The combination of recombinant factor VIIa and fibrinogen is effective in treatment for bleeding where direct pressure, tourniquets, indirect pressure, surgical ligation, bandaging, and transfusion of blood or plasma products are typically used. The combination of factor VIIa and fibrinogen is administered intravenously, either sequentially or simultaneously. The compositions may be safely circulated in the blood vessels to sites of injury. This is effective for single or multiple external or internal wounds.

The invention relates to pharmaceutical compositions and methods of treatment that promote hemostasis, slow or stop internal and/or external bleeding at sites of blood vessel injury. The compositions contain factor VIIa and fibrinogen.
Hemorrhage is the most common cause of death among injured or treated individuals including those who die prior to reaching care, who die in emergency medical care, e.g. emergency room, or who die in the operating room (Holcomb J B, Pusateri A E, MacPhee M J, Hess J R. New technologies in hemorrhage control. Current Opinion in Critical Care. 1997 December; 3:488-493; Holcomb J B, Pusateri A E, Harris R A, Reid T J, Hess J R, MacPhee M J. Dry fibrin sealant dressings reduce blood loss and improve survival in hypothermic coagulopathic swine with grade V liver injury. J Trauma. 1999 August; 46:233-242). The most common causes of death of individuals in post-operative critical care are those involving sequellae of poorly controlled hemorrhage and shock. In the prehospital setting, most internal bleeding is not accessible for direct intervention. In the hospital setting, there are sources of bleeding which cannot be immediately controlled with the best surgical techniques, e.g. deep liver injuries with liver vein disruption, pelvic ring fractures with direct bone bleeding, pelvic venous plexus tears, etc.
Blood coagulation is a complex process that involves formation of a preliminary clot by platelets followed by a cascade of events involving several factors that eventually leads to strengthening of the clot. A critical step in this process is the production of thrombin, a proteolytic enzyme. This enzyme is involved in aggregation of platelets and in the activation of cleavage of fibrinogen into fibrin. Fibrin forms much of the stabilizing matrix for the platelet plug. Through a multistep cascade, various blood coagulation proenzymes and procofactors that circulate in the blood are sequentially or simultaneously converted to their activated forms (designated by a lower case xe2x80x9caxe2x80x9d, e.g. factor VIIa). The proenzymes are generally inactive and are converted to the active form by proteolytic enzymes present in the cascade. This cascade involves two separate multistep pathways which lead to the conversion of prothrombin to thrombin.
The first pathway is rapid and is known as the extrinsic pathway. This pathway involves the activation of coagulation factor VII to factor VIIa (Jack Hirsh and Elizabeth A. Brain, Hemostasis and Thrombosis-A Conceptual Approach. (2d ed. 1983)). Coagulant factor VII circulates in the blood at a concentration of 0.5 xcexcg/ml plasma. The vast majority of circulating factor VII is inactive with about 1% of factor VII being in an active form. Activation of circulating factor VII requires exposure of factor VII to several cofactors. Factor VIIa, the active form, has little enzymatic activity until it complexes with tissue factor. Complex formation occurs at sites where the blood vessel endothelium is damaged or where underlying tissues, rich in tissue factor, is exposed, Also platelet activation exposes Factor VIIa to tissue factor that is normally stored internally in platelets. White blood cells will express tissue factor in response to inflammatory mediators and thereby cause the complex to be formed. Thus, seemingly large amounts of factor VIIa can circulate with little effect, but can be highly active at the requisite site by formation of the complex with tissue factor.
Activated factor VIIa converts factor X to factor Xa which in turn converts prothrombin to thrombin in the presence of the cofactors factor V, calcium ions and phospholipid.
The second, slower coagulation cascade is termed the intrinsic pathway and also involves factor VIIa as well. The intrinsic pathway comprises a series of reactions that leads to the activation of thrombin via activation of the Hageman factor (factor XII). This leads to the activation of factor XI which in turn results in the activation of factor IX in the presence of phospholipid. The activated factor IX (IXa), in the presence of factor VIII and phospholipid activates factor X, which cleaves prothrombin into the active form, thrombin. Factor VII is converted to the active form either by factor Xa in the presence of calcium and phospholipids, or by factor II (thrombin). In contrast to the extrinsic pathway, which leads to rapid blood coagulation at the point of injury, the intrinsic pathway strengthens the clot.
Factor VII has been purified and characterized as a single-chain glycoprotein of approximately 47,000 Daltons. It is converted to the active form by cleavage of an arginine-leucine bond which creates two chains held together by disulfide bonds (U.S. Pat. No. 5,504,067). Factor VIIa is more active than Factor VII by 100-fold. Efforts to use isolated factor VIIa in individuals with severe bleeding episodes have produced positive results, e.g. diminished blood loss of up to 50%. Recombinant factor VIIa has also been administered to individuals with various bleeding disorders, e.g. coagulation abnormalities with beneficial results.
Recombinant factor VIIa was also administered to a 19 year old Israeli soldier shot in the abdomen (Blauhut B. Indications for prothrombin complex concentrates in massive transfusions. Thromb Res 1999; 95(4 Supp 1):S63-9.). This patient arrived at the hospital in shock with a large paraspinal exit wound. Upon abdominal exploration, the patient was found to have multiple organ injuries and a laceration of the inferior vena cava. Surgeons rapidly repaired the injuries and tied off the inferior vena cava. At this point, the patient had received 40 units of blood. The patient was cold and coagulopathic, bleeding 300 ml/minute from soft tissue injuries. The surgeons thought the case was unsalvageable. However, upon administration of recombinant factor VIIa, the bleeding was immediately decreased to 15 ml/min, allowing surgeons to identify and the several more bleeding sites. A second dose of recombinant factor VIIa resulted in complete cessation of bleeding. Other conditions where beneficial results have been achieved include gastric ulcer bleeding from arterial erosion, thrombocytopathies, and children with dengue hemorrhage fever and shock.
A study (submitted for publication) was conducted involving recombinant factor VIIa as an adjunct to conventional liver packing for the treatment of a model of American Association for the Surgery of Trauma (AAST) grade 5 liver injury in swine rendered cold and coagulopathic by exchange transfusion of 60% of their blood volume with cold hydroxyethyl starch. This study examined the efficiency of factor VIIa on extreme cases where large amounts of blood loss have occurred and the patient is in trauma. It is well understood that patient chances of survival and quality of life will improve as blood loss is diminished. There was a 46% reduction in blood loss, which is a statistically significant decrease. The treatment corrected coagulopathy and caused no identifiable untoward effects.
Hemophilia is an excessive bleeding disorder due to the lack of one or more factors involved in the blood coagulation cascade. Hemophilia A is characterized by a lack of function associated with coagulation factor VIII, either through an absence of active factor VIIIa or inhibition of factor VIII. Hemophilia B is characterized by an absence of coagulation factor IX. Both forms of hemophilia are associated with bleeding disorders potentially leading to severe injury or death. In the 1970""s, hemophilia patients were sometimes treated with xe2x80x9cactive factor concentratesxe2x80x9d. These mixtures of the activated Vitamin K dependent factors (factors II, VII, IX, and X) were frequently effective in stopping hemophilic bleeding, but were associated with thrombotic side effects. Efforts to isolate the beneficial components in these mixtures culminated in 1982 with Hedner""s isolation of factor VIIa in pure form from large volumes of plasma and her subsequent successful treatment of bleeding episodes in two patients with hemophilia A (Hedner U. Treatment of Patients with factor VIII and factor IX inhibitors with special focus on the use of recombinant factor VIIa. Thromb Hemost 1999; 82:531-539). Since then, more than 2400 bleeding episodes in more than 500 hemophilia patients have been treated with the recombinant protein. The expanded use of recombinant factor VIIa is now being incorporated into patients with various bleeding disorders, including platelet dysfunction syndromes and patients on anticoagulants.
A shortcoming of this treatment and others is that factor VIIa does not provide any of the material components of the clot itself. Unfortunately, the addition of factor VIIa alone in many instances is insufficient to produce clinically significant results. Factor VIIa can be rendered ineffective if supporting components are not present or are depleted from the system, either by a genetic deficiency or decreased concentration due to a medical condition.
Fibrin has been used as an administered blood coagulant as early as 1909 when wound scabs were dried, powdered, and sprinkled on wounds (Tock B, Drohan W, Hess J, Pusateri A, Holcomb J, MacPhee M. Hemophilia and advanced fibrin sealant technologies. Hemophilia 1998; 4:449-455.). Fibrinogen was isolated from human plasma in bulk quantities by Cohn during World War II, who made fibrin glues and fibrinogen concentrates for infusion. The use of fibrinogen or cleaved fibrin was stopped because the purification process would isolate hepatitis virus along with the fibrinogen and put individuals at risk for viral infection. The FDA removed the last human fibrinogen products from the market on Dec. 31, 1977. As a result, clinicians switched to using single donor blood products, fresh frozen plasma and cryoprecipitate as sources of injectable fibrinogen to treat severe surgical bleeding.
The human fibrinogen protein ordinarily circulates in the plasma at concentrations of 2-4 g/L plasma. In the uncleaved form, fibrinogen is inert in the bloodstream, and the activated form is not normally found in healthy blood vessels. Activation by thrombin occurs by cleavage of small activation peptides from the free ends of the paired xcex1 and xcex2 chains. This converts fibrinogen to fibrin monomer by exposing xe2x80x9cstickyxe2x80x9d ends on the fibrin monomeric units. The polymer can be formed by building a matrix from fibrin monomers. Fibrin binds to collagen and receptors on platelets, anchoring it to tissue in wounds and the other components of the clot. Adherent clot begins to form at the edge of the wound and builds a mass of adherent clot which grows toward the center of the wound, recruiting platelets which form the basis for new activation sites.
Because fibrin is a structural protein, its effect is a direct function of the amount present. A correlation between fibrinogen content and clot strength has been reported. (Holcomb J B, Harris R A, MacPhee M J, Charles N C, Beall L D, Hess, J R. Effect of fibrin bandage fibrinogen concentration on blood loss after grade V liver injury in swine. Mil Med, accepted for publication). The concentration of fibrin in injured vessels is a direct function of the rate of production from fibrinogen and the rate of loss through the wound or from breakdown. The rate of fibrin production is a function of the thrombin enzyme activity and of the concentration of the fibrinogen substrate. Thus, when a wound is formed that breaks a blood vessel, blood is exposed to tissues which activate the coagulation system. Activation starts the clotting at the edge of the wound and builds a mass of adherent clot which grows toward the center of the wound by recruiting platelets which form the basis for new activation sites and tying them to the wound edge with fibrin. As long as the strength of the clot and its adherence to the wound edge are greater than the other forces operating on the wound such as blood pressure, the clot continues to grow and progressively occludes and seals the wound. This basic coagulation mechanism works well in small wounds, poorly in large arterial disruptions, and performs variably for wounds of intermediate severity.
All publications cited herein, including patent applications, are hereby incorporated by reference in their entirety.
The present invention includes compositions of factor VIIa and fibrinogen and methods of using these compositions to minimize or stop traumatic bleeding at internal and/or external wound sites by activating the blood clotting system at sites of injury. The composition may be used in the field. This should allow more individuals to reach the hospital alive with more of their own blood, thus minimizing the need for transfusions of plasma. This will also minimize the risk of introducing detrimental foreign agents and also economize the therapeutic benefit.
It is an object of the present invention to provide compositions and methods for treatment of bleeding episodes, such as hemorrhaging, hemophiliac bleeding and excessive bleeding due to platelet disorders. It is a further object of the present invention to provide compositions and methods for the therapy of individuals with blood clotting deficiencies. It is a further object of the present invention to provide compositions and methods for the therapy of individuals with bleeding disorders. The composition of the present invention can decrease blood loss and is easily transportable for use in remote locations.
