The present invention relates to compositions and methods for improving outcomes in vascular interventional procedures. In particular, the present invention relates to compositions and methods for improving outcomes in vascular interventional procedures using an anti-no-reflow guide wire that attenuates the “no-reflow” phenomenon that is associated with negative outcomes.

Atherosclerotic vascular disease remains a major cause of morbidity and mortality in spite of numerous advances in pharmacological modalities to modify associated risk factors. Atherosclerotic involvement of the myocardium, brain and kidneys is responsible for the majority of adverse affects of the disorder. Coronary artery disease remains the leading cause of death in the Westernized world. Approximately 1.5 million Americans per year suffer a myocardial infarction with an annual death toll of 400,000 (see e.g., Thom, T., et al., Circulation 113: 85 (2006)). Cerebrovascular disease is the third leading cause of death with stenosis of the internal carotid artery accounting for 20% of strokes and transient ischemic attacks (TIAs) (see e.g., Heart Disease and Stroke Statistics—2006 Update Dallas, Tx; AHA, (2006); Roffie, M., and Yadav, J. S., Circulation 114: el (2006)). Renal artery stenosis due to atherosclerosis is relatively common (6-8%) in patients >65 years of age and often results in progressive renal failure, worsening hypertension and precipitation of congestive heart failure and unstable angina (see e.g., Hansen, K. J., et al., J. Vasc. Surg. 36: 443 (2002); Pasternak, R. C., et al., Circulation 109: 2605 (2004)).
The rapid evolution of percutaneous balloon angioplasty (PTA) followed by the development of stent technology has resulted in increased utilization of vascular interventional procedures in the treatment of atherosclerotic-induced stenosis of the major blood vessels supplying the myocardium, brain, kidneys and peripheral vessels. Coronary artery stenting has surpassed coronary artery bypass surgery (CABG) as a treatment of choice to revascularize patients with a single or double vessel coronary artery disease with more than 700,000 procedures performed in the United States each year. Furthermore, stenting procedures are frequently performed in CABG patients who have degenerative and stenotic saphenous vein grafts (SVG) secondary to atherosclerosis.
In reference to the heart, patients with atherosclerosis may present with stable angina, acute coronary syndromes (ACS), namely unstable angina and non-ST segment elevation myocardial infarction (NSTEMI), or acute ST segment elevation infarction (STEMI). These syndromes occur in the setting of an unstable ulcerative plaque associated with a variable thrombus burden. These conditions can be successfully treated in the majority of patients with stent implantation resulting in restoration of normal vessel caliber. However, the introduction of a guide wire, balloon, stent or embolic protection device (EPD) may compromise tissue blood flow through macro-embolization of thrombotic and atherosclerotic debris into the distal vessel (see e.g., Topol, E. J., and Yadav, J. S., Circulation 101: 570 (2000)). This has been shown to occur in 14% of STEMI patients treated with percutaneous coronary intervention (PCI) and is associated with larger infarct size, worse left ventricular function and higher mortality (see e.g., Henriques, J. P., et al., Eur. Heart J. 23: 1112 (2002)). Embolization with atheromatous debris is even more frequent during PCI of SVG's (˜80%) and results in increased mortality (see e.g., Trono, R., et al., Cleve. Clin. J. Med. 56:581 (1989)).
Vascular interventional procedures performed in the presence of an occlusive thrombus may also compromise tissue blood flow either through micro-embolization or via microvascular injury induced by the deterious effects of reperfusion (see e.g., Constantini, C. O., et al., J. Am. Coll. Cardiol. 44: 305 (2004); Kenner, M. D., et al., J. Am. Coll. Cardiol. 76: 861 (1995); van't H of A. W., et al., Circulation 97: 2302 (1998); Forman, M. B., et al., Cardiovascular Drug Reviews 24: 116 (2006)). The common occurrence of micro-embolization after interventional procedures has recently been appreciated by the frequent retrieval of atheroembolic material from EPDs. These particles consist of cellular and non-cellular elements with wide variations in size and volume (see e.g., Akbar O., et al., Am. Heart J. 152: 207 (2000)). Although the pathogenesis of reperfusion injury is complex and multi-factorial, the introduction of activated neutrophils and platelets associated with release of various vasoconstrictors produced from circulating cells and dysfunctional endothelial cells may contribute to a progressive decrease in flow during the peri-reperfusion period; defined as the "no-reflow" phenomenon (see e.g., Forman, M. B. et. al, Cardiovascular Drug Reviews 24: 116 (2006)). Impaired tissue perfusion occurs in 29-44% of reperfused patients, the highest incidence with occlusion of the left anterior descending coronary artery (50-80%), and correlates with infarct size, ventricular function and early and late mortality (see e.g., Bax, M., et al., J. Am. Coll. Cardiol. 43: 534 (2004); Ito, H., et al., Circulation 93: 1993 (1996); Deluca, G., et al., Circulation 109: 958 (2004); Wu, K. C., et al., Circulation 97: 765 (1998)). Furthermore, numerous studies have demonstrated that abnormal tissue perfusion, as assessed by myocardial blush grade (MBG), is an independent, multivariate predictor of both early and late mortality in STEMI undergoing thrombolysis or PCI. Abnormal MBG (0-1) results in a 7-fold increase in mortality which is maintained for up to 2 years (see e.g., Gibson, C. M. and Schömig, A., Circulation 109: 3096 (2004); Forman, M. B., and Jackson, E. K., Clin. Cardiol. 30: 583 (2007)). Abnormal tissue perfusion following PCI in patients with NSTEMI is also associated with higher risk of myocardial necrosis and death at 6 months and 1 year (see e.g., Wong, G. C., et al., Circulation 106: 202 (2002)). Therefore, the development of devices or pharmacologic strategies that preserve tissue perfusion by attenuating the no-reflow phenomenon has important clinical implications.
PCI results in myocardial cell necrosis in 22-44% of patients after an otherwise uncomplicated procedure irrespective if the procedure is elective for stable angina or emergent for ACS (see e.g., Ali, O. A., et al., Am. Heart J. 152: 207 (2006); Johansen, O., et al., Eur. Heart J. 19: 112 (1998)). Elevations of cardiac enzymes (for example creatine kinase-myocardial band (CK-MB) and Troponin I) significantly increase the risk of early and late mortality and myocardial infarction (see e.g., Cavallini, C., et al., Eur. Heart J. 26:1494 (2005); Antman, E. M., et al., N. Engl. J. Med. 335: 1342 (1996)). Furthermore increasing levels of cardiac enzymes are associated with parallel increases in mortality (see e.g., Antman, E. M., et al., N. Engl. J. Med. 335: 1342 (1996); Brener, S. J., et al., Eur. Heart J. 23: 869 (2002)). MRI studies have confirmed that mild increases in CK-MB after PCI are due to microinfarction secondary to embolic microvascular obstruction (see e.g., Ricciardi. M. J., et al., Circulation 103:2780 (2001)). PCI with stent deployment amplifies myonecrosis probably secondary to increased vascular trauma and release of vasoconstrictor mediators such as serotonin (see e.g., Lesoco, D., et al., Am J. Cardiol. 84:1317 (1999)). While preloading with a potent thienopyridine platelet inhibitor (600 mg of clopidogrel) reduced cell necrosis in a large study, 14% of patients continued to manifest evidence of micro-embolization (see e.g., Patti, G., et al., Circulation 111: 2099 (2005)). Therefore the common occurrence of embolization during routine interventional procedures provides further impetus to develop improved modalities to reduce this important complication.
In an attempt to reduce the incidence of macro- and micro-embolization after PCI, numerous pharmacological therapies and embolic and thrombectomy devices have been utilized in patients with STEMI. A potent glycoprotein IIa/IIIb inhibitor failed to reduce infarct size and improve tissue perfusion after PTA or primary stenting in STEMI patients (see e.g., Antoniucci, D., et al, J. Am. Coll. Cardiol. 42: 1879 (2003); Constantini, C. O., et al., J. Am. Coll. Cardiol. 44: 30 (2004)). In the EMERALD trial, the GuardWire distal balloon occlusive device did not improve tissue perfusion or decrease infarct size in 501 patients with STEMI undergoing PCI within 6 hours of symptoms (see e.g., Stone, G. W., et al., JAMA 293: 1063 (2005)). This occurred in spite of use of anti-platelet agents and removal of embolic debris in the majority of patients. The FilterWire system, which consists of a guide wire that incorporates a non-occluding polyurethane porous membrane filter in the shape of a wind sock, has been evaluated in two studies. In one study (hereinafter referred to as the "PROMISE study") no difference in infarct size or tissue perfusion assessed with flow velocity was observed in the FilterWire group in 200 patients with NSTEMI and STEMI (see e.g Gick M., et al., Circulation 112:1462 (2005)). Similar findings were observed in a second study (hereinafter referred to as the "DEDICATION study") where 676 patients with STEMI underwent PCI with and without distal protection. The filter wire system failed to improve ST segment resolution, regional ventricular function or major adverse cardiac events at 30 days (see Kelbaek, et al., J. Am. Coll. Cardiol. 51: 899 (2008).
A number of thrombectomy devices have also been utilized as an adjunct to PCI in STEMI. These include the X-Sizer system (consists of wire system with a helical shaped cutter and aspiration catheter), several aspiration devices (Diver, Export, Rescue catheter) and the angiojet rheolytic thrombectomy system in which high-velocity saline is directed back into the catheter. Eight trials have been conducted with the majority being small (see e.g., Brodie, B. R., J. Invasive Cardiol. 18: 24C (2006); Baim, D. S., J. Invasive Cardiol. 18: 28C (2006)). The two largest trials did not show improved tissue perfusion and one showed larger infarct size compared to control (see e.g., Kaltoft, A., et al., Circulation 114: 40 (2006); Ali, A., et al., J. Am. Coll. Cardiol. 48: 244 (2006)). These findings demonstrate that the current protective and embolic devices are not optimal in achieving complete thrombectomy or preventing distal embolization. Furthermore, they support the concept that other mechanisms, such as humoral factors and cytotoxic compounds, may also be playing an important role in microvascular damage after STEMI.
Prior to the introduction of PCI and stents, CABG was the most frequently utilized procedure to relieve myocardial ischemia in patients with coronary artery disease. However, 50-60% of SVG's develop severe significant atherosclerosis within ten years of surgery requiring catheter based intervention (see e.g., Bourasa, M. G., et al., Circulation 72: V71 (1985); Lau, G. T., et al., Semin. Vasc. Med. 4: 153 (2004)). The soft and friable nature of the lipid rich plaque in SVGs contributes to the frequent embolization of atherothrombolic material after PCI (see e.g. Popma, J. J., Cathet. Cardiovasc. Intervent. 57: 125 (2002); Webb, J., et al., J. Am. Coll. Cardiol. 34: 461 (1999); Safian, R. D., Prog. Cardiovasc. Dis. 44; 437 (2002)). Platelet clumping with subsequent activation and release of the potent vasoconstrictor serotonin may also reduce flow in the distal vascular bed. PCI of degenerated SVG's is associated with significant (˜20%) risk of major adverse clinical events (MACE), predominantly myocardial infarction and no-reflow (see e.g. Piana, R. N., et al., Circulation 89: 2514 (1994); de Feyter, P. J., et al., J. Am. Coll. Cardiol. 21: 1539 (1993)). A 3-fold elevation of CK-MB is associated with a 14% 30 day mortality compared with less than 1% without isoenzyme elevation (see e.g. Hong, et al., Circulation 100: 2400 (1999); Lefkovitz, J., et al., Circulation 92: 734 (1995)). Multi-variable predictors of MACE include the extent of graft disease (graft length disease and plaque volume), number of stents inserted and age of the patient (see e.g., Stone, G. W., et al., Circulation 108: 548 (2003)). The high peri-procedural complication rate has necessitated the use of adjunctive therapies to reduce the high adverse event rates. Administration of the IIb/IIIa platelet inhibitor (abciximab) and the thrombectomy catheter (X-sizer) failed to reduce MACE at thirty days (see e.g. Ellis, S. G., et al., J. Am. Coll. Cardiol. 32: 1619 (1998)). In contrast, the GuardWire, FilterWire and a proximal embolic protection system (Proxis) produced significant and equivalent reductions in peri-procedure complications at 30 days (see e.g., Stone, G. W., et al., Circulation 108: 548 (2003); Baim, D. S. et al., Circulation 105: 1285 (2003); Mauri, L., et al., J. Am. Coll. Cardiol. 50: 1442 (2007)). However, peri-procedural complications still occurred in ˜10% of patients with these devices emphasizing the need for complimentary devices and/or new pharmacologic interventions.
