vascular smooth muscle cells and the potency of the growth-promoting stimulus. Vasopressin-induced VEGF secretion by proliferating vascular smooth muscle cells could act as a paracrine hormone to powerfully influence the permeability and growth of the overlying vascular endothelium, vasopressin play a more fundamental role in the regulation of vascular function than has previously been recognized.

[Pharmacology of conivaptan hydrochloride (YM087), a novel vasopressin V1A/V2 receptor antagonist].

Pharmacology of conivaptan hydrochloride (YM087) was investigated in in vitro and in vivo studies. In radioligand binding study, YM087 showed high affinity for both V1A and V2 receptors in animal and human species. Affinity of YM087 for V1A and V2 receptors was comparable to that of vasopressin (AVP). In functional antagonistic activity study, YM087 concentration-dependently inhibited AVP-induced intracellular Ca2+ elevation via human V1A receptors and AVP-stimulated cAMP accumulation via human V2 receptors. Intravenous administration of YM087 dose-dependently inhibited AVP-induced pressor responses and produced a dose-dependent aquaresis in rats and dogs. Oral administration of YM087 showed a potent and long-lasting antagonistic activity on V1A and V2 receptors. YM087 was effective in dogs with heart failure and in heart failure rats with hyponatremia and edema. These results reveal that YM087 is the first orally active V1A/V2 receptor antagonist and suggest that YM087 may be useful in the treatment of congestive heart failure and hyponatremia.

Pharmacological characterization of YM087, a potent, nonpeptide human vasopressin V1A and V2 receptor antagonist.

The effects of YM087 (4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d] [1]benzazepin-6-yl)-carbonyl]-2-phenylbenzanilide monohydrochloride), a novel nonpeptide vasopressin (AVP) receptor antagonist, on [3H]AVP binding to human AVP receptors (V1A, V1B and V2) cloned and transiently expressed in COS-1 cells generated from monkey renal tissue were studied. Scatchard analysis of saturation isotherms for the specific binding of [3H]AVP to membranes, prepared from COS-1 cells transfected with human V1A, V1B and V2 receptors, yielded an apparent equilibrium dissociation constant (Kd) of 0.67 nM, 0.28 nM and 2.14 nM and a maximum receptor density (Bmax) of 2180 fmol/mg protein, 369 fmol/mg protein and 2660 fmol/mg protein, respectively. YM087 showed high affinity for AVP V1A and V2 receptors with Ki values of 6.3 and 1.1 nM, respectively, but had no effect on [3H]AVP binding to AVP V1B receptors. In COS-1 cells expressing either AVP V1A or V1B receptors, AVP caused a concentration-dependent increase in intracellular Ca2+ concentration ([Ca2+]i). YM087 inhibited the AVP-induced increase in [Ca2+]i in COS-1 cells expressing AVP V1A receptors in a concentration-dependent manner with an IC50 value of 14.3 nM, but did not influence this increase in AVP V1B-receptor expressing cells. In contrast, stimulation of COS-1 cells expressing AVP V2 receptors resulted in an accumulation of cAMP. YM087 inhibited AVP-induced cAMP production in COS-1 cells expressing AVP V2 receptors in a concentration-dependent manner with an IC50 value of 1.95 nM. In all assays used, YM087 was devoid of any agonistic activity. These results suggest that YM087 is a potent nonpeptide dual human AVP V1A and V2 receptor antagonist, and that YM087 will be a powerful tool in investigation of the physiological and pathophysiological roles of AVP.

Pharmacological characterization of the human vasopressin receptor subtypes stably expressed in Chinese hamster ovary cells.