Accordingly, in one aspect, the present invention provides compositions comprising factor VIIa and fibrinogen. Activated factor VIIa is capable of catalyzing the blood cloning cascade at sites of injury by facilitating the cleavage of fibrinogen to fibrin monomers that are used to build up the clot. In a preferred embodiment, factor VIIa is recombinantly produced to efficiently manufacture large quantities of factor VIIa while minimizing the risk of contamination. Activated factor VIIa is only functional at sites of blood vessel injury where there is exposure of tissue factor and factor VIIa will rapidly activate the coagulation cascade. In another preferred embodiment, fibrinogen is recombinantly produced to efficiently manufacture large quantities of fibrinogen while minimizing the risk of contamination. In a related aspect, the compositions of the present invention further contain one or more stabilizing agents. The compositions may be injected into the bloodstream of the individual where they can circulate to sites of injury. In some embodiments, the compositions are dissolved in a proper excipient for infusion. In other embodiments, the compositions are lyophilized for long term storage and ease of transportation.
Another embodiment relates to kits. A kit format would facilitate the use of factor VIIa and fibrinogen in a variety of situations, including those where immediate hospitalization is not possible or delayed, e.g., natural disasters, military combat locations, rural settings. The active components can be placed together or separately in one or more containers. In addition, the kits may include other items or materials which would be associated with a desired application including any excipient required for injection of factor VIIa and fibrinogen, device for injection (e.g. syringe), tourniquet, and alcohol cleaning packet. It is also contemplated that the fibrinogen, factor VIIa and any other sensitive active component or otherwise would be placed in a form and/or include materials which would promote stability of the compounds during storage including those which prevent microbial contamination. If the active materials are not in a form permitting direct use, the kit could include materials which aid in the conversion of the active ingredients to injectable form. Also, if desired, additional factors that may aid in the function of coagulation may be included. The kits also allow for convenient storage and transportation of the invention to remote locations.
In another aspect, the present invention provides methods for treating individuals with excessive bleeding. In a related aspect, the present invention provides methods for enhancing blood coagulation. In one embodiment, the present invention is used in individuals with mild to severe bleeding due to any variety of causes, including but not exclusive to: open wounds, liver hemorrhaging, hemophiliac bleeding episodes, bleeding disorders and blood clotting deficiencies. In a further embodiment, the present invention is administered to individuals in an amount effective to cause hemostasis. In yet a further embodiment, the present invention may be administered multiple times to cause hemostasis or to decrease bleeding.
The present invention includes effective formulations for treating hemorrhaging (i.e. induce coagulation, decrease bleeding, control bleeding, seal wounds). Each component is included in the composition in quantities sufficient to promote hemostasis. Factor VIIa is included in quantities to increase the amount of activated factor VIIa at sites of injury and promote the catalysis of clot formation. Fibrinogen is included in quantities to support maintenance of a circulating supply of clotting material.
The invention provides pharmaceutical compositions and methods for controlling bleeding, blood coagulation, and wound sealing. The composition comprising factor VIIa and fibrinogen effectively serves to activate the rapid blood coagulation factor cascade and provide the necessary components for strong clot formation. While introduction of these two factors is beneficial to hemostasis through decreasing blood clotting times, the benefit to the individual is also seen in the diminished blood loss, resulting in less cold transfusions and healthier individuals which translates into faster healing times. Also, rapid blood clotting means less blood loss into the local wound hematoma, meaning less blood to resorb and fewer complications, such as infection.
The coagulation combination of factor VIIa and fibrinogen may be injected into the bloodstream without putting individuals at high risk for blood vessel occlusion. The two components may be injected simultaneously or sequentially or at multiple sites to enhance delivery and/or effect depending on the situation. The activity of the components is dependent upon the components of the present invention circulating to the sites of injury. Since the factors are free to circulate in the bloodstream, they can be effective in hemostasis, or clot formation, or decreasing bleeding at multiple sites of injury. Because the components of the composition circulate to the sites of injury, the sites of injury do not have to be specified prior to administering treatment.
The combination of recombinant factor VIIa and fibrinogen is effective in cases of moderate and severe bleeding or wound sealing where direct pressure, tourniquets, indirect pressure (e.g. liver packing), surgical ligation, bandaging, and transfusion of blood or plasma products are typically used. Other methods previously used to induce coagulation (e.g. estrogen) or inhibit fibrinolysis (e.g. aprotinin) are effective for small wounds, but not effective in large vessel hemorrhage. The combination of factor VIIa and fibrinogen is administered intravenously, and the compositions are circulated to sites of injury. This is especially effective for multiple wounds, especially in cases where bleeding from damaged vessels is obstructive to treatment and observation and can complicate location of the bleeding sources, inaccessible internal bleeding and individuals with prolonged bleeding. This also saves time in treatment by not having to localize injury sites prior to treatment. The use of these two administered blood coagulation components can reduce bleeding by 50% or more, and can cause complete cessation of bleeding in as little as one administration.
Other conditions that can be treated with the combination of the present invention include use in surgery (e.g. central line incisions, atrioventricular shunts), surgical bleeding from the microvasculature, postoperative bleeding episodes, clinical procedures (e.g. needle biopsies), prophylactic administration during clinical procedures, dental procedures, surgery or procedure that is contraindicated in high risk individuals (e.g. cirrhosis patients) and platelet dysfunction. Also, the combination is useful in situations where stabilization of an individual may have a negative effect on the bleeding of the individual, including attempts at resuscitation, temporal factors associated with stabilizing an individual in an emergency room, and a xe2x80x9cbloody vicious cyclexe2x80x9d where care givers attempt to correct anatomy in the operating room, leading to long operations which result in more bleeding, more resuscitation with more hypothermia and dilutional coagulopathy leading to increased bleeding. The effect of administration of this combination is that it will extend the golden hour and save lives and limbs in trauma cases, military/combat related events where medical attention is removed, severe hemorrhaging (e.g. liver), stabilization of an individual (such that proper diagnosis may be performed). In addition, the increased ability to promote hemostasis minimizes necessity for blood product transfusions and reduces the need for tourniquets, effectively saving limbs.
Definitions
As used herein, a xe2x80x9crecombinantxe2x80x9d protein include those proteins made by recombinant techniques. These proteins include those which resemble the natural protein as well as those modified to enhance activity, protein half-life, protein stability, protein localization and protein efficacy.
An xe2x80x9cindividualxe2x80x9d is a vertebrate, preferably a mammal, more preferably a human. Mammals also include, but are not limited to, farm animals, sport animals and pets.
An xe2x80x9ceffective amountxe2x80x9d is an amount sufficient to offer beneficial or desired clinical results. An effective amount can be described in individual amounts, such as the quantity injected (e.g. 3 g fibrinogen material), or as the desired relative amounts (e.g. 160 IU/kg body weight). An effective amount can be administered in one or more administrations. For purposes of this invention, an effective amount of factor VIIa and fibrinogen is an amount that is sufficient to cause hemostasis, clot formation, decrease bleeding, blood coagulation, or decrease blood loss.
As used herein, xe2x80x9chemostasisxe2x80x9d is the arrest of bleeding, involving the physiological process of blood coagulation at ruptured or punctured blood vessels and possibly the contraction of damaged blood vessels.
As used herein, xe2x80x9ctreatmentxe2x80x9d is a method for obtaining beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of bleeding, stabilization of the individual, preventing bleeding. xe2x80x9cTreatmentxe2x80x9d can also mean prolonging survival of the individual.
As used herein, xe2x80x9cbleeding disorderxe2x80x9d is defined as decreased ability to control bleeding due to one of the following: vascular defects, thrombocytopenia, thrombocytopathia, defects in blood coagulation or excessive fibrinolytic activity.
The pharmaceutical combination of the present invention is used to cause hemostasis, wound sealing, blood clotting, decrease of blood loss or help effect blood coagulation. The pharmaceutical combination of the present invention can be manufactured and kept stable in a variety of dry and wet forms. The dry powders or the liquid solutions can be mixed, sterilely packaged, and stored for years dry or months wet. Both proteins are isolated by chromatography in essentially pure form at the end of production. Thus, the use of this pharmaceutical combination is safer than administering fresh frozen plasma, since it eliminates complications associated with other blood products (e.g. blood typing, foreign matter, viral contaminants). Other ingredients may be added for stability of the two components, such as sugars, polysaccharides, such as low molecular weight dextrins, polyalcohols such as glycerol, and antioxidants, such as bisulfite or ascorbate, which act as stabilizers during the lyophilization process, or vitamin K or albumin. Vitamin K is an essential element for factor VIIa activity and albumin has been shown to act as a stabilizer for factor VIIa activity. The stabilizing agents are generally present in a concentration from 0.1 to 5% weight/volume. The combination can be rehydrated easily in solution with appropriate excipients, such as but not limited to sucrose solution, saline or distilled water. Each excipient rapidly dissolves the components of the composition. The two proteins have no significant chemical or physical interactions in solution. The composition may be reconstituted and administered by a medic, corpsman, or medical staff member and use in remote settings is possible.
In some embodiments, one or both of the components of the present invention may be recombinantly produced or modified. A recombinant or modified form of either protein retains the functional characteristics of the native protein. The native activity may be assessed by a prothrombin assay to determine the effectiveness of the protein on blood coagulation time. The dosage of the components of the present invention depend upon the clinical situation including, but not limited to factors such as the inhibition or deficiency of clotting factors, the locations and severity of the hemorrhaging and the general physical condition of the individual. The dosage must be empirically evaluated by the clinician in their assessment of the most beneficial therapy for the individual. The components of the present invention may be administered sequentially or simultaneously. In most cases, the administration amount of factor VIIa is sufficient to produce a concentration of about up to 300 IU/kg body weight, preferably 25-250 IU/kg body weight, more preferably 50-200 IU/kg body weight, even more preferably 60-180 IU/kg body weight, although factor VIIa can be administered at higher concentrations if the situation warrants. One IU is the amount of factor VII and factor VIIa that circulates in 1.0 mL plasma of a normal person. The administration amount of fibrinogen is about up to 12.0 g/L plasma, preferably 0.25-10.0 g/L plasma, more preferably 0.5-6.0 g/L plasma, although fibrinogen can be administered at higher quantities if the situation warrants.
The administration of the composition of the present invention has activity from between 8-12 hours. An individual who has a bleeding episode may be reassessed and readministered the composition if bleeding has not decreased to an acceptable level. An acceptable level is defined as bleeding that is controlled and does not pose any threat to the life of the individual or cause any detrimental harm to the individual. The composition may be administered at time intervals much shorter than 8-12 hours, and may be as little as 0.5-2 hours. It must be noted that the components of the present invention have a limited biological half-life, which may factor into the frequency of administration. Thus, it may be beneficial to administer smaller doses more frequently. The composition of the current invention may be administered by bolus injection or by continuous infusion; the method of administration should be reflective of the purpose of administration. For example, if there is severe bleeding and complete or partial coagulation or decrease in bleeding is desired, a bolus injection would be preferred. In cases of prophylactic use, such as during controlled minor surgical procedures, a method of continuous infusion may be used.