PCI (PTA, stents) may also compromise blood flow in the subacute and chronic phase following an uneventful procedure. Abnormal vasomotor responses are invariably present after PTA and life threatening vasospasm has been observed at variable times after stent implantation (see e.g., Fischell, T. A., et al., J. Clin. Invest. 86:575 (1990); Brott, B. C., et al., J. Invasive Cardiol. 18:584 (2006)). Drug eluting stents (DESs) are currently the most frequently deployed stent in the USA and consist of a metal stent, polymer and impregnated drug; either an antineoplastic agent, paclitaxel (Taxus) or antiproliferative agents such as sirolimus (Cypher) and zotarolimus (Endeavor). DESs are associated with a small but potentially lethal increase in sub-acute and chronic thrombosis when compared with bare metal stents (BMSs) (see e.g., Camenzind, E., et al., Circulation 115:1440 (2007)). DESs activate pro-coagulant factors and may diminish the ability to develop collateral vessels with stent thrombosis (see e.g., Salloum, J. et al., J. Intervent. Cardiol. 17:575 (2005); Meier, P., et al., J. Am. Coll. Cardiol. 40:21 (2007)). A recent study demonstrates long term adverse effects of DES on endothelial cell function. Vasodilatory responses to acetylcholine were significantly impaired in segments distal to both paclitaxel and sirolimus stents when compared to BMS or a reference non stented vessel 6 months after implantation (see e.g., Kim, J. W., et al., J. Am. Coll. Cardiol. Intv. 1:65 2008). The hypothesis that chronic endothelial dysfunction may result in recurrent ischemia and late stent thrombosis is supported by two studies. In the BASKET study utilizing Taxus stents, cardiac death and infarction at 6 to 18 months was approximately four times greater in the DES arm compared with BMSs (see e.g., Pfasterer, M., et al., J. Am. Coll. Cardiol. 48:2584 (2006)). Recently, a post hoc analysis of the RRISC Trial revealed a significant increase in mortality with Cypher stents implanted in SVGs after a median follow-up of 32 months (see e.g., Vermeersch, P. et al., J. Am. Coll. Cardiol. 50:261 (2007)). Pathological studies with DESs have invariably shown incomplete endothelialization on strut surfaces extending beyond 40 months after implantation with extensive fibrin deposition (see e.g., Joyner, M., et al., J. Am. Coll. Cardiol. 48:193 (2006)). Chronic inflammatory cells (lymphocytes, macrophages and eosinophils) in the intima and media are also present in late stent thrombosis. Release of numerous vasoconstrictors and platelet aggregatory substances by these cells may also contribute to late stent thrombosis. The histological changes observed have been attributed to either direct toxicity and/or delayed hypersensitivity reaction to the drug or polymer, or excessive barotraumas (see e.g., Togni, M., et al., J. Invasive Cardiol. 18:593 (2006)). Local delivery of high concentrations of the physiological nucleotide adenosine that rapidly accelerates endothelial healing, prevents thrombus formation, reduces inflammatory cell infiltration and promotes new vessel formation would have important clinical implications.
While newer DESs are currently undergoing safety and efficacy trials, it appears likely that they will be associated with comparable side effects to the two currently approved stents due to their similar structure and mode of action. In Europe, BMSs are being increasingly utilized in large vessels (>3 mm) and in non-diabetic patients. While late stent thrombosis is rare, restenosis remains a significant problem with BMSs with an incidence of 17 to 25% in non-diabetics and 23 to 33% in diabetics with vessels of 3 mm. Since adenosine is a potent inhibitor of vascular smooth muscle proliferation and extracellular matrix production, it may prove useful in preventing restenosis following BMS implantation.
Carotid revascularization utilizing surgically performed carotid endarterectomy (CEA) has been shown to reduce stroke rate compared with medical therapy in patients with significant (greater than 50%) atherosclerotic narrowing of the carotid bifurcation and internal carotid artery (see e.g. Halliday, A., et al., Lancet 363: 1491 (2004); North American Symptomatic Trial Collaborators, N. Engl. J. Med. 325: 445 (1991)). The rapid development of catheter based technology has resulted in the evaluation of carotid artery stenting (CAS) as an alternative therapy to CEA (see e.g., Roubin, G. S., et al., Circulation 113: 2021 (2006)). CAS has now been approved by the Center for Medicare and Medicaid for patients who are at high risk for CEA (see e.g., Yadav, J. S., J. Am. Coll. Cardiol. 47: 2397 (2006)). Peri-procedural neurological and cardiovascular events remain the main complication of both procedures. Clinically silent micro-embolization occurred in 92% of patients undergoing CEA utilizing transcranial Doppler studies (see e.g., Grant, M., et al., Br. J. Surg. 8: 1435 (1994)). Similarly, 29% of patients manifested silent embolic events after CAS utilizing MRI (see e.g., Jaeger, H., Am. J. Neuroradiol. 23: 200 (2002)). The introduction of EPDs, which are now considered the standard of care, have reduced (by 50%), but not eliminated, embolization of atheromatous debris into the cerebral circulation after stenting (see e.g., Wholey, M. H., and Al-Mubarek, N., Catheter Cardiovasc. Intervent. 60: 259 (2003)). CAS with EPD in high risk patients, in whom a non-surgical approach is preferred due to lower morbidity and mortality, results in approximately 6-12% incidence of major adverse cardiac and cerebral vascular events (see e.g., Safian, R. D., et al., J. Am. Coll. Cardiol. 47: 2384 (2006); Yadav, J. S., et al., N. Eng. J. Med. 351: 1493 (2004)). Low risk patients undergoing CAS with EPD manifest an event rate of 2-3% (see e.g., Zahn, R., et al., Eur. Heart J. 25: 1550 (2004); Kastrur, A., et al., Stroke 34: 813 (2003)). Complications remain high in the elderly (>80 years) with approximately 17.1% incidence of death or stroke at 30 days (see e.g., Hobson, R. W., et al., J. Vasc. Surg. 40: 1106 (2004)).
The reasons why EPDs are not fully protective are multifactorial. Atheromatous material may be dislodged from the aortic arch or common carotid artery during manipulation of the guide catheter and wire prior to the insertion of the EPD. The EPDs are bulky and may induce further embolization during deployment in calcified and tortuous vessels. While EPD devices are universally beneficially, the duration of the deployment significantly increase the risks of complications. For example, deployment of the Filter protection device greater than 20 minutes has been shown to double the risk of death and stroke compared with deployment times of less than 20 minutes (see e.g., Yadav, J. S., Circulation 47: 2397 (2006)). The device may also produce vascular damage (endothelial dysfunction and dissection) and result in incomplete capture or retrieval of debris. Finally, humoral factors released during deployment of the EPD and stent may result in vasospasm or hyperperfusion syndrome, the latter being responsible for 1.3% of intracranial hemorrhage in high risk patients (see e.g., Abou-Chebl, et al., J. Am. Coll. Cardiol. 43: 1596 (2004)).
Renal artery stenosis is a progressive disease associated with high morbidity and mortality and therefore mandates the use of aggressive treatment to improve prognosis (see e.g., Hansen, K. J., et al., J. Vasc. Surg. 36: 443 (2002); Pasternak, K. J. et al., Circulation 109: 2605 (2004)). Renal artery stenting (RAS) has emerged as the treatment of choice due to its excellent success rate and good long term patency (see e.g., Isles, C. G, et al., Q. J. M. 92: 159 (1999)). A major concern is the 20-30% deterioration of renal function after RAS, the highest incidence in patients with underlying renal dysfunction and in those undergoing stent placement compared to PTA (see e.g., Dorros, G., et al., Am. J. Cardiol. 75: 1051 (1995); Leertouwer, T. C., et al., Radiology 216: 7885 (2000); Guerrero, B., et al., Am. J. Cardiol. 90: 63H (2002)). While the etiology of renal dysfunction after RAS is multifactorial, athero-embolism plays an important role over the 3-8 weeks after the procedure (see e.g., Scolari, F., et al., Am. J. Kidney Dis. 36: 1089 (2000)). Most renal lesions involve extensive atheromatous disease of the aorta which amplifies the chance of plaque detachment during the interventional procedure through cholesterol crystal embolization. The high occurrence of embolization has recently been confirmed with EPD where atheromatous debris is captured in greater than 80% of cases (see e.g., Henry, M., et al., J. Endovasc. Ther. 8: 227 (2001)). Atheroembolism has also been shown to adversely affect survival. Since EPDs have only been used in a few small non-randomized series, their long-term effects on renal function and mortality are unknown (see e.g., Henry, et al., Catheter Cardiovasc. Interv. 60: 299 (2003); Hayspiel, K. D., et al., J. Vasc. Interv. Radiol. 16: 125 (2005)). Numerous limitations are present in deployment of EPDs in renal vessels compared with coronary and carotid vessels. Deployment may be difficult due to the sharp angulation of the renal artery from the aorta and its early bifurcation. Furthermore, incomplete capture of embolic debris is more likely in the renal vasculature due to the high incidence of cholesterol crystal embolizations which due to their small size are not captured by EPDs and by the frequent occurrence of branching of the renal vessels.
Vascular occlusive disease of the femoropopliteal system is a frequent cause of claudication and critical limb ischemia in patients with peripheral arterial disease. Percutaneous interventional procedures are frequently utilized in patients with peripheral vascular disease and are complicated by significant peripheral emboli in up to 5% of cases which may lead to serious complications such as amputation or emergency bypass surgery (see e.g., Lin, P. H., et al., J. Surg. Res. 103: 153 (2002); Uher, P., et al., J. Endovasc. Ther. 9: 67 (2002)). Embolization occurs more frequently in high risk patients (up to 37%) such as after thrombolytic therapy or with mechanical thrombectomy (see e.g., Rickard, M. J., et al., Cardiovasc. Surg. 5: 634 (1997)). Macroscopic debris was retrieved in all cases in a small series undergoing an interventional procedure for femoral occlusion (see e.g., Siablis, D., et al., Eur. J. Radiol. 55: 243 (2005)). This has resulted in the use of EPDs in a few high risk patients undergoing interventions (see e.g., Wholey, M. H., et al., Catheter Cardiovasc. Inter. 64:227 (2005)). The current role of EPDs in peripheral vascular disease remains to be determined. The limitations of these devices are likely to be comparable to interventions in other vascular beds. Additional disadvantages include loss of lesion location and potentiation of thrombus formation with occlusive balloon devices, incomplete sealing and excessive movement with subsequent vasospasm with filter devices and technical inability to place the device due to the small size of the femoropopliteal system (see e.g., Wholey, M., et al., Endovascular Today, June: 67 (2007)). These limitations support the need for further technical advances in this field.
Adenosine is an endogenous nucleoside that functions as a local hormone and is found in numerous tissues and organs throughout the body. Adenosine, through activation of four well characterized receptors (A1, A2A, A2B and A3), ameliorates many of the adverse processes activated during vascular interventional procedures and thereby exerts multiple protective effects. The protective effects of adenosine include: (a) preservation of microcirculatory flow by reversing the affects of numerous potent vasoconstrictors present in the atherosclerotic ischemic vessel through adenosine's powerful vasodilatory properties; (b) inhibition by adenosine of vascular thrombosis and embolization via adenosine's anti-platelet effects and its ability to restore the profibrinolytic activity of endothelial cells; (c) reduction by adenosine of the cytotoxic effects of free radicals and activated neutrophils; (d) restoration by adenosine of cellular calcium homoestasis; (e) promotion by adenosine of vessel repair (vasculogenesis) and acceleration of the development of new blood vessels (angiogenesis); (f) preservation of vascular patency of interventional site (PTC and/or stent) by limiting intimal hyperplasia via inhibition of vascular smooth muscle cell proliferation and extracellular matrix production (see e.g., Forman, M. B., et al., Cardiovasc Res. 27: 9 (1993); Forman, M. B., et al Cardiovasc. Drug Reviews 24: 116 (2006)). Thus adenosine would be expected to attenuate the no-reflow phenomenon via multiple mechanisms with reversal of vasoconstriction and anti-platelet activity being paramount. The latter is supported by the experimental observation that adenosine functions as an antithrombotic in the ischemic myocardium. Following low flow ischemia, endogenous adenosine inhibits the formation of thromboemboli formed by platelets and platelet-neutrophil aggregates via inhibition of P-selectin receptors on these cells (see e.g., Minamino, T., et al., J. Clin. Invest., 101: 1643 (1998)).
Two small studies have evaluated the effect of intracoronary adenosine on myocardial cell necrosis following non-urgent PCI in stable and unstable angina. Both an intracoronary infusion or bolus administered via the guide catheter prior to the procedure significantly attenuated the rise in creatine kinase-myocardial band (CK-MB) and Troponin 124 hours after PCI (see e.g., Lee. C-H., et al., Eur. Heart J. 28:19 (2007); Desmet, W. J., et al., Heart 88: 293 (2002)). The extremely short half plasma life (˜1-2 secs) of adenosine coupled with dilutional effects of ostial administration, likely diminished its vascular protective effects when the PCI was performed. Medicating the distal vascular bed before and throughout the procedure with concentrated amounts of the drug would optimize its vascular and cardioprotective effects.
Large doses of intravenous adenosine have been shown to have cardioprotective affects with reperfusion therapies in STEMI (see e.g., Maffey, K. W., et al., J. Am. Coll. Cardiol. 34: 1711 (1999); Ross, A. M., et al., J. Am. Coll. Cardiol. 45: 1775 (2005); Kloner, R. A., et al., Eur. Heart J. 27: 2400 (2006)). However, due to the rapid clearance of the drug, large doses are required to obtain an adequate blood level at the target organ, and results in significant side effects. Therefore, there is a need in the art to provide methods and compositions using adenosine-based technology for attenuating the no-reflow phenomenon and reducing or preventing vascular and organ damage during vascular interventions on various organ systems.