Three subtypes of human (h) arginine vasopressin (AVP) receptors, hV1A, hV1B and hV2, were stably expressed in Chinese hamster ovary (CHO) cells and characterized by [3H]-AVP binding studies. In addition, the coupling of the expressed receptor protein to a variety of signal transduction pathways was investigated. Scatchard analysis of saturation isotherms for the specific binding of [3H]-AVP to membranes, prepared from CHO cells transfected with hV1A, hV1B and hV2 receptors, yielded an apparent equilibrium dissociation constant (Kd) of 0.39, 0.25 and 1.21 nM and a maximum receptor density (Bmax) of 1580 fmol mg(-1) protein, 5230 fmol mg(-1) protein and 7020 fmol mg(-1) protein, respectively. Hill coefficients did not differ significantly from unity, suggesting binding to homogenous, non-interacting receptor populations. Pharmacological characterization of the transfected human AVP receptors was undertaken by measuring the relative ability of nonpeptide AVP receptor antagonists, YM087, OPC-21268, OPC-31260, SR 49059 and SR 121463A, to inhibit binding of [3H]-AVP. At hV1A receptors, the relative order of potency was SR49059>YM087>OPC-31260>SR 121463A> >OPC-21268 and at hV2 receptors, YM087=SR 121463A>OPC-31260>SR 49059> >OPC-21268. In contrast, the relative order of potency, at hV1B receptors, was SR 49059> >SR 121463A=YM087=OPC-31260=OPC-21268. In CHO cells expressing either hV1A or hV1B receptors, AVP caused a concentration-dependent increase in intracellular Ca2+ concentration ([Ca2+]i) with an EC50 value of 1.13 nM and 0.90 nM, respectively. In contrast, stimulation of CHO cells expressing hV2 receptors resulted in an accumulation of cyclic AMP with an EC50 value of 2.22 nM. The potency order of antagonists in inhibiting AVP-induced [Ca2+]i or cyclic AMP response was similar to that observed in radioligand binding assays. In conclusion, we have characterized the pharmacology of human cloned V1A, V1B and V2 receptors and used these to determine the affinity, selectivity and potency of nonpeptide AVP receptor antagonists. Thus they may prove to be a valuable tool in further examination of the physiological and pathophysiological roles of AVP.

Pharmacological profile of YM087, a novel potent nonpeptide vasopressin V1A and V2 receptor antagonist, in vitro and in vivo.

The biochemical and pharmacological profile of YM087, 4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin- 6-yl)-carbonyl]-2-phenylbenzanilide monohydrochloride, a newly synthesized nonpeptide vasopressin (AVP) antagonist, was investigated in several in vitro and in vivo studies. YM087 showed high affinity for V1A receptors from rat liver and V2 receptors from rat kidney with Ki values of 0.48 and 3.04 nM, respectively. YM087 also inhibited [3H]oxytocin (OT) binding to rat uterus (OT receptors) plasma membranes with a Ki value of 44.4 nM, and at 100 microM did not affect the binding of [3H]AVP to anterior pituitary (V1B receptors) plasma membranes, which indicated that it had less affinity for these OT and V1B receptors. YM087 had no effect on cytosolic free calcium concentration ([Ca++]i) itself, but suppressed AVP-induced increase in [Ca++]i of cultured vascular smooth muscle cells at the same concentrations as the binding affinities. Furthermore, YM087 potently blocked AVP-induced cAMP production of cultured renal epithelium cells concentration dependently and had no agonistic activities. In in vivo studies, intravenous administration of YM087 inhibited the pressor response to exogenous AVP in pithed rats and produced an aquaretic effect in dehydrated conscious rats in a dose-dependent manner. These results demonstrate that YM087 is a potent and nonpeptide dual AVP V1A and V2 receptors antagonist and can be used in future studies to help clarify the physiological and pathophysiological roles of AVP.

1-desamino-8-D-arginine vasopressin (DDAVP) as an agonist on V1b vasopressin receptor.

1-desamino-8-D-arginine vasopressin (DDAVP) is considered a standard vasopressin V2 receptor-selective agonist with a potent antidiuretic effect through V2 receptor without the induction of vasoconstriction through V1a receptor. Furthermore, DDAVP was reported to act as an agonist on non-V1a, non-V2 receptor to cause the accumulation of intracellular Ca2+ in several tissues. However, the agonistic activity of DDAVP against the other vasopressin receptor, V1b (or V3), which can accumulate intracellular Ca2+ and which we recently cloned, has not been clarified. Hence, we compared the characteristics of DDAVP on V1b receptor with those on the other vasopressin receptors. In binding experiments, DDAVP more strongly inhibited [3H]arginine vasopressin binding to V1b than to V2 receptor (Ki: 5.84 nM vs 65.9 nM). In addition, DDAVP dose-dependently stimulated inositol turnover in human V1b receptor-expressing COS-1 cells. DDAVP acted as a full agonist on human V1b receptor (EC50: 11.4 nM) as well as on human V2 receptor (EC50: 23.9 nM). However, DDAVP behaved as a partial agonist toward rat V1b receptor (intrinsic activity: 0.7, EC50: 43.5 nM), while there was no significant difference in the agonistic properties of arginine vasopressin on human and rat V1b receptor. In conclusion, DDAVP acts as an agonist on V1b receptor, as it does on V2 receptor. These findings will allow us to better understand the physiological role of V1b receptor in pancreatic beta cells and in the renal inner medullary collecting duct, and help us to identify as yet unknown vasopressin receptors through which DDAVP cause the accumulation of intracellular Ca2+ in other tissues.