The activation of factor VIIa leads to an approximate 100-fold amplification of thrombin formation, leading to the initiation of blood coagulation at the site of injury. Coupled to the increase in thrombin production is an increase in activity of platelets, resulting in an increase of platelet activation by 10,000-fold. Platelet activation results in further activation of the coagulation cascade and adhesion of platelets to the site of injury. The combination of activated coagulation factors results in an overall synergistic effect on blood coagulation by 1,000,000-fold.
In some embodiments the invention can be assembled into a kit. The kit would contain both components, factor VIIa and fibrinogen, as well as any necessary excipients, such as but not limited to saline and sucrose solution, and any additional factors for stabilization or effectiveness of the components of the composition, such as, but not limited to sugars, antioxidants, vitamin K, and albumin. Sugars and antioxidants act as stabilizers during the lyophilization process. In addition, the kit may comprise other elements involved in the delivery of the composition, including a device for injection of the composition of the current invention (e.g. syringe), tourniquet, and alcohol swab to clean the site of injection. Other elements may also be included in a kit including elements involved in wound closure such as suture material, needles and forceps. Having the present invention in a kit form would allow mobile use of the invention in locations not amenable for full hospital facilities.
The present invention is useful for states of bleeding, including traumatic hemorrhaging, inaccessible internal injuries, or individuals with bleeding episodes who have blood disorders.
Both elements of the present invention have excellent safety profiles. Hundreds of individuals get recombinant factor VIIa and tens of thousands receive fibrinogen in the form of blood products each day. Both components of the present invention are well characterized proteins that have been characterized in terms of distribution, metabolism, and excretion. The two components are not known to have any metabolic interference between the components or effects on clearance between the components or with other drugs to any significant extent that are likely to be used in subsequent surgical and medical care of the typical trauma victim.
Factor VIIa is defined as a polypeptide of about 47,000 Daltons and is involved in the coagulation cascade. Factor VIIa is further defined as any whole factor VIIa polypeptide or functional equivalent, including but not limited to deletions, insertions, mutations, modifications, truncations and transpositions of amino acids from the polypeptide sequence. The functionality of factor VIIa or a functional equivalent may be tested by administering a prothrombin assay. The prothrombin assay is commonly used in the art to determine effectiveness of a component to coagulate blood. The prothrombin assay is performed by adding tissue extract and calcium to plasma and added factor VIIa or a putative functional equivalent. This will initiate clotting in a functional system and if the added factor VIIa or putative functional equivalent is functional, then the coagulation time should decrease with respect to a control sample in which factor VIIa or a putative functional equivalent was not added.
Factor VIIa can be prepared as previously described (Fair et al., 1983). The factor VIIa protein can be recombinantly produced or modified as well. The essential difference between the recombinant factor VIIa protein and non-recombinant factor VIIa protein is that a recombinant factor VIIa protein is produced by recombinant techniques. The protein may be modified in a number of ways, including but not limited to chemical modification, glycosylation, methylation, hydroxylation, amino acid deletion, insertion, mutation, truncation and transposition. A recombinant form of factor VIIa will still retain the functional characteristics of native factor VIIa. The functionality of the recombinant protein may be tested using a prothrombin assay to determine the effectiveness of the protein on blood coagulation time. The benefit of using the recombinant activated form is that large quantities can be safely, effectively and economically produced. The amino acid sequence of factor VII (Hagen et al., 1986) is converted to the mature form by removing the leader sequence of 60 amino acids and activation occurs by cleavage of a peptide bond between arginine-212 and isoleucine-213. This cleavage may be accomplished in vitro by incubation of the factor VII protein with factor Xa. Alternatively, recombinant factor VIIa is commercially available from Novo Nordisk (Bagsvaerd, Denmark). The administration dose of factor VIIa is effective to produce in the plasma an effective level of about up to 300 IU/kg body weight, preferably between 25-250 IU/kg body weight, more preferably between 50-200 IU/kg body weight, even more preferably between 60-180 IU/kg body weight, although factor VIIa may be administered in higher concentration. It is known that an average individual has about 40 mL of plasma per kilogram of body weight and that in normal circulation, there is about 1 IU factor VII and factor VIIa per milliliter of plasma. Thus, there is about 40 IU/kg body weight with 99% being the inactive factor VII form. Addition of 180 IU/kg body weight of activated factor VIIa would yield a total of about 220 IU/kg body weight, of which 82% would be the active factor VIIa form. Increasing the administration to 300 IU/kg results in 88% of circulating factor VII being the active factor VIIa form. Thus, while the concentration may be increased beyond 300 IU/kg body weight, there is a diminishing return on increased percentage of active factor VIIa. Albumin or other stabilizing agents present should be at a concentration from about 0.1-5% weight/volume.
It is a necessary aspect of the invention that factor VIIa is in an activated form. Normal circulating levels of factor VIIa represent only 1% of circulating factor VII. The activated factor VIIa must compete at sites of injury with the inactive factor VII for binding to tissue factor. By introducing additional quantities of factor VIIa, the likelihood of factor VIIa binding to tissue factor, as opposed to inactive factor VII binding tissue factor may be increased from 1% to 25%, preferably 50%, more preferably 60%, 70%, or 80% or greater.
The administration of factor VIIa may be of benefit for individuals suffering from a bleeding episode, including those with brain injury. Brain has the highest concentrations of tissue factor in the body (Bouchard B A, Shatos M A, Tracy P B. Human brain pericytes differentially regulate coagulation. Atherioscler Thromb Vasc Biol 1997; 17:1-9). The only clinical experience is in individuals with hemophilia who occasionally bleed into their head. Treatment with recombinant factor VIIa has reduced the mortality of this complication from 50% to 8%. Its effect on individuals with normal coagulation is not known.
The human fibrinogen protein ordinarily circulates in high quantities in plasma (2-4 g/L). Fibrinogen acts as a plug substrate for sealing vessel injury sites. At times of injury, the body is stimulated to produce excess amounts of fibrinogen. The activation response to produce increased quantities of fibrinogen produces levels of fibrinogen 2-3 times the normal level. This upregulation and production of fibrinogen takes approximately 1-2 days, at which time large quantities of blood loss may have already occurred. This delayed process is often ineffectively late in cases of severe bleeding or bleeding at critical sites. Introduction of fibrinogen will increase the concentration of fibrinogen in the plasma in a shorter time period. Thus, the introduction of excess fibrinogen will allow the extrinsic coagulation pathway to occur without being hindered by a lack of fibrinogen working material. Use of plasma and blood products have been used to replenish the diminished supply of fibrinogen in the past. A single dose of 3-10 grams of fibrinogen is equivalent to the fibrinogen content of 10-25 units of fresh frozen plasma or cryoprecipitate.
Fibrinogen is further defined as any whole fibrinogen polypeptide or functional equivalent, including but not limited to deletions, insertions, mutations, modifications, truncations and transpositions of amino acids from the polypeptide sequence. The functionality of fibrinogen or a functional equivalent may be tested by administering a prothrombin assay to determine the effectiveness of the polypeptide on blood coagulation time.
It is now possible to manufacture injectable fibrinogen solutions which are virus-free. Fibrinogen may be produced by bulk purification from plasma and followed by further purification with detergent treatment or other means to inactivate contaminants such as viral contaminants, for example Hepatitis virus particles. Alternatively, fibrinogen is commercially available from multiple companies (e.g. Baxter, Alpha Therapeutics). Alternatively, fibrinogen may be recombinantly produced. The essential difference between the recombinant fibrinogen polypeptide and non-recombinant fibrinogen polypeptide is that a recombinant fibrinogen polypeptide is produced by recombinant techniques. The fibrinogen polypeptide may be modified in a number of ways, including but not limited to chemical modification, glycosylation, methylation, hydroxylation, amino acid deletion, insertion, mutation, truncation and transposition. A recombinant form of fibrinogen polypeptide will still retain the functional characteristics of native fibrinogen polypeptide. The functionality of the recombinant protein may be tested using a prothrombin assay to determine the effectiveness of the polypeptide on blood coagulation time. The essential difference between recombinant fibrinogen and non-recombinant fibrinogen is that recombinant fibrinogen does not occur in nature, or contains elements or modifications not normally found in nature. The benefit of using the recombinant activated form is that large quantities can be safely, effectively and economically produced.
Fibrinogen is relatively less soluble than some other plasma proteins. 10% solutions (1 g/10 mL) are feasible, whereas solutions above 15% are viscous and difficult to rehydrate. Attempts at modifying fibrinogen have resulted in decreased solubility. A normal individual weighing 70 kg has about 3 liters of plasma volume each containing 2-4 g/L of fibrinogen. A dose of 3 grams, which would insure the minimum plasma fibrinogen concentration of 1 g/L and raising the plasma concentration by 25-50% can be formulated and administered in as little as 30 mL. Fibrinogen may be administered in a dosage effective to produce in the plasma an effective level of about up to 12.0 g/L, preferably 0.25-10.0 g/L, more preferably 0.5-6.0 g/L, although fibrinogen may be administered in higher quantities. Factors that may be involved in determining the amount of fibrinogen administered include the amount of fibrinogen suspected to be lost through bleeding, the number and severity of hemorrhaging sites, and the location of injection(s). For example, higher overall fibrinogen quantities may be achieved by multiple injections of 6.0-12.0 g injections near multiple sites of hemorrhaging injury.
Safety considerations regarding the administration of blood products have previously prevented the administration of blood products to individuals with plasma fibrinogen concentrations greater than 1 g/L. The clinical argument is that bleeding in individuals with plasma concentrations for fibrinogen greater than 1 g/L indicates a surgical, rather than coagulopathic matter. This has been found to not necessarily be the case and it may be advantageous to administer the clot forming substrate fibrinogen, especially in individuals who have been bleeding profusely and have diminished quantities of fibrinogen. Likewise, safety precautions prevent the administration of activated fibrin, which may form unwanted thrombi within blood vessels at random locations.
The combination of the present invention is administered by infusion using a pharmaceutically acceptable carrier such as, but not limited to, simple sugar solutions, saline or buffered saline. Factor VIIa is administered in a dosage effective to produce in the plasma an effective level of about up to 300 IU/kg body weight, preferably between 25-250 IU/kg body weight, more preferably between 50-200 IU/kg body weight, even more preferably between 60-180 IU/kg body weight. Fibrinogen is administered in a dosage effective to produce in the plasma an effective level of about up to 12.0 g/L, preferably 0.25-10.0 g/L, more preferably 0.5-6.0 g/L plasma.
Intravenous injection of the two components, factor VIIa and fibrinogen, is a safe means of administration that allows the two components to circulate to sites of blood vessel injury. The composition of the present invention may be injected in a bolus injection or through continuous infusion. The two components are active only at locations of vessel damage and can be effective at multiple injury sites, including internal wounds that are inaccessible, or combinations of internal and external hemorrhaging, or injuries that can only be treated by packing (e.g. liver hemorrhaging). None of the components of the invention is thrombotic in normal vessels. Recombinant factor VIIa is only effective at locations where the endothelium has been breached and the factor VIIa protein is accessible to tissue factor. Factor VIIa circulates with a relatively long half-life, about 8-12 hours in plasma. Fibrinogen can only be converted to the matrix forming fibrin following a series of events involving factor VIIa at sites of injury. This combination activates factors IX and X to activate thrombin which breaks down fibrinogen to form fibrin monomer. Factor IX, X and thrombin (factor II) cannot be injected due to the significant risk of causing intravessicular blood clots. Activated factor VIIa is 100 times more functional in the presence of tissue factor, which is exposed at blood vessel injury sites. This means that the combination is preferentially active at sites of injury, where it is needed for hemostasis, or wound sealing, or decreasing bleeding or blood coagulation.
The following examples are provided to illustrate but not limit the invention.