Anti-no-reflow guide wire for vascular interventional procedures


A method for controlling interference between base stations in a radio communication system in which an indirect interface for indirectly connecting the base stations exists and an direct interface for directly connecting the base stations does not exist, the method includes: converting a first interference control message used in the direct interface into a format of a protocol of the indirect interface to thereby generate a second interference control message; and transmitting the second interference control message through the indirect interface.

In next generation multimedia radio communication systems which have been actively studied in recent years, It is required that a variety of information (e.g., video and radio data) beyond the early voice-oriented services is processed at a higher data transfer rate.
Accordingly, orthogonal frequency division multiplexing (OFDM) capable of having a high data transfer rate has attracted attention. The OFDM is a multi-carrier modulation scheme in which data transmission is achieved by dividing a frequency band into a plurality of orthogonal subcarriers. Orthogonal frequency division multiple access (OFDMA) provides multi-user multiplexing by combining the OFDM with frequency division multiple access (FDMA), time division multiple access (TDMA) or code division multiple access (CDMA).
A radio communication system includes a base station (BS) and at least one user equipment (UE). The UE may be fixed or mobile and can also be referred to as a mobile station (MS), a user terminal (UT), a subscriber station (SS), a wireless device, and the like.
The base station commonly refers to a fixed station which communicates with the user equipment, and it can also be referred to as a Node-B, a base transceiver system (BTS), an access point (AP), and the like. Hereinafter, an uplink (UL) refers to a transmission from the user equipment to the base station, and a downlink (DL) refers to a transmission from the base station to the user equipment.
Meanwhile, as the use of privately owned base stations or private-purpose base stations increases in addition to the use of existing service provider-owned base stations or public-purpose base stations, femtocell base stations have been used.
A femtocell is a service area of an ultra-small communication base station (a femtocell base station) used indoors, for example, in private homes or offices. The femtocell has advantages in that it can provide a fixed mobile convergence (FMC) service at a low cost by connecting the mobile terminal to the Internet, and can efficiently provide a variety of FMC services by expanding an indoor coverage and improving a call quality.
The demand for femtocell standardization was proposed as a standardization item in the 3rd Generation Partnership Project (3GPP) in the early 2007, and femtocell standardization activities have been carried out as a main issue in the 3GPP2 since June 2007. The femtocell is referred to as a home node B (HNB) in the 3GPP. TSG-RAN WG4 (Technical Specification Group-Radio Access Network Working Group 4) has led the discussion about the standardizations of 3G HNB based on wideband CDMA (WCDMA) and Long Term Evolution (LTE) Home evolved Node B (HeNB) based on LTE.
Also, in the 3GPP2, methods for minimizing the influence of the existing networks and the interfaces between macrocells have become a main issue. While various problems such as a network architecture for circuit switched/packet switched (CS/PS) service, an interface management, a handover scheme, an access system selection, a synchronization, and the like, have been under discussion, the 3GPP2 having first carried out the standardization activities took the leading position in the femtocell standardization over the 3GPP.
The femtocell can provide a high-capacity service, which has been provided in an existing wired broadband service, at a low cost under radio environments by configuring cells in a small size and remarkably increasing a frequency reuse rate, to thereby provide a high-speed data service regardless of places of users. Hence, such a femtocell technology has showed a possibility as the foundation for introduction of new services and expansion of next generation mobile communication markets following 3G.
However, since such femtocell base stations are installed in an uncoordinated, random and dense fashion, interference may occur more than in the existing macrocell base stations.
The interference between the femtocell base stations may degrade the quality of service (QoS) provided to the mobile terminal and also cause a call drop. Therefore, there is a need for technologies which can minimize interference occurring between the femtocell base stations in order for the femtocell base stations to successfully operate.
An Evolved-Universal Terrestrial Radio Access Network (E-UTRAN) architecture in which no femtocell base stations are included will be first described. The base stations (Evolved Node-Bs (eNBs)) are connected through interfaces to Evolved Packet Cores (EPCs) which are upper nodes. The EPCs may include a Mobility Management Entity (MME) and/or a Serving-GateWay (S-GW).
In the E-UTRAN architecture, an interface between the eNBs is referred to as an X2 interface, and an interface between the EPC and the eNB is referred to as an S1 interface. That is, the X2 interface refers to an interface which directly connects the eNBs to each other, and the S1 interface refers to an interface which indirectly connects the eNBs to each other passing through the MME and/or the S-GW.
In general, interference between the macrocell base stations can be reduced by exchanging an interference control message between the macrocell base stations. In this case, the interference control message is exchanged through the X2 interface.
However, the interference control message having been used in the existing X2 interface cannot be exchanged in a femtocell environment where no X2 interface exists, and the interference-related messages associated with the S1 interface have to be newly defined.