[Intraocular neovascularization].

To investigate the mechanism of intraocular neovascularization, we studied how vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) are expressed in the ocular tissues under hypoxic conditions. Prior to proliferation of vascular endothelial cells resulting in neovascularization, the retinal tissues such as pericytes, retinal glial cells, ganglion cells, and ciliary epithelium react directly to hypoxia expressing VEGF and/or IL-8 and stimulate endothelial cell proliferation in a paracrine manner. We demonstrated that transcription factor activator protein-1 (AP-1) is activated for expression of VEGF messenger ribonuculeic acid (mRNA) and in a similar way nuclear factor kappa B (NF-kappa B) is activated for expression of IL-8 mRNA. However, hypoxia-induced expression of VEGF and/ or IL-8 is only one aspect of the complicated processes in intraocular neovascularization. We hope that further detailed analysis of the mechanism will make it possible to inhibit and treat clinically intraocular neovascularization in the near future.

Molecular cloning and characterization of rat V1b vasopressin receptor: evidence for its expression in extra-pituitary tissues.

Arginine vasopressin (AVP) modulates the secretion of ACTH through vasopressin receptor subtype V1b in the pituitary. We recently cloned human V1b, but several inconsistencies were found between the characteristics of this cloned receptor and those of rat pituitary membrane shown by previous workers. To clarify this issue, we report here the molecular cloning and functional expression of the cDNA encoding V1b in rat pituitary. This receptor encodes 425 amino acid protein having the highest identity with the human V1b (81%). Expression of this receptor in COS-1 cells showed pharmacological characteristics of V1b consistent with those of rat pituitary membrane. Northern blot and RT-PCR analyses revealed that mRNA of this receptor was expressed not only in anterior pituitary, but also in other tissues. This finding raises the possibility that V1b may play a role in regulating cell functions of these tissues.

Extensive specifically localized myocardial calcium deposition in a hemodialysis patient.

A 51-year-old female who was hospitalized for evaluation of frequent episodes of hypotension, died unexpectedly. At autopsy, there were many fine, white granular deposits in the myocardium, which were more prominent in the subepicardium of the left ventricle than in the subendocardium. Pathologic calcification is sometimes seen in chronic hemodialysis patients and in some organs the sites of calcium deposition are quite specific. There have been few reports concerning the pattern of calcium deposition in the myocardium and, to our knowledge, the reason for this characteristic distribution is unknown. However it may relate to hydrogen ion concentration in the myocardium.

Circulating immunoreactive endothelin in ischemic heart disease.

Circulating immunoreactive endothelin (ir-ET) was measured in nine patients with acute myocardial infarction (AMI), 10 patients with stable angina pectoris (SAP), and 25 normal control subjects. In patients with AMI, the plasma ir-ET level was elevated in the acute phase and was highest on the day of onset (AMI: 3.8 +/- 1.7 pg/ml, normal control value: 0.5 +/- 0.2 pg/ml). The plasma ir-ET level showed a positive correlation with the wall motion abnormality index (rs = 0.56, p less than 0.01), thrombin-antithrombin III complex (rs = 0.55, p less than 0.01), and beta thromboglobulin (rs = 0.39, p less than 0.05). An especially high plasma ir-ET level was detected in patients in whom the Killip subset was IV. The plasma ir-ET level was not increased in patients with SAP (0.8 +/- 0.3 pg/ml). The plasma ir-ET level is increased in the acute phase of AMI. A pathophysiologic state characterized by cardiac dysfunction, an activated coagulation system, and platelet hyperactivity may be associated with this increase in plasma ir-ET.

[Malignant thymoma detected by thallium-201 myocardial scintigraphy].

We present two cases of malignant thymoma which showed a remarkable accumulation of thallium-201 chloride on myocardial scintigraphy. A 69 year-old man underwent stress 201Tl scintigraphy to evaluate myocardial ischemia and abnormal accumulation of thallium activity was observed in the anterior mediastinum by chance. It was more clearly visualized on delayed image. Moreover, abnormal uptake of 67Ga citrate was also observed in the same region. In another 68 year-old woman, there was high uptake on 201Tl scintigraphy, but no abnormal uptake using 67Ga. The diagnosis of malignant thymoma was confirmed by operation in each patient. These two cases had no abnormality in the mediastinum on the chest X-ray film and one of them had no uptake of 67Ga, 201Tl scintigraphy was more useful to detect malignant thymoma.