Compositions for treatment of hemorrhaging with activated factor VIIa in combination with fibrinogen and methods of using same

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


An apparatus and method thereof for sampling multipath signal data in a receiver. The apparatus includes a plurality of demodulators coupled in parallel, each of the plurality of demodulators receiving digital baseband signal data and demodulating the digital baseband signal data, a controller coupled to the plurality of demodulators, and a timer coupled to the controller. The timer generates a controller interrupt at a specified frequency. The controller interrupt causes the controller to sample demodulated signal data from the plurality of demodulators. The specified frequency is greater than the symbol rate.

The present invention pertains to the field of wireless communication technology. More specifically, the present invention pertains to demodulating and processing signals received by a receiver in a spread spectrum communication system.
Wireless telephony has become a widely available mode of communication in modern society. Variable rate communication systems, such as Code Division Multiple Access (CDMA) spread spectrum systems, are among the most commonly deployed wireless technology. Variable rate communication systems transmit data in units called data frames.
A CDMA system utilizes digital encoding for every telephone call or data transmission in order to provide privacy and security. Unique codes are assigned to every communication, which distinguish it from the multitude of calls simultaneously transmitted over the same broadcast spectrum. Users share time and frequency allocations and are channelized by unique assigned codes. The signals are separated at the receiver in a known manner so that the receiver accepts only signals from the desired channel.
One of the main advantages of a CDMA system is the capability to use signals that arrive at the receiver with different time delays, referred to as multipath. The different time delays are caused by, for example, the receiver location and the path taken by the transmitted signal (e.g., the signal might reflect off of a building). CDMA combines the multipath signals to create a stronger signal at the receiver.
In a typical implementation, a CDMA receiver (e.g., a rake receiver) uses multiple receivers or demodulators (referred to as fingers). Each finger demodulates the signal, and the results are combined to make a stronger signal.
Prior Art FIG. 1 illustrates an exemplary receiver 10 of the prior art. The transmitted signal is received by analog transceiver 12 using an antennae (not shown). Analog transceiver 12 digitizes the received signal and provides the results to digital transceiver 14. Each demodulator 15a, 15b, 15c and 15d (e.g., fingers) is assigned to demodulate the transmitted signal that traveled by a different path to receiver 10 (that is, a multipath signal). Digital transceiver 14 also includes processing hardware 16 for operations such as combining, deinterleaving, and decoding.
A disadvantage to the prior art is the use of hardware for operations such as combining, deinterleaving, and decoding. In particular, the use of hardware for these operations limits the flexibility available for implementing different approaches. For example, the hardware is likely designed for a particular approach, and thus may not be readily adaptable to different approaches. Hardware components can also be expensive to manufacture. Software, on the other hand, can provide greater flexibility and may also be less expensive than hardware. Thus, in some instances it is desirable to replace the hardware with software or a combination of hardware and software.
When software is introduced, the functions formerly performed with hardware will be performed with different techniques that can be used in software. One such hardware function is accounting for the time offsets associated with the different arrival times of multipath signals. The time delays are asynchronous. Hardware implementations (e.g., processing hardware 16) account for the time offsets using various techniques known in the art.
With software, the multipath signal is demodulated by each finger and the resulting data are stored in a buffer (other operations known in the art may also be performed). In each finger, the data are integrated until one symbol (equivalent to 64 chips) is stored. When one symbol is stored in a finger, that finger generates an interrupt that is sent to the processor (e.g., a digital signal processor, DSP). In response to the interrupt, the processor reads the stored symbol from that finger and processes the symbol data. At the same time, data from other fingers can also be read and processed.
For the purpose of reducing overall power consumption in the receiver, it is desirable to put the processor into xe2x80x9csleepxe2x80x9d mode whenever possible. Otherwise, the processor continues to consume the full power it needs, reducing the time between battery charges or necessitating larger batteries. Consumers desire less expensive, lighter and convenient receivers, and so increasing the frequency of battery charges or the size of the battery is contrary to consumer preferences.
However, the prior art is problematic because of the different time offsets associated with a multipath signal. As a result of the offset, each finger will store a symbol at different times. Hence, interrupts are sent to the processor frequently. Frequent interrupts to the processor either do not provide the opportunity to place the processor into sleep mode, or reduce the amount of time that the processor is in sleep mode. For example, each time the processor is ready to enter its sleep mode, an interrupt is received and so the processor is constantly xe2x80x9cawakexe2x80x9d and at full power; or, just as the processor enters its sleep mode, it may be xe2x80x9cawakenedxe2x80x9d by another interrupt and so is not powered down for an extended period. In some instances, additional power is needed to wake up the processor, and so frequent wakeups can also increase overall power consumption and reduce the time between battery charges.
Another disadvantage to the prior art is that frequent interrupts can disrupt or delay the other processing functions performed by the processor. That is, if the processor is servicing an interrupt, it may not be able to perform other processing that is needed. As a result, the other processing functions are delayed or slowed, reducing the overall performance of the receiver.
Accordingly, what is needed is an apparatus that can be used with software and that can efficiently account for the asynchronous time offsets associated with multipath signals. What is also needed is an apparatus that addresses the above needs and reduces the number of processor interrupts, reduces processor power consumption, and improves processing performance. The present invention provides a novel solution to the above needs.
These and other objects and advantages of the present invention will become obvious to those of ordinary skill in the art after having read the following detailed description of the preferred embodiments which are illustrated in the various drawing figures.
The present invention provides an apparatus and method thereof that can be used with software and that can efficiently account for the asynchronous time offsets associated with multipath signals. The present invention also provides an apparatus and method thereof that address the above needs, reduce the number of processor interrupts, reduce processor power consumption, and improve processor performance.
The present embodiment of the present invention pertains to an apparatus and method thereof for sampling multipath signal data. In a preferred embodiment, the apparatus is disposed within a receiver used in a communication system, in particular a communication system that uses code division multiple access (CDMA) spread spectrum type communication signals (e.g., multipath signals).
In the present embodiment, the apparatus includes a plurality of demodulators, each of the plurality of demodulators receiving signal data and demodulating the signal data, a controller coupled to the plurality of demodulators, and a timer coupled to the controller. The timer generates a controller interrupt at a specified frequency. The controller interrupt causes the controller to sample demodulated signal data from the plurality of demodulators. In one embodiment, the specified frequency is greater than the symbol rate. In another embodiment, the specified frequency is equal to the symbol rate.
In one embodiment, each demodulator includes a buffer, and the demodulated signal data are stored in the buffer. The demodulated signal data stored in the buffer subsequent to a controller interrupt can be distinguished from the demodulated signal data stored in the buffer prior to the controller interrupt (for example, by using a status bit).