Method and apparatus for controlling interference between base stations

Electronics and Telecommunications Research Institute


There is provided a semiconductor memory which allows a redundant memory cell to be disposed at the center while maintaining the continuity of layout units of direct peripheral circuits and allows the total yield of the memory cell and the direct peripheral circuits to be improved. The inventive semiconductor memory is a 64 M-bits or 256 M-bits DRAM using a hierarchical word line structure or a multi-division bit line structure and comprises a main row decoder region, a main word driver region, a column decoder region, a peripheral circuit/bonding pad region, a memory cell array, a sense amplifier region, a sub-word driver region, intersection regions and the like formed on one semiconductor chip.

1.Field of the Invention
The present invention relates to a technology of highly integrated semiconductor memory and more specifically to a technology effectively applied to the disposition of a redundant memory cell and to a layout method of word drivers and sense amplifiers connected to the redundant memory cell.
2. Description of the Related Art
In the field of highly integrated semiconductor memories examined by the inventor, a technology of having a small number of redundant memory cells in addition to normal memory cells and of switching an access to the redundant memory cell when the normal memory cell is defective is widely used in order to improve the production yield.
As for the semiconductor memory having the redundant memory cells in addition to the normal memory cells as described above, there is a technology described in Japanese Patent Publication No. 2555252 entitled "Semiconductor Memory Device" for example. According to this technology, column redundancy is implemented by having a normal memory cell array and a redundant memory cell array in which a plurality of normal memory cell array blocks and a plurality of redundant memory cell array blocks are controlled in common by respective column decoders.
Noticing on the high integration of the semiconductor memory having the redundant memory cells in addition to the normal memory cells as described above, the inventor examined the disposition of the redundant memory cell and the layout method of word drivers and sense amplifiers connected to the redundant memory cell. The contents examined by the inventor will be explained below by using FIG. 10.
FIG. 10 shows the disposition of the redundant memory cell. This redundant memory cell is positioned at the peripheral part of a normal memory cell array 15 as shown in FIG. 10(a). Further, sense amplifier regions 16, sub-word driver regions 17 and their intersection regions 18 are disposed adjacent to and around the memory cell array 15 as shown in FIG. 10(b).
By the way, with the high integration of the semiconductor memory, while the plane size of the memory cell may be refined further by forming it in 3-D, direct peripheral circuits such as the word drivers and sense amplifiers connected with the memory cell must be reduced in the plane direction in correspondence to the memory cell. However, their layout is not easy because they are different from the memory cell and cannot be formed in 3-D.
Then, as a countermeasure thereof, there has been widely used a method of reducing an occupied area by sharing contacts, through holes, power sources and signal lines in a plurality of units of those circuits in a repeating pitch in which a plurality of memory cells are put together. For instance, it has been applied in the layout unit of word drivers corresponding to 16 word lines W and in the layout unit of sense amplifiers corresponding to 16 bit lines BL.
Meanwhile, along with the high integration of the memory, the yield of the redundant memory cell has also become a problem. Then, the redundant memory cell is disposed at the center of an array where the manufacturing condition is stable to make it alive. Because its test before setting a fuse may be eliminated or may be simplified if the redundant memory cell is surely alive, the whole test time may be shortened.
However, it has been difficult to lay out only the sub-word drivers or sense amplifiers related to the redundant memory cell specially because the number of word lines or bit lines of the redundant memory cell is smaller than the layout units. It is because the layout unit is too small so that the contacts, through holes, power sources and signal lines cannot be shared as described above. Further, there has been a possibility that the characteristics and yield of the sub-word drivers or sense amplifiers for the redundant memory cell become abnormal if the repeated shapes are different.


A method for preparing a high-performance tantalum target, a high-performance target prepared by the method, and a use of the high-performance target. The method for preparing the high-performance tantalum target comprises: firstly, preparing a tantalum ingot into a forging blank by a method of cold forging in conjunction with hot forging; then, rolling the forging blank by a hot rolling method; and finally, performing leveling, and performing discharging, milling and surface treatment according to a size of a finished product, so as to obtain the tantalum target. The tantalum target prepared by the method has uniform crystallization, with a grain size between 50 μm and 120 μm. A texture component where a texture (110) dominants in the thickness direction of the target is obtained. A total proportion of three textures (111), (110) and (100) is between 40% and 50%, ensuring a consistent sputtering rate of the tantalum target during use.

Tantalum target materials are mainly applied in semiconductor film coating industry.
Physical vapor deposition (PVD), being one of the most essential processes in semiconductor chip production, is aimed at depositing a metal or a compound of a metal in a form of thin film onto a silicon wafer or other substrates, and finally forming complex wiring structure in semiconductor chip by cooperation of photolithography, etching and the like. PVD is completed via a sputtering machine station, and sputtering target materials are a very important and key consumptive material used in the process. Common sputtering target materials comprise highly pure tantalum, and also other nonferrous metals such as Ti, Al, Co, Cu or the like.
With increase of a wafer size from 200 mm (8 inches) to 300 mm (12 inches), the size of corresponding sputtering target material has to be increased so as to meet basic requirements of film coating by PVD. Meanwhile, when line width is decreased from 130-180 mm to 90-45 mm, the sputtering target material is changed from ultrahigh-purity Al/Ti system to ultrahigh-purity Cu/Ta system based on conductivity of a conductor and matching performance of a barrier layer. Ta target materials have increasing importance in the semiconductor sputtering industry, and demand therefore is bigger and bigger.
In prior art, tantalum target materials are mainly obtained by a process of cold rolling or cold forging. The texture components in the thickness direction of the target materials obtained are not uniform, which mainly embodies in texture (100) dominating in the upper and lower surfaces of the target materials but texture (111) dominating therebetween. Such target materials may be used on a machine station with low use requirements, but when they are used on a high-end machine station such as 12″ machine station, the inconsistent sputtering rate occurring is unacceptable.

Method for preparing high-performance tantalum target

NINGXIA ORIENT TANTALUM INDUSTRY CO., LTD.


An apparatus and method for remotely disassembling a failed high explosive ype mine. The apparatus is mounted on a mobile chassis and has a remote operator shelter for control of the apparatus. The apparatus has a stripper assembly to remove appendages from the body of the mine. A chuck assembly moves the stripped body of the mine to a cutter assembly and rotates the body of the mine so that the electronics assembly is severed from the body of the mine. A puller assembly extracts the safe and arming device from the high explosive filler in the body of the mine. In an alternate embodiment, a rammer assembly has a pressing cylinder to push the electronics assembly and the safe and arming device from the center of the body of the mine as the outer portion of the body of the mine is firmly retained on the frame of the rammer assembly. Video cameras on the apparatus are provided to permit remote control of the disassembly.

The disposal and disassembly of failed (dud) high explosive type mines presents a serious safety problem. Since there exist several different designs and configurations for the mines, a correspondingly different disassembly means must be used for the various mines. The applicants are aware of the following U.S. patents which have been directed to deactivating or disposal of munitions or explosive devices:
______________________________________ Inventor(s) U.S. Pat. No. ______________________________________ Deck et al 1,958,420 Hopkins 2,404,441 Piggot et al 2,491,516 Plumley 3,109,369 Porter et al 3,117,518 Jones et al 3,229,561 Carr et al 4,621,562 Proctor et al 4,779,511. ______________________________________
None of these references have been specifically directed to the family of scatterable mines which have components which differ from the devices disclosed in the references.
The various types of scatterable mines are in the shape of a cylinder approximately five (5) inches in diameter and three (3) inches high. Of the two basic mine configurations, the first has a plastic aeroballistic housing surrounding the metal mine body circumference giving an overall box shape with approximate dimensions of five (5) by six (6) by three (3) inches. The second configuration has metal spring fingers which surround the circumference. Within the mine body there is a safe and arming device located near the center and a potted electronic assembly near the cylinder top. The safe and arming device and the electronics must be separated from the high explosive filler and other components of the mine for safe and complete failure analysis.

Apparatus and method for remote disassembly of failed high explosive type mine

The United States of America as represented by the Secretary of the Army


Data is stored in a non-volatile memory such as a flash memory. The non-volatile memory has two memory areas. When power of a device is turned on, data in the two memory areas are compared to determine which memory area includes old data, and the old data is erased. When the power is turned off, a control setting of the device used immediately before the power is turned off is stored as new data in the memory area from which the old data is erased. When the power is applied again, the new data is read, and the control setting is restored in the device.

1) Field of the Invention
The present invention relates to a memory control device that stores last memory data when power of a device is turned off, and reads the last memory data when the power is turned on.
2) Description of the Related Art
Some devices have a so called last memory function. A device is said to have the last memory function if, when power is turned off while the device is operating, data relating to the control settings of the device is stored in a recording medium just before the power is turned off. In such a device, when the power is turned on again, the control settings are read from the recording medium. As a result, the control settings of the device can be automatically restored to the one before the power is turned off.
Thus, the recording medium used in such devices must be able to retain data even after the power is turned off. Examples of such recording media are hard disk drives (HDD) and non-volatile memories. Examples of the non-volatile memories are flash memories, electrically erasable programmable read only memories (EEPROM), ferroelectric random access memories (FeRAM), and magnetoresistive random access memories (MRAM). The volatile recording media can also be used as the recording media. However, the volatile recording media require power supply from an auxiliary source to retain data. Examples of the volatile recording media are static random access memories (SRAM) and synchronous dynamic random access memories (SDRAM).
The flash memories are particularly advantageous; because, the flash memories are compact, light-weight, and data can be written on them in short time There are various conventional methods of writing data in the flash memory, such as those disclosed in Japanese Patent Application Publication No. H11-328982 and Japanese Patent Application Publication No. H8-272698.
The HDDs require large current, and takes time to write data because mechanical operations are required. On the other hand, with the flash memories, data writing cannot be immediately executed because data in the flash memory needs to be erased first. Erasing of data takes about 0.5 second to 2 seconds, and writing of data takes about 6 microseconds (μs) to 100 μs. Therefore, when the HDDs or the flash memories are used, the power needs to be retained for some time even after the power is turned off. This requires a high-capacity condenser, which occupies the space and increases the cost.
The EEPROM cannot store a large amount of data because it is small in capacity. The FeRAM and the MRAM are expensive because they are not yet mass produced. The SRAM and the SDRAM require auxiliary power, which not only leads to more space and cost, but also consumption of dark current.
There are devices that can be detached while the power is on, and the power is turned off when the device is detached. Such detachable devices are particularly required to quickly write data in a recording medium, so as to retain the data after being detached (i.e., after the power is turned off).

Memory control device, in-car device, memory control method, and computer product for managing data in response to various power states


A heterojunction bipolar transistor includes a ballast resistor layer of which resistance increases with an increase in temperature. The ballast resistor layer includes a first ballast resistor sub-layer having a positive temperature coefficient of resistivity in a first temperature range and a second temperature range and a second ballast resistor sub-layer having a negative temperature coefficient of resistivity in the first temperature range and a positive temperature coefficient of resistivity in the second temperature range.

1. Field of the Invention
The present invention relates to a heterojunction bipolar transistor, a power amplifier including the same, and a method for fabricating a heterojunction bipolar transistor.
2. Description of the Related Art
Japanese Unexamined Patent Application Publication No. 2005-236259 discloses a heterojunction bipolar transistor (hereinafter referred to as an HBT in some cases) including an n-type InGaP emitter layer, an AlGaAs emitter ballast resistor layer, and a GaAs layer interposed therebetween. The AlGaAs emitter ballast resistor layer is formed by metal-organic vapor phase epitaxy and has an Al-to-As molar ratio of about 0.33, an Si concentration of about 1×1017 cm−3, and a film thickness of about 120 nm.
In general, a power amplifier uses a large amount of electricity and therefore includes a large number of HBTs (hereinafter referred to as unit HBTs), connected in parallel, having a small emitter size.
However, the following case occurs: the case where all unit HBTs connected in parallel do not operate uniformly because of unevenness due to a HBT-fabricating process or the like. In this case, currents may possibly concentrate on specifics of the unit HBTs to cause thermal runaway, leading to element breakdown.
In order to prevent the thermal runaway, a ballast resistor is generally provided in an emitter or a base for each unit HBT.
A technique disclosed in Japanese Unexamined Patent Application Publication No. 2005-236259 is described herein in association with a mechanism for preventing thermal runaway by an AlGaAs emitter ballast resistor layer. The temperature dependence of resistivity of the AlGaAs emitter ballast resistor layer is as illustrated in FIG. 20. When a unit HBT begins to thermally run away, the temperature thereof increases due to current concentration. The emitter ballast resistance of the unit HBT beginning to thermally run away increases sharply with the increase in temperature thereof (for example, at about 100° C. or higher as illustrated in FIG. 20). The sharp increase in emitter ballast resistance thereof suppresses the emitter-base voltage of the unit HBT beginning to thermally run away and therefore suppresses the concentration of currents on the unit HBT beginning to thermally run away, thereby avoiding thermal runaway.
On the other hand, a power amplifier needs to keep power amplifier (power amplifying) characteristics not only at room temperature but also at elevated temperatures (for example, about 85° C. to 100° C.) as a whole. However, other unit HBTs that are not in thermal runaway are each equipped with an emitter ballast resistor. As is clear from FIG. 20, the emitter ballast resistance of an HBT increases by about 13% or about 21% at, for example, about 85° C. or about 100° C., respectively, as compared to the emitter ballast resistance at room temperature, that is, the parasitic resistance thereof increases.
Therefore, in the case of fabricating a power amplifier by the technique disclosed in Japanese Unexamined Patent Application Publication No. 2005-236259, the thermal runaway of HBTs can be prevented. However, there is a problem in that the increase in emitter ballast resistance due to an increase in temperature deteriorates power amplifier characteristics at elevated temperatures.

Heterojunction bipolar transistor, power amplifier including the same, and method for fabricating heterojunction bipolar transistor


A riding simulator whrein the basic stepping actions of a real horse is closely simulated. The riding simulator includes an artificial horse body, horse body supporting structures for circularly movably supporting the lower ends of forelegs and hind legs of the horse body, swing adjusting devices for driving the horse body supporting structures and for moving the horse body in both vertical and longitudinal directions, and phase adjusting devices for adjusting the phase difference between the vertical motion and the longitudinal motion of the horse body when the horse body supporting structures are driven. The riding simulator also includes provision for enabling the rider to give aids to the horse body so that the basic stepping actions of a real horse can be simulated.

1. Field of the Invention
The present invention relates to a riding simulator of the type including an artificial horse body which can closely simulate the basic stepping actions of a real horse.
2. Description of the Prior Art
Conventionally, riding machines using artificial horse bodies have been commercially available for amusement as used in merry-go-rounds in amusement parks. As will be easily found on riding of such a riding machine, it is quite different in movement from a real horse. More specifically, in the above prior art riding machines, some carry out a complicated movement of the artificial horse body comprising a circular motion which is the synchronous combination of a vertical motion and a longitudinal motion, while most of them are limited to a linear motion only in a vertical or longitudinal direction. Even in the riding machine capable of a circular motion, to say nothing of the one limited only to a linear motion, the length of swing (i.e. the radius of the circular motion) is fixed, and no phase difference between the vertical motion and the longitudinal motion has been taken into consideration. Only the rotational speed of a driving motor for driving the horse body has been designed to be manually controlled so as to increase a feeling of speed-up.
Furthermore, in such a prior art riding machine, the rider cannot give any aids to the horse body. More specifically, it is impossible for the rider to control the horse body by giving signs to the abdomen of the horse body through his legs or to the head of the horse body through reins so as to start the horse body, change the gait, or stop the horse body.
In actual riding, however, there are three kinds of gaits: walk, trot and canter. The gaits are different from each other in the number and length of swing and in phase difference between the vertical motion and longitudinal motion of the horse body. Thus, in order to obtain a riding feeling close to the riding on a real horse, it is necessary to drive the horse body at the number and length of swing and the phase difference commensurate with each gait and to permit control of the horse body such as for starting, change of gaits and stopping thereof by aids given through legs of the rider or reins.
It can be said that the prior art riding machine is used just as a playing machine and never has such functions as to provide a real riding feeling.
In these years, there is a tendency of increasing the number of people who want to acquire riding technique. If a beginner of riding rides on a real horse, his riding posture and aids through shift of his weight are incorrect and unstable at first. This may cause disorder of training of the real horse or increase stress of the real horse, so that, in some cases, the real horse may turn restive, causing a fall of the rider therefrom. This has been a significant difficulty for beginners to acquire proper riding technique.
However, the movement of the prior art riding machine is quite different from the stepping action of a real horse, as described above, so that such a prior art riding machine cannot be used for training of riding. Therefore, it has been long desired to provide an artificial horse body which can closely simulate the stepping action of a real horse so as to permit proper and ready acquirement of the riding technique.


A microwaveable food container that incorporates at least one microwave-obstructing movable object. An actuator-induced controlled movement of the at least one microwave-obstructing movable object serves to controllably vary the microwave power density reaching a material which is located within the food container.

Microwave ovens are widely regarded as being quite good for cooking vegetables, and tolerably good for cooking a quick meal. However, many people regard dishes cooked in a microwave oven as being typically markedly inferior to food cooked using traditional cooking methods.
Different kinds of food which is not pre-cooked require different amounts of cooking time in a microwave oven to be at their best in terms of taste, texture and appearance. But in a pre-packaged food container containing a meal comprising different types of food which is designed for cooking in a microwave oven, different types of food making up a meal must perforce be cooked for the same amount of time.
In traditional (i.e., non-microwave) cooking methods, different food items making up a 'meal', or a dish in its entirety (e.g., a lasagna) are quite often first cooked by one cooking method—and then by a different method. Thus, lasagna may for example first be baked, and in the final stage of cooking, it may be grilled on the top to crisp and brown the upper areas of the dish. This 'first cooking by one method, and then by another' is not generally possible in the case of existing pre-packaged 'microwave meals'.
In traditional cooking, different types of food making up a meal interact with each other while they are being cooked, thereby exchanging flavors, and creating distinctive near flavors as a result of that interaction. But a significant amount of such interaction of different kinds of food items comprising a 'meal' in a pre-packaged 'microwave meal' container is in many cases not possible, with consequently inferior results, when compared with traditionally cooked meals.
The key to much of the flavour of conventionally (i.e., non-microwave) cooked food is a sequence of chemical events called the Maillard reaction. Cooking food with microwaves in many cases does not allow the Maillard reaction to take place—or at least, not to a great extent.
The inventions disclosed herein aim to address and resolve the above deficiencies of pre-prepared meals provided in food containers to be cooked in a microwave oven—and to provide other novel inventions to enhance the taste, quality, texture and appearance pre-prepared 'microwave meals', to enable dishes cooked in a microwave oven to more closely emulate the taste, texture and appearance of food cooked using traditional cooking methods.

Enhancements of the food cooking capabilities of food containers to be used in a microwave oven


In operation, a first request for data is sent to a cache of a first node. Additionally, it is determined whether the first request can be satisfied within the first node, where the determining includes at least one of determining a type of the first request and determining a state of the data in the cache. Furthermore, a second request for the data is conditionally sent to a second node, based on the determination.