Efficient method of providing symbol data from demodulator to a processor

Philips Electronics North American Corporation


A soil adjuvant, comprising dried glutamic acid fermentation solubles, dried corn fermentation solubles, or a mixture of dried glutamic acid fermentation solubles and dried corn fermentation solubles, wherein said dried solubles have been dried to a total moisture content of less than 30% by weight at a temperature not less than about 80xc2x0 F. and not more than about 900xc2x0 F. The dried fermentation solubles can be mixed with a carrier, such as corn middlings, in a ratio of 1:10 to 10:1 by weight.

Not Applicable.
This invention relates principally to usage of glutamic acid fermentation solubles, and corn fermentation solubles, for application as a soil adjuvant.
Soil fertility, the ability of the soil to supply nutrients to plants, is a major factor in the production of forages, row crops, and horticultural ornaments. Plants need to be supplied either naturally or artificially with phosphorus (P), calcium (Ca), magnesium (Mg), potassium (K) and nitrogen (N). Applying nutrients to maintain and improve soil fertility becomes necessary as soils are depleted of nutrients by crop removal, leaching, and erosion and as attempts are made to push yields higher and higher.
Modern agricultural and horticultural practice requires artificial supplementation of soils with the nutrients plants need to grow. These nutrients are supplied in blends and marketed under the generic term fertilizer. Commonly, fertilizers are formulated using industrial byproducts. These byproducts often contain contaminants such as heavy metals, which are environmentally damaging. In addition, conventional blends of nitrogen, macro and micronutrients can themselves be environmentally problematic due to their highly soluble nature. Often times, these materials are applied during periods that do not allow for maximum plant uptake or degradation by soil microflora. This causes these materials to leach through the soil or actually run off and become major sources of environmental contamination, seriously polluting ground water, lakes, rivers, and streams. Although encapsulation technology of conventional fertilizers does reduce degradation rate, it does not eliminate entirely, the inherent environmental hazards of these materials. This is because these materials do not contain the full spectrum of nitrogen sources that are required by soil bacteria, molds, and fungi to maximize nitrogen degradation. Attempts to rectify this problem through the supplementation of other nitrogen sources such as animal or poultry waste have not proven successful due to the solubility of the nitrogen contained in these materials and their high content of macro minerals, particularly phosphorus. Government has recognized this problem as a major threat to potable water supplies as well as to fresh and saltwater fisheries and to the overall maintenance of a healthy global ecosystem. Legislation has already been passed to control the rates and times of soil fertilization, but environmental control through the law is expensive and inefficient. One solution is to develop a method for soil fertilization that takes full advantage of soil dynamics through the supplementation of nitrogen in a form that varies in its structural complexity and availability. This material would actually stimulate the growth of soil microflora, which in turn would maximize nutrient availability for plants under cultivation, thus eliminating the risk of run off associated with inefficient nutrient use.
This invention contemplates the use of a composition which is obtained from glutamic acid fermentation solubles, corn fermentation solubles, or a mixture thereof, and any other related source materials that provide the components of these types of fermentation solubles. The solubles are dried to a maximum moisture content of about 30%, at a low temperature. The solubles are preferably dried to a moisture content somewhere in the vicinity of 14%, more or less, for use as a soil adjuvant. The dried fermentation solubles are then blended with a source of organic and inorganic nitrogen, of variable solubles in the form of nonprotein nitrogen, peptides, amino acids, and intact protein, derived in the preferred embodiment of the invention from glutamic acid fermentation solubles and/or corn fermentation solubles to which a carrier and additional amino acids may be added.
The application of this material to soil will stimulate the growth of both aerobic and anaerobic populations of soil microflora. These bacteria, molds and fungi convert the material into an organic biomass as well as into inorganic components made available at the rates regulated by the action of the microflora themselves. The net result is nutrient availability in a form and rate that maximizes plant growth while simultaneously minimizing nutrient leaching and run off.
I have found that a composition of dried freed amino acids, peptides, organic and inorganic nitrogen, as well as structural fiber and nonstructural carbohydrates as needed is useful as a soil adjuvant that stimulates soil bacterial growth. The soil adjuvant stabilizes soil nutrient dynamics with the specific objective of maximizing plant uptake of nutrients while preventing loss of nutrients through leaching and run off.
In the preferred embodiment of the invention, this composition is obtained from either glutamic acid fermentation solubles, corn fermentation solubles or a mixture thereof. Any other source material that provides the components of these fermentation solubles may be used. Some common sources are fermentation byproducts derived from a fermentation of fungal or bacterial origin. Examples include corn step liquor, corn distiller""s solubles, and rye distiller""s solubles. The origin of the base materials is not important. A carrier such as wheat middlings, etc., can be included if desired and in view of the drying method used. Any amount of carrier can be used. Typical ratios (wt/wt) of dried solubles to wheat middlings are from about 10:1 to about 1:10 including all values and subranges there between. Either of these solubles alone or individually, blended onto a carrier if necessary, are suitable. When the corn and glutamic acid fermentation solubles are mixed, they are mixed in any proportion, either before or after drying and each optionally on a carrier if mixed dry.
The one or more solubles is then dried to a maximum moisture content of about 30% at low temperature. Moisture contents of 0%, 8%, 14%, etc., are acceptable. Drying methods which may be used include vacuum drying, direct and indirect heat application, spray drying, evaporation, etc. A forced air grain processor, otherwise useful to roast soybeans, is preferred. Regardless of the method used, drying must be done at temperatures which will allow for modification of the solubility of the nitrogen fractions without denaturing them.
I have provided a blended source of organic and inorganic nitrogen of variable solubilities in the form of nonprotein nitrogen, peptides, amino acids and intact protein derived, in the preferred embodiment of the invention, from glutamic acid fermentation solubles and/or corn fermentation solubles to which a carrier and additional amino acids can be added, and which is superior to prior art compositions.
Glutamic acid fermentation solubles and corn fermentation solubles are the liquid effluents having greater than 30 wt. % water (moisture), typically 50-60% from the bacterial fermentation process used to produce monosodium glutamate and lysine hydrochloride, respectively. These processes are well known and common manufacturing processes, and the nomenclature by which these products are defined has been determined by the Association of American Feed Control Officials. Glutamic Acid Fermentation Solubles are comprised of a combination of water, nonprotein nitrogen, primarily in the form of ammonium chloride, peptides and free amino acids derived from the hydrolysis of the microorganisms used to produce the fermentation, glutamic acid and inorganic salts such as MgSO4, NaCl, KH3PO4. Corn Fermentation Solubles are comprised of a combination of water, nonprotein nitrogen, primarily in the form of ammonium sulfate, peptides and free amino acids derived from the hydrolysis of the microorganisms used to produce the fermentation and inorganic salts such as MgSO4, NaCl and MnSO4.
Any amino acid may be added to the invention mixture described above.
The invention is useful as soil adjuvant for any agronomic or horticultural use.
The invention soil adjuvant may be applied to the soil at any time during the production cycle. The amount added will generally vary with the soil type and plant species to be fed.
Having generally described this invention, a further understanding can be obtained by reference to certain specific examples which are provided herein for purposes of illustration only and are not intended to be limiting.