Current cache coherence protocols typically fail to recognize and take advantage of the difference in data transfer latency between on-node cache requests and cache requests on other nodes. Many times, this results in coherence protocols incurring the latency of unnecessary node hops while performing a cache request. There is thus a need for addressing these and/or other issues associated with the prior art.

System, method, and computer program product for conditionally sending a request for data to a node based on a determination


Integrated circuits as well as fabrication and operating methods are presented in which user circuitry of the IC is selectively disabled in response to detection of a single event latchup condition in a sensing circuit that is prone to latchup in response to ionic radiation at a specific linear energy transfer level.

Continuing performance improvements and scaling of semiconductor devices has generally resulted in operational capabilities in excess of minimum requirements for extraterrestrial applications such as satellites in which higher levels of radiation are experienced. However, devices capable of operating in high radiation environments may be subject to usage regulations established for satellite operation, such as International Traffic in Arms Regulations (ITAR), despite being designed for other uses. Such radiation hardened (rad-hard) products are typically regulated if they satisfy all performance criteria set forth in the ITAR regulations. One ITAR criteria relates to maximum ion linear energy transfer (LET), and requires regulation of devices that are free of single event latchup with a dose rate latchup of 5×108 Rads (Si)/second or greater. Commercializing potentially rad-hard devices in certain countries may involve obtaining export licenses or costly product testing and sorting to verify unsuitability for satellite operation and such costs may inhibit the ability to export such products. Accordingly, improved integrated circuit designs and methods are desirable to ensure that ordinary products designed for non-satellite usage do not qualify for export restrictions per ITAR regulations.

Integrated circuit with automatic deactivation upon exceeding a specific ion linear energy transfer (LET) value


A gas measurement system of this invention includes a housing adapted to be mounted on an airway adapter, and a luminescence quenching gas measurement assembly disposed in the housing. The luminescence quenching gas measurement assembly includes a source disposed in a first plane, and at least one detector also disposed in the first plane.

1. Field of the Invention
The present invention relates to a mainstream respiratory gas measurement system with integrated signal processing and improved optical design, and to a method of assembling such a system.
2. Description of the Related Art
Respiratory gas measurement systems comprise gas sensing, measurement, processing, communication, and display functions. They are considered to be either diverting, i.e., sidestream, or non-diverting, i.e., mainstream. A diverting gas measurement system transports a portion of the sampled gases from the sampling site, which is typically a breathing circuit or the patient's airway, through a sampling tube, to the gas sensor where the constituents of the gas are measured. A non-diverting or mainstream gas measurement system does not transport gas away from the breathing circuit or airway, but measures the gas constituents passing through the breathing circuit using a gas sensor disposed on the breathing circuit.
Conventional mainstream gas measurement systems include a gas sensing, measurement and signal processing components required to convert the detected or measured signal, for example a voltage, into a value, such as transmittance, that may be used by the system to determine a constituent of a gas being measured. In a conventional mainstream gas measurement system, a gas sensor is coupled to a sample cell that is placed at the breathing circuit. The gas sensor located on the airway adapter disposed in the breathing circuit only includes the components required to output a signal corresponding to a property of the gas to be measured. Placement of the sample cell directly at the breathing circuit results in a "crisp" waveform that reflects in real-time the partial pressure of the measured gas, such as carbon dioxide or oxygen, within the airway. The sample cell, which is also referred to as a cuvette or airway adapter, is located in the respiratory gas stream, obviating the need for gas sampling and scavenging, as required in a sidestream gas measurement system.
For a conventional gas measurement system that is capable of measuring carbon dioxide, the gas sensor includes a source that emits infrared radiation, which includes the absorption band for carbon dioxide. The infrared radiation is emitted in a direction that is normal to the flow path of the respiratory gas stream. Carbon dioxide within the sample gas absorbs the radiation at some wavelengths and passes other wavelengths. The conventional gas sensor includes photodetectors that measure the transmitted radiation.
For gas measurement systems that are capable of measuring oxygen using luminenscence quenching measurement techniques, the gas sensor may include an excitation source that emits visible radiation, which excites a photosensitive chemical disposed on or within a substrate, and a detector, which measures the radiation emitted by the chemical upon exposure to oxygen. The gas concentration may be determined from the time response of the luminescence using known relationships, such as the Stern-Volmer relationship.
A conventional mainstream host system contains the electronics that control the emitter in the gas sensor, and provides the gas measurement functions based on the output signals from the detector. Mainstream gas measurement systems known in the art transmit analog signals along a cable, typically 6 to 8 feet in length, between the host system and the gas sensor and, as such, are susceptible to electromagnetic interference (EMI). This is particularly important given the trend towards requiring compliance with increased electromagnetic immunity levels in international medical device standards. An example of such conventional mainstream gas measurement systems are shown in U.S. Pat. No. 4,914,720 issued to Knodle et al and U.S. Pat. No. 5,793,044 issued to Mace et al.
With the measurement and signal electronics located in the host system, existing mainstream gas measurement systems are complex and costly to interface to host systems. The host system conventionally includes circuitry to perform functions such as (1) creating timing signals; (2) supplying pulsatile power to a solid state infra-red emitter; (3) measuring and precisely controlling the temperature of the infra red detectors; (4) measuring and controlling an airway adapter heater; (5) signal conditioning including filtering and programmable gain setting; and (6) watchdog circuitry to prevent accidental destruction of the infra-red emitter.
Additionally, to be accepted in clinical use, a mainstream gas measurement system must be designed in a robust manner such that it is unaffected by typical mechanical abuse and environmental variations in temperature and humidity. The instrument, or at least the gas measurement system portion of the instrument, must be small and light weight so as to not interfere with the motions of the patient, or with other medical equipment or treatments. In order to achieve the goals of being small and lightweight, the optical portion of the gas measurement system must also be designed such that they occupy as little space as possible and weigh as little as possible.
Given these known complexities of conventional gas measurement systems, it is desirable to provide a mainstream gas measurement system that is small, lightweight, and simpler to interface to host systems. It is also desirable that such a system provide improved methods of assembly over known gas measurement systems.


A scripting engine for network communication software is described. The scripting engine includes a sequencer table and plurality of secondary tables. The sequencer table and plurality of secondary tables provide a table-based command-processing engine to control the functionality of the network communication software. The sequencer table includes commands that are read in a sequential order. The commands are grouped into command types that each defines a specific set of related functionality. Each of the plurality of secondary tables is mapped to a particular one of the command types. Each of the secondary tables includes one or more records containing one or more specific instructions to enable the network communication software application to perform a particular operation indicated by the command, when the network communication software application instructs the scripting engine to process the sequencer table.

As used herein, a network communication application is software that is used to communicate (via one or more computers) with network equipment in communication networks and extract data from the network equipment for purposes of managing the communication networks. Communication networks may consist of hundreds of different types of network equipment and include different types of networks, such as Internet Protocol (IP) networks, asynchronous transfer networks, optical networks, wireless networks, a combination of any such networks, and the like. Enabling a network communication application (via one or more computers) to communicate with the various different types of networks and network equipment is daunting given the many incompatibilities and differences associated with languages and protocols used by such networks and equipment.
Complicating matters further is the challenge associated with dealing with changes made to the many different types of network equipment residing in the different network environments. To account for these ever-constant changes, it is often necessary to change, update, patch or otherwise modify software code associated with the network communication application in order for the network communication application to communicate with newly added or updated network equipment.
Modifying a network communication application to account for changes made to network equipment in communication networks is not a trivial matter for a software developer. Typically a network communication application is a very sophisticated program containing millions of lines of code. Besides the volume of software code, the software developer has to account for the many dependencies hidden in the software code, which may be affected by modifying the code. A dependency is a logical constraint between two or more portions of code or two or more portions of operations performed by the code. For example, where the order of a first operation in a sequential program produces a result that is an operand of a second operand, a dependency is formed such that the second operand cannot be performed until the first operation has been completed, since the first operand value would not otherwise be available.
Accounting for dependencies when modifying an application often can take more time than it may have taken to create and develop the software application in the first place. These costly implementation delays increase the expense associated with modifying and updating network communication applications, and such delays further inconvenience customers that depend on the applications.

Scripting engine having a sequencer table and a plurality of secondary tables for network communication software


The present disclosure involves systems, software, and computer implemented methods for identifying suggested connections between content within a portal webpage. One example process includes operations for identifying a portal page associated with two or more individual content components to be presented to a user, and determining at least one possible connection between at least one pair of the two or more individual content components based, at least in part, on related content component metadata associated with each determined pair of individual content components. The at least one determined possible connection is prioritized based, at least in part, on a combined set of at least one of the related content component metadata and a set of user-specific data. At least a portion of the prioritized possible connections are then presented as suggested connections within the portal page.

Enterprise portals are frameworks for integrating information, people and processes across organizational boundaries. Portals can provide a secure unified access point, often in the form of a web-based user interface, and are designed to aggregate and personalize information through application-specific portlets and components. One hallmark of enterprise portals is the decentralized content contribution and content management, which keeps the information always updated. In many cases, specific portal pages may be defined by a highly experienced administrator using a portal content administration environment or a key user within a particular organization using specific tools to define aspects, relationships, and connections for and between content provided within specific portal pages.