Method for the production of a unique soil adjuvant for horticultural and agronomic use


Methods and devices for coupling the output light energy of one or more stacked laser emitter bar arrays using a beam interleaver and beam combiner to achieve high brightness and coupling efficiency. Some embodiments may include wavelength control devices and methods such as VIGs and the like.

Applications requiring light energy and specifically laser energy may benefit from the use of solid state light sources such as laser diodes which are commonly available, reliable to operate and relatively cost effective as a laser energy source. Such devices may include a plurality of laser emitters in a single bar that emit laser light simultaneously in a common direction. In addition, multiple solid state or laser emitter bars may be disposed in a stacked configuration so as to generate even higher power levels. Typically the emitters of such solid state emitter bars are spaced from each other to allow sufficient cooling without the need for elaborate and expensive cooling systems.
Laser diode bars are often used for communication technology devices, medical applications and other applications where it is desirable to couple the output of all the emitters of a single solid state emitter bar or multiple bars in a stacked configuration into a single optical fiber or other optical conduit. The spatial distribution of the emitters of a bar or stack of solid state emitter bars can make coupling the output of multiple emitters challenging, particularly when coupling to a small diameter optical fiber.
While the use of a micro-lens array reduces the divergence angle among the longitudinally separated beams emanating from the emitters of a bar, a solid state emitter bar which incorporates several, transversely separated emitters requires that an objective lens or lenses having a large numerical aperture be used if the beam is to be concentrated into a usefully small spot. Large numerical aperture objective lenses tend to be expensive. The problem becomes even more difficult when more power is required than can be delivered by a single laser bar. If it is attempted to use two laser bars, the lateral separation of their beams adds to the difficulty.
As such, what has been needed are methods and devices for coupling the output of multiple emitters of a laser emitter bar or stacked laser emitter bar array while maintaining a high degree of brightness and coupling efficiency.

Coupling devices and methods for stacked laser emitter arrays


The present invention relates to chemical compounds having a general formula I

Protein kinases represent a large family of enzymes, which catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. Common points of attachment for the phosphate group to the protein substrate include, for example, a tyrosine, serine or threonine residue. For example, protein tyrosine kinases (PTKs) are enzymes, which catalyze the phosphorylation of specific tyrosine residues in cellular proteins. Examples of kinases in the protein kinase family include, without limitation, ab1, Akt, Aurora-A, Aurora-B, bcr-ab1, Blk, Brk, Btk, c-kit, c-Met, c-src, c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK, Yes, and Zap70. Due to their activity in numerous cellular processes, protein kinases have emerged as important therapeutic targets.
Protein kinases play a central role in the regulation and maintenance of a wide variety of cellular processes and cellular function. For example, kinase activity acts as molecular switches regulating cell proliferation, activation, and/or differentiation. Uncontrolled or excessive kinase activity has been observed in many disease states including benign and malignant proliferation disorders as well as diseases resulting from inappropriate activation of the immune system (autoimmune disorders), allograff rejection, and graft vs host disease. In addition, endothelial cell specific receptor PTKs, such as VEGF-2, Tie-2 and Lck mediate the angiogenic process and are, therefore, involved in supporting the progression of cancers and other diseases involving uncontrolled vascularization.
Angiogenesis is the process of developing new blood vessels, particularly capillaries, from pre-existing vasculature and is an essential component of embryogenesis, normal physiological growth, repair, and tumor expansion. Angiogenesis remodels small vessels into larger conduit vessels, a physiologically important aspect of vascular growth in adult tissues. Vascular growth is required for beneficial processes such as tissue repair, wound healing, recovery from tissue ischemia and menstrual cycling.
Certain diseases and/or pathological conditions develop as a result of, or are known to be associated with, the regulation and/or deregulation of angiogenesis. For example, ocular neovascularisation such as retinopathies (including diabetic retinopathy), age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, and arteriosclerosis have been found to be caused, in part, due the loss of regulation and/or maintenance of vascular growth. Inflammatory diseases such as a rheumatoid or rheumatic inflammatory disease, and especially arthritis (including rheumatoid arthritis) where new capillary blood vessels invade the joint and destroy cartilage, have been associated with angiogenesis. In addition, chronic inflammatory disorders such as chronic asthma, arterial or post-transplantational atherosclerosis, endometriosis, and neoplastic diseases including so-called solid tumors and liquid tumors (for example, leukemias), have been found to be linked to the regulation and control of angiogenesis.
The involvement of angiogenesis in major diseases has lead to the identification and development of various targets for inhibiting angiogenesis. These targets relate to various receptors, enzymes, and other proteins in the angiogenic process or cascade of events leading to angiogenesis, such as, for example, activation of endothelial cells by an angiogenic signal, synthesis and release of degradative enzymes, endothelial cell migration, proliferation of endothelial cells, and formation of capillary tubules.
One target identified in the cascade of events leading to angiogenesis is the Tie receptor family. The Tie-1 and Tie-2 receptors are single-transmembrane, tyrosine kinase receptors (Tie stands for tyrosine kinase receptors with immunoglobulin and EGF homology domains). Tie-2 is an endothelial cell specific receptor tyrosine kinase, which is involved in angiogenic processes, such as vessel branching, sprouting, remodeling, maturation and stability. Tie-2 is the first mammalian receptor for which both agonist ligand(s) (for example, Angiopoietin-1 ("Ang1") which binds to and stimulates phosphorylation and signal transduction of Tie-2), and context dependent agonist/antagonist ligand(s) (for example, Angiopoietin-2 ("Ang2")) have been identified. Knock out and transgenic manipulation of the expression of Tie-2 and its ligands indicates that tight spacial and temporal control of Tie-2 signaling is important for the proper development of new vascularization.
Biological models suggest that the stimulation of Tie-2 by the Ang1 ligand is directly involved in the branching, sprouting and outgrowth of new vessels, and recruitment and interaction of periendothelial support cells important in maintaining vessel integrity and inducing quiescence. The absence of Ang1 stimulation of Tie-2 or the inhibition of Tie-2 autophosphorylation by Ang2, which is produced at high levels at sites of vascular regression, may cause a loss in vascular structure and matrix contacts resulting in endothelial death, especially in the absence of growth/survival stimuli.
Recently, upregulation of Tie-2 expression has been found in the vascular synovial pannus of arthritic joints of humans, consistent with the role in inappropriate neovasculariation. This finding suggests that Tie-2 plays a role in the progression of rheumatoid arthritis. Point mutations producing constitutively activated forms of Tie-2 have been identified in association with human venous malformation disorders. Tie-2 inhibitors would, therefore, be useful in treating such disorders, as well as in other instances of improper neovasacularization. However, with the recent recognition of Ang3 and Ang4 as additional Tie-2 binding ligands, targeting a Tie-2 ligand-receptor interaction as an anti-angiogenic therapeutic approach is less favorable. Accordingly, a Tie-2 receptor kinase inhibition approach has become a strategy of choice.
Another angiogenic factor responsible for regulating the growth and differentiation of the vascular system and its components, both during embryonic development and normal growth, as well as in a wide number of pathological anomalies and diseases, is Vascular Endothelial Growth Factor ("VEGF"; originally termed "Vascular Permeability Factor", VPF), along with its cellular receptors (see G. Breier et al., Trends in Cell Biology, 6:454-456 (1996)).
VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein related to "Platelet-Derived Growth Factor" (PDGF). It is produced by normal cell lines and tumor cell lines; is an endothelial cell-specific mitogen; shows angiogenic activity in in vivo test systems (e.g. rabbit cornea); is chemotactic for endothelial cells and monocytes; and induces plasminogen activators in endothelial cells, which are involved in the proteolytic degradation of extracellular matrix during the formation of capillaries. A number of isoforms of VEGF are known, which show comparable biological activity, but differ in the type of cells that secrete them and in their heparin-binding capacity. In addition, there are other members of the VEGF family, such as "Placenta Growth Factor" (PlGF) and VEGF-C.
VEGF receptors (VEGFR) are also transmembrane receptor tyrosine kinases. They are characterized by an extracellular domain with seven immunoglobulin-like domains and an intracellular tyrosine kinase domain. Various types of VEGF receptor are known, e.g. VEGFR-1 (also known as flt-1), VEGFR-2 (also known as KDR), and VEGFR-3.
A large number of human tumors, especially gliomas and carcinomas, express high levels of VEGF and its receptors. This has led to the belief that the VEGF released by tumor cells stimulates the growth of blood capillaries and the proliferation of tumor endothelium in a paracrine manner, and through the improved blood supply, accelerate tumor growth. Increased VEGF expression could explain the occurrence of cerebral edema in patients with glioma. Direct evidence of the role of VEGF as a tumor angiogenesis factor in vivo has been shown in studies in which VEGF expression or VEGF activity was inhibited. This was achieved with anti-VEGF antibodies, with dominant-negative VEGFR-2 mutants, which inhibited signal transduction, and with antisense-VEGF RNA techniques. All approaches led to a reduction in the growth of glioma cell lines or other tumor cell lines in vivo as a result of inhibited tumor angiogenesis.
VEGF's are unique in that they are the primary angiogenic growth factors known to contribute to vascular hyperpermeability and the formation of edema. Indeed, vascular hyperpermeability and edema that is associated with the expression or administration of many other growth factors appears to be mediated via VEGF production.
Inflammatory cytokines stimulate VEGF production. Hypoxia results in a marked upregulation of VEGF in numerous tissues, hence situations involving infarct, occlusion, ischemia, anemia, or circulatory impairment typically invoke VEGF/VPF-mediated responses. Vascular hyperpermeability, associated edema, altered transendothelial exchange and macromolecular extravasation, which is often accompanied by diapedesis, can result in excessive matrix deposition, aberrant stromal proliferation, fibrosis, etc. Hence, VEGF-mediated hyperpermeability can significantly contribute to disorders with these etiologic features. As such, the regulation of angiogenesis via the VEGF receptor activity has become an important therapeutic target.
Angiogenesis is regarded as an absolute prerequisite for tumors that grow beyond a diameter of about 1-2 mm. Up to this size, oxygen and nutrients may be supplied to the tumor cells by diffusion. Every tumor, regardless of its origin and its cause, is thus dependent on angiogenesis for its growth after it has reached a certain size.
Three principal mechanisms play an important part in the activity of angiogenesis inhibitors against tumors: 1) Inhibition of the growth of vessels, especially capillaries, into vascular resting tumors, with the result that there is no net tumor growth owing to the balance that is achieved between cell death and proliferation; 2) Prevention of the migration of tumor cells owing to the absence of blood flow to and from tumors; and 3) Inhibition of endothelial cell proliferation, thus avoiding the paracrine growth-stimulating effect exerted on the surrounding tissue by the endothelial cells which normally line the vessels. See R. Connell and J. Beebe, Exp. Opin. Ther. Patents, 11:77-114 (2001).
The inhibition of vascular growth in this context has also shown beneficial effects in preclinical animal models. For example, inhibition of angiogenesis by blocking vascular endothelial growth factor or its receptor has resulted in inhibition of tumor growth and in retinopathy. Also, the development of pathological pannus tissue in rheumatoid arthritis involves angiogenesis and might be blocked by inhibitors of angiogenesis.
The ability to stimulate vascular growth has potential utility for treatment of ischemia-induced pathologies such as myocardial infarction, coronary artery disease, peripheral vascular disease, and stroke. The sprouting of new vessels and/or the expansion of small vessels in ischemic tissues prevents ischemic tissue death and induces tissue repair. Regulating angiogenesis by inhibiting certain recognized pathways in this process would therefore, be useful in treating diseases, such as ocular neovascularization, including retinopathy, age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease rheumatoid arthritis, chronic inflammatory disorders such as chronic asthma, arterial or post-transplantational atherosclerosis, endometriosis, and neoplastic diseases such as leukemias, otherwise known to be associated with deregulated angiogenesis. Treatment of malaria and related viral diseases may also be mediated by HGF and cMet.
Other receptor tyrosine kinases such as FGFR-1, PDGFR, FLK-1 (Fetal Liver Kinase-1) and c-Met have also been suggested to play a role in angiogenesis. C-met is a unique receptor tyrosine kinase, which comprises, in its native form, a 190 kDa heterodimeric (a disulfide-linked 50 kDa α-chain and a 145 kDa β-chain) membrane-spanning tyrosine kinase protein (Proc. Natl. Acad. Sci. USA, 84:6379-6383 (1987)). C-Met is mainly expressed in epithelial cells and stimulation of c-Met leads to scattering, angiogenesis, proliferation and metastasis. (See Cytokine and Growth Factor Reviews, 13:41-59 (2002)). The ligand for c-Met is hepatocyte growth factor (also known as scatter factor, HGF and SF). HGF is a heterodimeric protein secreted by cells of mesodermal origin (Nature, 327:239-242 (1987); J. Cell Biol., 111:2097-2108 (1990)).
Various biological activities have been described for HGF through interaction with c-met (Hepatocyte Growth Factor-Scatter Factor (HGF-SF) and the c-Met Receptor, Goldberg and Rosen, eds., Birkhauser Verlag-Basel, 67-79 (1993). The biological effect of HGF/SF may depend in part on the target cell. HGF induces a spectrum of biological activities in epithelial cells, including mitogenesis, stimulation of cell motility and promotion of matrix invasion (Biochem. Biophys. Res. Comm., 122:1450-1459 (1984); Proc. Natl. Acad. Sci. U.S.A., 88:415-419 (1991)). It stimulates the motility and invasiveness of carcinoma cells, the former having been implicated in the migration of cells required for metastasis. HGF can also act as a "scatter factor", an activity that promotes the dissociation of epithelial and vascular endothelial cells (Nature, 327:239-242 (1987); J. Cell Biol., 111:2097-2108 (1990); EMBO J., 10:2867-2878 (1991); Proc. Natl. Acad. Sci. USA, 90:649-653 (1993)). Therefore, HGF is thought to be important in tumor invasion (Hepatocyte Growth Factor-Scatter Factor (HGF-SF) and the C-Met Receptor, Goldberg and Rosen, eds., Birkhauser Verlag-Basel, 131-165 (1993)).
HGF and c-Met are expressed at abnormally high levels in a large variety of solid tumors. High levels of HGF and/or c-Met have been observed in liver, breast, pancreas, lung, kidney, bladder, ovary, brain, prostate, gallbladder and myeloma tumors in addition to many others. The role of HGF/c-Met in metastasis has been investigated in mice using cell lines transformed with HGF/c-Met (J. Mol. Med., 74:505-513 (1996)). Over-expression of the c-Met oncogene has also been suggested to play a role in the pathogenesis and progression of thyroid tumors derived from follicular epithelium (Oncogene, 7:2549-2553 (1992)). HGF is a morphogen (Development, 110:1271-1284 (1990); Cell, 66:697-711 (1991)) and a potent angiogenic factor (J. Cell Biol., 119:629-641 (1992)).
Recent work on the relationship between inhibition of angiogenesis and the suppression or reversion of tumor progression shows great promise in the treatment of cancer (Nature, 390:404-407 (1997)), especially the use of multiple angiogenesis inhibitors compared to the effect of a single inhibitor. Angiogenesis can be stimulated by HGF, as well as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).
Elevated levels of HGF and c-Met have also been observed in non-oncological settings, such as hypertension, myocardial infarction and rheumatoid arthritis. It has been observed that levels of HGF increase in the plasma of patients with hepatic failure (Gohda et al., supra) and in the plasma (Hepatol., 13:734-750 (1991)) or serum (J. Biochem., 109:8-13 (1991)) of animals with experimentally induced liver damage. HGF has also been shown to be a mitogen for certain cell types, including melanocytes, renal tubular cells, keratinocytes, certain endothelial cells and cells of epithelial origin (Biochem. Biophys. Res. Commun., 176:45-51 (1991); Biochem. Biophys. Res. Commun., 174:831-838 (1991); Biochem., 30:9768-9780 (1991); Proc. Natl. Acad. Sci. USA, 88:415-419 (1991)). Both HGF and the c-Met protooncogene have been postulated to play a role in microglial reactions to CNS injuries (Oncogene, 8:219-222 (1993)).
In view of the role of HGF and/or c-Met in potentiating or promoting such diseases or pathological conditions, it would be useful to have a means of substantially reducing or inhibiting one or more of the biological effects of HGF and its receptor. Thus, a compound that reduces the effect of HGF would be a useful compound.
Non-receptor tyrosine kinases represent a collection of cellular enzymes, which lack extracellular activity and transmembrane sequences. Examples of non-receptor tyrosine kinases identified include over twenty-four individual kinases, comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, jak, Ack, and LIMK). Src is thought to be the largest family including Src, TES, FYN, Lyn, Lck, blk, Fgr, and Yrk. The Src subfamily has been linked to oncogenesis and immune responses. See Bohlen, Oncogene, 8:2025-2031 (1993), which disclosure is incorporated herein by reference in its entirety. These kinases have also been found to be involved in cellular signaling pathways in numerous pathogenic conditions, including cancer, psoriasis, and other hyper-proliferative disorders or hyper-immune responses. Thus, it would be useful to inhibit the activity of non-receptor kinases as well.
Many classes of compounds have been proposed to generally or specifically inhibit kinase activity. For example, the Kirin publication WO 03/000660 describes substituted phenyl compounds, U.S. Pat. No. 6,143,764 describes substituted quinolines, WO 02/32872 describes substituted quinolines, and WO 00/47212 describes substituted quinazoline derivatives. However, there is always a need to improve the pharmacokinetic and pharmacodynamic profile of kinase inhibitor compounds for improved physiological efficacy and enhanced treatment of kinase-related pathological conditions and/or disease states. Further, there is a need to treat disease states associated with angiogenesis such as cancer, rheumatoid arthritis, and other conditions where active angiogenesis is undesirable.

This patent is subject to a terminal disclaimer.

Protein kinase modulators and method of use

Abstract: wherein A, B, D, E, G, H1-5 and R1-4 are defined herein, and synthetic intermediates, which are capable of modulating various protein kinase receptor enzymes and, thereby, influencing various disease states and conditions related to the activities of these kinases. For example, the compounds are capable of modulating kinase enzymes thereby influencing the process of angiogenesis and treating angiogenesis-related diseases and other poliferative disorders, including cancer and inflammation. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of protein kinases.


An electrical power connector is disclosed having a plug and receptacle. The plug includes a coupling ring having a single handle extending radially therefrom. The coupling ring is freely rotatable within limits on the plug when the plug is not coupled to the receptacle. The receptacle includes one or more bayonet ramps to which the coupling ring can be coupled. Advantageously, the plug can be coupled to the receptacle with 120xc2x0 rotation or less by rotating the coupling ring 120xc2x0 or less. The plug and receptacle each include a colored locking indicator to indicate to the person coupling the plug to the receptacle that the receptacle and plug are properly aligned to each other when coupled. Also an audible indication of locking is provided when the electrical plug and receptacle are fully coupled.