Runtime connection suggestion engine for portal content


Disclosed are pyrimidine derivatives represented by general formula (I) ##STR1## wherein X represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a haloalkyl group or a cyano group; Y.sup.1 represents an alkyl group, a cyanoalkyl group, an alkoxy group, an alkenyl group substituted with a hydroxy group and a halogen atom, an alkynyl group which may be substituted with a hydroxy group, a methylamino group, an alkoxyalkyloxy group, an alkylthioalkyl group or a group of the formula --CH.sub.2 OR.sup.1 where R.sup.1 represents a hydrogen atom, an alkyl group, an alkenyl group or an alkynyl group; Y.sup.2 represents a halogen atom, an alkyl group or a haloalkyl group; R represents a hydrogen atom, an alkyl group, a nitroso group, an alkoxyalkyl group, an alkoxyalkyloxyalkyl group, an alkenyl group, an alkynyl group, a formyl group or an alkylthioalkyl group, with the proviso that (a) when Y.sup.1 represents an alkynyl grop or when Y.sup.1 represents an alkoxy group and Y.sup.2 represents a halogen atom or an alkyl group, X and R are not a hydrogen atom simultaneously, (b) when Y.sup.1 and Y.sup.2 each represents an alkyl group, R is not a hydrogen atom, or (c) when Y.sup.1 represents an alkyl group and Y.sup.2 represents a halogen atom, X and R are not a hydrogen atom simultaneously or X is not a halogen atom nor an alkyl group. Also, agricultural or horticultural compositions containing the pyrimidine derivatives as active ingredient are disclosed, which show high controlling activities for cucumber gray mold (Botrytis cinerea), cucumber downey mildew (Pseudoperonospora cubensis), Alternaria sooty spot of Chineese mustard (Alternaria brassicicola), rice blast (Pyricularia oryzae), etc.

Many investigations on 2-anilinopyrimidine derivatives have heretofore been made, and some compounds are known to have activity chiefly in the field of fungicides. For instance, East German Patent No. 151,404 describes that 2-anilinopyrimidine derivatives represented by the general formula ##STR2## wherein R.sup.2 and R.sup.3 independently represent a hydrogen atom, an alkyl group which may be substituted, an aryl group, an aralkyl group, a halogen atom, a hydroxy group, an alkoxy group, an aryloxy group, a mercapto group, an alkylthio group, a carboxy group, an alkoxycarbonyl group, a carbamoyl group, a cyano group, a cyanato group, an isocyanato group, a thiocyanato group, an isothiocyanato group, a sulfo group, a halogenosulfonyl group, an amino group which may be substituted, a nitro group, or an acetyl group which may be substituted, and R.sup.4 and R.sup.5 represent a hydrogen atom or an alkyl group, have a fungicidal activity. Also, British Patent No. 1,245,085 discloses the fungicidal activity of pyrimidine derivatives represented by the general formula ##STR3## wherein A and A.sup.1 represent a hydrogen atom, a nitro group, an amino group, a halogen atom, a hydrocarbon group or hydrocarbon groups which may be substituted, R.sup.6 and R.sup.7 represent a hydrogen atom or organic groups, and A.sup.2 represents a halogen atom.
These conventional compounds are, however, found to have defects that their fungicidal activity is weak, and moreover their anti-microbial spectrum is narrow.

Pyrimidine derivatives, process for preparing the same and agricultural or horticultural fungicidal composition containing the same


A hybrid vehicle propulsion system and method of operation have been provided. As one example, the system comprises an internal combustion engine including at least a combustion chamber configured to propel the vehicle via at least a drive wheel, a motor configured to propel the vehicle via at least a drive wheel, an energy storage device configured to store energy that is usable by the motor to propel the vehicle, a fuel system configured to deliver gasoline and alcohol to the combustion chamber in varying relative amounts, a control system configured to operate the motor to propel the vehicle and to vary the relative amounts of the gasoline and alcohol provided to the combustion chamber in response to an output of the motor.

Engines have been described utilizing multiple injector locations with different fuel types. One example is described in the papers titled "Calculations of Knock Suppression in Highly Turbocharged Gasoline/Ethanol Engines Using Direct Ethanol Injection" and "Direct Injection Ethanol Boosted Gasoline Engine: Biofuel Leveraging for Cost Effective Reduction of Oil Dependence and CO2 Emissions" by Heywood et al. Specifically, the Heywood et al. papers describe directly injecting ethanol to improve charge cooling effects, while relying on port injected gasoline for providing the majority of combusted fuel over a drive cycle. Thus, it has been demonstrated that the selective use of a knock suppressing substance such as ethanol with gasoline fueled engines can reduce knock during boosted operation, particularly where the engine may otherwise be knock limited.
The inventor of the present application has recognized various issues with the above approach. As one example, the engine output may be significantly reduced where the availability of the knock suppressing substance on-board the vehicle is low. For example, even when the engine has sufficient fuel reserves remaining on-board the vehicle, the depletion of the knock suppressing substance may once again cause the engine to be knock limited, thereby reducing the level of boost that may be provided to the engine. This reduction in engine output, under some conditions, may surprise the vehicle operator or may cause dissatisfaction with the performance of the vehicle.
As another example, where the knock suppressing substance is separated on-board the vehicle from a fuel mixture, the consumption of the knock suppressing substance at a rate that is greater than the separation rate may likewise cause the knock suppressing substance to eventually become exhausted. Thus, the vehicle operator may attempt or may be unable to initiate a vehicle control operation that is no longer practicable due to the reduced availability the knock suppressing substance. Alternatively, with each of the above examples, if the engine is instead permitted to be operated in a state where knock occurs without the use of the knock suppressing substance, engine damage may occur, or noise and vibration harshness (NVH) as a result of the engine knock may again cause dissatisfaction with the vehicle operator.
In response to at least the above issues, the inventor has provided, as one example, a hybrid vehicle propulsion system, comprising an internal combustion engine including at least a combustion chamber configured to propel the vehicle via at least a drive wheel; a motor configured to propel the vehicle via at least a drive wheel; an energy storage device configured to store energy that is usable by the motor to propel the vehicle; a fuel system configured to deliver gasoline and alcohol to the combustion chamber in varying relative amounts; and a control system configured to operate the motor to propel the vehicle and to vary the relative amounts of the gasoline and alcohol provided to the combustion chamber in response to an output of the motor.
As another example, the inventor has provided a method of operating a hybrid electric vehicle propulsion system including an engine and an electric motor coupled to at least a drive wheel of the vehicle, the method comprising operating the electric motor to propel the vehicle by supplying electrical energy to the motor from an energy storage device; and delivering a fuel and a knock suppressing substance to the engine in varying relative amounts responsive to a condition of the energy storage device.
In this way, the utilization of a knock suppressing substance such as an alcohol can be coordinated with other sources of vehicle propulsion, including an electric motor or other suitable drive motor, enabling a more consistent drive feel for the vehicle operator for a variety of operating conditions, such as where the availability of the knock suppressing substance or the amount of energy stored by the motor's energy storage device are reduced.

This patent is subject to a terminal disclaimer.

Hybrid vehicle propulsion system utilizing knock suppression


A disposable gel pad for cushioning the plate of an operating table's patient support apparatus is a block of gel with one face of the block adapted to locate the pad on the plate. Usually the pad will be enclosed in a film envelope. A pocket in the envelope allows the pad to engage the plate. Stick on patches which provide a pocket and sacroiliac pads axe variants. Sacroiliac pads can be cast with a soft gel front for patient contact joined to a hard gel rear for screw or bayonet fixing to the patient support apparatus.

In our co-pending application for Patent No. PCT/AU2005/000732, we describe a set of clamps for fixing to the side rail of an operating table. The clamps lock in different angular positions and have at one end a plate which is adjusted to lie next to the torso of the patient on the operating table. When the clamps are paired and both left and right hand side of the patients body are confined by plates, the theatre staff can arrange the patient in a suitable position for the operation in hand knowing firstly that the patient will not fall from the table even when there is rapid repositioning as a result of cardiac arrest, and secondly that the surgeon has good access to the operating site.
The prior art devices for contacting the patient are steel or aluminium plates either circular and rectangular about the size of a human hand but mote usually they are a vinyl covered, upholstered pad fixed to a metal plate which is in turn mounted on an arm for bringing it close to the patients body. While metal apparatus is easy to sterilise, the pads described above and clothing and drapes are more difficult. The vinyl surface of the pad is gathered, tucked or pleated to be a close fit on the convex curves of the pad. Laundering deals with reusable items while masks, gloves and dressings are disposable, but surface application of antiseptic to the vinyl pads may be effective, but sometimes it is not.
The previously known pads are an integral part of the patient support system and present a sterilisation problem for the theatre staff.


A bone implant system is provided including a bone graft body having at least a demineralized surface for implantation at a bone site, the bone graft body including at least one attachment member. At least one bone delivery carrier including a covering is provided, the carrier configured to be attachable to the bone graft body and including at least one compartment. An affixing member may be provided for attaching the at least one bone delivery carrier to the at least one attachment member of the bone graft body. A demineralized bone matrix material is disposed within the at least one compartment, wherein the covering retains the demineralized bone matrix material for placement at the bone site and facilitates transfer of cells into and out of the covering.

The use of bone grafts and bone substitute materials in orthopedic medicine is known. While bone wounds can regenerate without the formation of scar tissue, fractures and other orthopedic injuries take a long time to heal, during which time the bone is unable to support physiologic loading unaided. Metal pins, screws, rods, plates and meshes are frequently required to replace the mechanical functions of injured bone. However, metal is significantly more stiff than bone. Use of metal implants may result in decreased bone density around the implant site due to stress shielding. Physiologic stresses and corrosion may cause metal implants to fracture. Unlike bone, which can heal small damage cracks through remodeling to prevent more extensive damage and failure, damaged metal implants can only be replaced or removed. The natural cellular healing and remodeling mechanisms of the body coordinate removal of bone and bone grafts by osteoclast cells and formation of bone by osteoblast cells.
Conventionally, bone tissue regeneration is achieved by filling a bone repair site with a bone graft. Over time, the bone graft is incorporated by the host and new bone remodels the bone graft. In order to place the bone graft, it is common to use a monolithic bone graft or to form an osteoimplant comprising particulated bone in a carrier. The carrier is thus chosen to be biocompatible, to be resorbable, and to have release characteristics such that the bone graft is accessible. Generally, the formed implant, whether monolithic or particulated and in a carrier, is substantially solid at the time of implantation and thus does not conform to the implant site. Further, the implant is substantially complete at the time of implantation and thus provides little ability for customization, for example by the addition of autograft.
The use of bone grafts is generally limited by the available shape and size of grafts. Bone grafts using cortical bone remodel slowly because of their limited porosity. Traditional bone substitute materials and bone chips are more quickly remodeled but cannot immediately provide mechanical support. In addition, while bone substitute materials and bone chips can be used to fill oddly shaped bone defects, such materials are not as well suited for wrapping or resurfacing bone.
Bone graft materials are often used in spine fusion surgery. Current spinal fusion implants utilize grafts of either bone or artificial implants to fill the intervertebral disc space.
Interspinous process devices have been developed as a minimally invasive surgical option for treating conditions such as lumbar spinal stenosis. A spacer fits between the spinous processes in the back of the spine. Its role is to keep the space for the nerves open by spreading the vertebrae apart.
As to bone grafts, allograft bone is a reasonable bone graft substitute for autologous bone. It is readily available from cadavers and avoids the surgical complications and patient morbidity associated with harvesting autologous bone. Typically, allograft bone is a load-bearing matrix comprising cross-linked collagen, hydroxyapatite, and osteoinductive bone morphogenetic proteins. Human allograft tissue is widely used in orthopedic surgery.
Indeed, allograft is a preferred material by surgeons for conducting interbody fusions because it will remodel over time into host bone within the fusion mass. Current concepts of using allograft implants in an interspinous process fusion involve fully mineralized pieces of solid cortical allograft. However, though allograft tissue has certain advantages over other treatments, allograft implants have some limitations, e.g., it is typically available in only limited size ranges, thus making it difficult to provide a perfect fit to the geometry of the spine in particular, to the geometry of the spinous processes. This could significantly increase the amount of time necessary for bone fusion to occur. Indeed, a conventional cortical allograft implant may have an improper fit between the cortical allograft implant and the spinous processes resulting in several gaps that prevent successful bone fusion from occurring.
Therefore, it would be desirable to construct an implant, particularly an interspinous implant device, which enhances allograft treatment.