The present invention relates generally to electrical connectors, and more particularly, to electrical power connectors.
Electrical power connectors for connecting a receptacle and plug are known. These connectors are used in transit applications, power applications, light rail applications, tractor trailer trucks and buses, among other applications.
Power connectors, by virtue of their wire size, are inherently large and bulky. The cables used with power connectors are heavy and cumbersome. Traditional methods for coupling connectors of these types are via thread or bayonet coupling or locking levers. All are very difficult to implement as the contacts, due to their size, have very high insertion and extraction forces. The weight of the cable connector, its physical size, and its location on a panel or a vehicle make it very difficult to align and couple.
In many instances, to couple an electrical power connector becomes a two-man operationxe2x80x94one to hold and guide the plug and a second to activate the coupling mechanism. Bayonet or lever-lock is preferred over threads as the activation requires less movement of the coupling mechanism. A bayonet lock requires only a portion of a turn, but is difficult to accomplish because the entire plug has to be aligned with the receptacle and then the plug including cables has to be held in place while a coupling ring has to be rotated to effect mating between the plug and receptacle. A thread usually requires three or more turns. A lever connector is generally rectangular with two hasps on the side which need to be activated nearly simultaneously in order not to xe2x80x9ccockxe2x80x9d the plug into the receptacle.
Accordingly, a need exists in the art for an electrical power connector which requires less than one turn to couple. A further need exists for an electrical power connector in which coupling can be accomplished by a single person.
It is an object of the present invention to provide an electrical power connector in which the electrical connector can be coupled by a single person.
It is another object of the present invention to provide an electrical power connector in which coupling between a plug and receptacle requires less than 360xc2x0 rotation of the coupling mechanism.
It is another object of the present invention to provide an electrical power connector in which a plug can be coupled to a receptacle in 120xc2x0 rotation or less.
It is yet a further object of the present invention to provide an electrical power connector having a receptacle with a bayonet ramp and a plug having a coupling ring with a handle.
These and other objects of the present invention are accomplished by providing an electrical power connector having a plug and receptacle. The plug includes a coupling ring having a handle extending radially therefrom. The coupling ring is freely rotatable within limits on the plug when the plug is not coupled to the receptacle. The receptacle includes one or more bayonet ramps to which the coupling ring can be coupled. Advantageously, the plug can be coupled to the receptacle with 120xc2x0 rotation or less by rotating the coupling ring 120xc2x0 or less. The plug and receptacle each include a colored locking indicator to indicate to the person coupling the plug to the receptacle that the receptacle and plug are properly aligned to each other when coupled. Also an audible indication of locking is provided when the electrical plug and receptacle are fully coupled.
Advantageously, the coupling ring, with a handle, allows the user to hold and guide the connector with one hand and couple it with the other. The arrangement of the present invention limits the travel of the coupling ring and handle such that it can be easily located in the proper position for coupling. Once the connector is positioned for alignmentxe2x80x94moving the handle in an arc of 90xc2x0 to 120xc2x0 allows the bayonet ramps to engage and supply the mechanical advantage to couple and uncouple easily. A clamping mechanism built into the panel or undercarriage, nests and holds the handle in place so it cannot be inadvertently uncoupled.
These and other objects of the present invention are achieved by an electrical power connector including a plug having at least one contact and a receptacle including a corresponding at least one contact. The receptacle has at least one ramp. The plug and the receptacle have an unmated condition and a mated condition. A coupling ring has a handle extending therefrom and includes at least one locking pin. A first stop and a second stop are each positioned in either the coupling ring and the receptacle such that said coupling ring is rotated less than 360xc2x0 to move the connector from the unmated condition to the mated condition.
The foregoing and other objects of the present invention are achieved by an electrical connector including a plug having at least one male contact and at least one pin and a receptacle including a corresponding at least one female contact and at least one corresponding ramp for receiving the at least one locking pin. A handle is operatively associated with one of the plug and the receptacle and has a first surface and a second surface. A first surface and a second surface are each connected to one of the plug and the receptacle. The first surface and the second surface are circumferentially spaced from each other less than 360xc2x0. The plug and the receptacle are in an unmated condition when the first surface of the handle abuts the first surface. When the handle is rotated, the plug and the receptacle are brought into a mated condition when the second surface of the handle abuts the second stop.
The foregoing and other objects of the present invention are achieved by a method of coupling an electrical connector. The electrical connector includes a plug and a receptacle. The plug is aligned with the receptacle. The plug has at least one alignment key. The receptacle has a corresponding at least one keyway. A coupling ring is moved to a first circumferential position. The plug is mated to the receptacle when the coupling ring is rotated less than 360xc2x0 to a second circumferential position.
Still other objects and advantages of the present invention will become readily apparent to those skilled in the art from the following detailed description, wherein the preferred embodiments of the invention are shown and described, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized, the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the invention. Accordingly, the drawings and description thereof are to be regarded as illustrative in nature, and not as restrictive.


A memory apparatus includes multiple memory circuits and an interface circuit to present to a host system emulated memory circuits. The interface circuit includes a first component of a first type and a second component of a second type, the first component and the second component being operable to present a host-system interface to the host system and to present a memory-circuit interface to the plurality of memory circuits, in which there is a difference in at least one aspect between the host-system interface and the memory circuit interface. At least one of the first and second components is operable to identify one or more memory circuits that is not being accessed and to perform a power-saving operation on the one or more memory circuits identified as not being accessed, where the power-saving operation includes placing the memory circuits identified as not being accessed in a precharge power down mode.

1. Technical Field of the Invention
This invention relates generally to digital memory such as used in computers, and more specifically to organization and design of memory modules such as DIMMs.
2. Background Art
Digital memories are utilized in a wide variety of electronic systems, such as personal computers, workstations, servers, consumer electronics, printers, televisions, and so forth. Digital memories are manufactured as monolithic integrated circuits ("ICs" or "chips"). Digital memories come in several types, such as dynamic random access memory (DRAM), static random access memory (SRAM), flash memory, electrically erasable programmable read only memory (EEPROM), and so forth.
In some systems, the memory chips are coupled directly into the system such as by being soldered directly to the system's main motherboard. In other systems, groups of memory chips are first coupled into memory modules, such as dual in-line memory modules (DIMMs), which are in turn coupled into a system by means of slots, sockets, or other connectors. Some types of memory modules include not only the memory chips themselves, but also some additional logic which interfaces the memory chips to the system. This logic may perform a variety of low level functions, such as buffering or latching signals between the chips and the system, but it may also perform higher level functions, such as telling the system what are the characteristics of the memory chips. These characteristics may include, for example, memory capacity, speed, latency, interface protocol, and so forth.
Memory capacity requirements of such systems are increasing rapidly. However, other industry trends such as higher memory bus speeds, small form factor machines, etc. are reducing the number of memory module slots, sockets, connectors, etc. that are available in such systems. There is, therefore, pressure for manufacturers to use large capacity memory modules in such systems.
However, there is also an exponential relationship between a memory chip's capacity and its price. As a result, large capacity memory modules may be cost prohibitive in some systems.
What is needed, then, is an effective way to make use of low cost memory chips in manufacturing high capacity memory modules.

Memory apparatus operable to perform a power-saving operation


Protective and sports eyeglasses having a pair of integrally formed, wraparound lenses. The lenses have toric inner and outer surfaces which match each other on both meridians so that the lenses have zero power. A shock-absorbing nosepiece includes a base portion which wraps around a bridge integrally formed with the lenses and a pair of resilient, relatively large nose pads projecting downwardly and rearwardly along respective inside edges of the lenses. The nose pads are spaced slightly from the lenses so that they are capable of absorbing shocks imparted to the lenses. A pair of temples are pivotally secured to respective lenses by hinges which are embedded in respective mounting pads integrally formed in the lenses. The lenses may be formed from a tough, shock-resistant plastic, such as polycarbonate, and they may be provided with a hard, non-scratch coating.

Non-corrective eyeglasses, such as sunglasses or protective eyeglasses, normally utilize spherical lenses which have substantially the same radius of curvature in both the horizontal and vertical meridians. Such eyeglasses usually do not have sufficient wrap depth to adequately shield the eye from light, wind, and objects at the sides. A large wrap depth is achieved by using lenses which have a sufficiently small radius of curvature to allow the lenses to curve around the sides of the wearer's face. However, spherical lenses having sufficient curvature in the horizontal meridian to provide an adequate wrap depth have an excessive radius of curvature in the vertical meridian, which causes the lenses to project forwardly an excessive distance, thus giving a "bug-eyed" appearance. U.S. Pat. No. 3,526,449, issued to Bolle et al, discloses eyeglasses which use a spherical lens having substantial wrap depth and also use relatively wide temples to shield the wearer's face.
Attempts have been made to provide a lens having sufficient wrap depth without causing the lens to project forwardly an excessive distance, principally by varying the radius of curvature of the lens in the horizontal meridian. Accordingly, the lenses have relatively little curvature at the front, but the curvature increases substantially toward the outer edges of the lenses. An example of this technique is illustrated in U.S. Pat. No. 2,537,047, issued to Gatten. The principal disadvantage of such lenses is the optical distortion caused where the radius of curvature in a horizontal meridian quickly changes. As a result, the optical quality of prior art eyeglasses incorporating this technique has not been particularly great.
Another problem associated with protective eyeglasses adapted for sports use is the inability of the eyeglasses to absorb shocks imparted to the lenses. Conventional eyeglasses generally utilize a nosepiece which is either integrally formed with the lenses or frame or rigidly secured to the frame. As a result, shocks imparted to the lenses by objects are coupled directly to the nose of the wearer, sometimes causing injury.

Eyeglasses adapted for sports and protective use