The object of the invention is a pharmaceutically acceptable composition suitable to achieve a systemic therapeutical response due to its antitussis action in warm-blooded animals, characterized in that it contains, per dosage unit: (I) an amount therapeutically efficacious by systemic way due to the antitussis action of salified dextrorphan, and (II) a pharmaceutically non-toxic excipient acceptable for intranasal administering.

Dextrorphan is the dextro isomer of levorphan, this latter being an opium substance endowed with marked analgesic activity. Differently from levorphan, dextrorphan does not have any analgesic activity, nor has it any affinity for the opium receptors (and therefore it causes neither dependence nor tolerance) (Benson W. M., Stefko P. L., Randall L. O.; J. Pharmacol. Exp. Therap. 109, 189, 1953), but is endowed with a considerable antitussis action (Goodman L. S., Gilman A.: "The Pharmacological Basis of Therapeutics", page 263, McMillan Pub. Co. Inc., New York 1975).
Many investigations have shown that this compound, either in free or in conjugated form, is the major metabolite of dextromethorphan (Axelrod J., J. Pharmacol. Exp. Ther. 117, 322, 1956; Elison C., Elliott, J., Pharmacol. Exp. Ther. 144, 265, 1964; Kamm J., Taddeo A., Van Loon E., J. Pharmacol. Exp. Ther. 158, 437, 1967; Willner, Arzneim. Forsch. 13, 20, 1963), a drug which has been marketed worldwide as a sedative for tussis. It has been demonstrated indeed (Aylward M., Maddock J., Davies D. E., Protheroe D. A., Leideman T.; Eur. J. Respir. Dis. 65, 283, 1984) that the clinical efficaciousness of dextromethorphan is best correlated not to its hematic levels (which are practically negligible in correspondence of the peak time of the therapeutical effects), but to the hematic levels of dextrorphan, so that the concentration of said metabolite in the biological fluids is commonly determined for the kinetic study of dextromethorphan (Ramachander G., Williams F. D., Emele J. F.; J. Pharm. Sci. 66, 1047, 1977). The hematic levels of dextrorphan which are observed after the oral administering of dextromethorphan remain stable over longer, than three hours. But it must be remembered that the metabolic conversion of dextromethorphan into dextrorphan does not occur always in a constant and foreseeable way. In fact, this reaction depends on sex (Ramachander G., Bapatla K. R., Emele J. F.; J. Pharm. Sci. 67, 1326, 1978), i.e., it is much faster in male sex, and, like all the metabolic reactions of the exogenous substances, it can be influenced by the state of health of the patient, by his age, etc. (Goodman L. S., Gilman A.: "The Pharmacological Basis of Therapeutics", pages 16-17, Mc Millan Int. Co., New York 1975).
Another interesting consideration is that dextrorphan has a toxicity by parenteral way even lower than dextromethorphan (Benson W. M., Stefko P. L., Randall L. O.; J. Pharmacol. Exp. Therap., 109, 189, 1953). One could thus think to directly use dextrorphan as a tussis sedative agent.
But a severe hindrance to a therapeutical use thereof is constituted by the fact that this component is not absorbed when it is administered by oral way (Schanker L. S., Shore Parkhurst P. A., Brodie B. B., Hoghen C. A. M., J. Pharmacol. Exp. Therap., 120, 528, 1957).

Pharmaceutical compositions containing dextrorphan for intranasal application


The present invention provides a nano-micellar preparation containing vinca alkaloids antitumor agent for intravenous injection, which cincludes a therapeutically effective amount of vinca alkaloids antitumor agent (vinblastine, vincristine, vindesine and vinorelbine), a phosphatide derivatized with polyethylene glycol, together with pharmaceutically acceptable adjuvants. The preparation is prepared by encapsulating the medicament with a nano-micelle to obtain the nano-micellar preparation containing vinca alkaloids antitumor agent for injection. The vinca alkaloids antitumor agent and the phosphatide derivatized with polyethylene glycol form a nano-micelle with a highly uniform particle size. In the micelle, the hydrophobic core of encapsulated medicament is surrounded by polyethylene glycol molecules to form a hydrophilic protective layer, so that the medicament is prevented from contacting with the enzymes and other protein molecules in blood and being recognized and phagocytozed by reticuloendothelial system in body, and the circulation time in vivo of the micelle is prolonged.

Vinca alkaloids antitumor agent is a class of effective broad-spectrum antitumor agent, which is important and widely used in the clinic treatment of various cancers, such as leukaemia, lymphoma, breast cancer, lung cancer, liver cancer and many other solid tumors. This class of antitumor agents mainly includes vinblastine (VLB), vincristine (VCR), vindesine (VDS) and vinorelbine (VNR). Similar to other cytotoxic antineoplastics, these antitumor agents, however, lack selectivity for tumor tissues and lead to a severe dose-dependent acute toxicity, which is represented clinically as nausea, emesis, alopecia, and blood vessel irritation. More severe are the inhibition of bone marrow and strong neurotoxicity, and repeated administration will lead to severe complications. The toxic side effect of vinca alkaloids antitumor agent greatly limits their clinic application in the long-term treatment for tumors.
One approach to significantly decrease toxicity of vinca alkaloids antitumor agent is to alter their tissue distribution and improve their selectivity for tumor tissues. The liposome preparation of vinca alkaloids antitumor agent could reduce the toxic side effect of the agent and increase their distribution in tumor tissues, so as to mitigate their dose-dependent acute toxicity. The liposome preparation has been approved for the clinic treatment of various types of cancer and a satisfying therapeutical effect has been achieved. Two liposomal products, amphotericin liposome and paclitaxel liposome, have been approved by China State Drug Administration. The liposome preparations of vinca alkaloids antitumor agent, however, also suffer from many disadvantages. For example, the medicament is encapsulated in inner water phase and released from the liposome quickly, which results in instability of the preparation. The minimal size of the liposome is 50 nm and the entry of the liposome into cells is completed via fusion and pinocytosis mechanisms. Thus, the cytotoxic effect of the medicament encapsulated in liposome is weaker than that of free medicament. The production process of the liposome is complicated and the complexing of several lipid components (at least two lipid components) is required, wherein special equipments and devices are required to control the particle size. In addition, flocculation occurs frequently during the storage.
In water, amphiphilic molecules will aggregate spontaneously to form micelle when the concentration of the molecules is beyond critical micelle concentration. Taking advantage of this property, medicament is encapsulated in the hydrophobic core of the micelle. Micellar preparations have been used in clinic treatment practice for a long time. For example, deoxycholate sodium was utilized to solubilize amphotericin B and the like. A paper titled with "polymer micelle: a novel drug carrier" by Kun etc., summarized the use of micelle as a drug carrier (Adv. Drug. Del. Rev., 21:107-116, 1976). Recently, as a targeting, long-circulating and sustained release drug carrier, polymer micelle has been paid a great attention and becomes a research focus in the drug delivery systems. Yokoyama et al employed polymers to encapsulate antitumor drug and investigated its activity against solid tumor and cytotoxicity as well as its long-circulating property in blood, wherein the polymers was capable of forming micelle (Cancer res. 51: 3229-3236(1991)). Lipids modified with PEG-phospholipid have been demonstrated to be characterized by their long circulation in animal and human body, and can be safely used in clinic treatment (Gregoriadis, G. TIBTECH, 13: 527-537, 1995). As a carrier for drugs with poor solubility, polyethylene glycol-phospholipid micelle has been comprehensively summarized by investigators (Torchilin, V. P. J. controlled Release, 73:137-172).
Polyethylene glycol (PEG) is a water-soluble polymer that is stable under physiological condition. Because the space structure of PEG is capable of preventing the approach of plasma proteins, PEG has been widely used to modify the properties of phospholipid and protein drugs. In nanoparticle delivery system, PEG is capable of forming a hydrophilic protection layer on the surface of particles to prevent the aggregation of the particles, avoiding being recognized and phagocytized by reticuloendothelial system in body, and extending the retention time of drugs in blood circulation, whereby a long circulation is achieved.
Nano-micelle prepared from a phospholipid derivatized with polyethylene glycol possesses advantages over other nanoparticles. Its size is small between 10 nm and 30 nm. The nano-micelle is a dynamically stable system, which avoids the disadvantage of other nanoparticle delivery system, i.e. easy to aggregate, and on the other hand reaches lesion sites more easily, whereby the drug distribution in the tumor tissue is increased.

Nano anticancer micelles of vinca alkaloids entrapped in polyethylene glycolylated phospholipids

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