Chemistry: analytical and immunological testing – Involving an insoluble carrier for immobilizing immunochemicals
Reexamination Certificate
2000-02-28
2003-05-27
Le, Long V. (Department: 1641)
Chemistry: analytical and immunological testing
Involving an insoluble carrier for immobilizing immunochemicals
C435S004000, C435S287900, C424S001290, C424S009330, C422S051000, C436S524000
Reexamination Certificate
active
06569688
ABSTRACT:
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to intravascular apparatus and method for preventing restenosis of a patient's blood vessel by locally treating a portion of the vessel. More particularly, the present invention relates to an implantable carrier for insertion into a blood vessel, the carrier including biologically active agents immobilized thereto for selectively reacting with a supplied substance to locally produce a therapeutic agent. Preferably, the biologically active materials are enzymes reacting with a substrate introduced to the patient's body as part of his diet to produce a therapeutic agent having cell proliferation inhibiting activity.
It is well known that excessive proliferation of vascular smooth muscle cells contributes to restenosis and reocclusion of coronary arteries following procedures such as percutaneous transluminal coronary angioplasty (PTCA), artherectomy, laser angioplasty and arterial bypass graft.
Various attempts have been made to provide intravascular implants for preventing restenosis and reocclusion of blood vessels, the implants incorporating therapeutic agents such as cell proliferation inhibiting factors for locally treating the vessel. Examples are disclosed in U.S. Pat. Nos. 5,314,688, 5,514,379, 5,512,291, 5,500,013 and 5,429,634.
However, most of these disclosures provide intravascular devices loaded with biologically active agents such as drugs, drug-producing enzymes or drug-producing cells, the biologically active agents being slowly released from the device to the circulating blood.
The maximal amount of such biologically active agents incorporated into the intravascular device is limited by the physical dimensions of the device, thereby substantially limiting the effective period of treatment. When treating restenosis caused by progressive cell proliferation, it is necessary to supply therapeutic agents for at least several months in order to produce a substantial therapeutic effect. The prior art fails to provide an effective therapeutic treatment for such an extended period of time.
Further, the prior art fails to provide an efficient method for controlling the concentration of the therapeutic agent at the site of treatment, or alternatively to produce trends in such concentration.
Further, by using biologically active agents such as drug-producing enzymes which are slowly released into the blood circulation, the prior art provides a systemic rather than local treatment. Once these drug-producing enzymes are released into the circulation, their concentration at the site of treatment is significantly diluted and accordingly, their activity is substantially diminished.
Further, because of the systemic nature of such method of therapy, it does not enable to use therapeutic agents having a substantially short life time, since once such therapeutic agents are in the blood circulation, they are likely to loose their activity before having the chance to reach the site of treatment.
Further, none of the above disclosures provides apparatus and method wherein a therapeutic agent is locally and controllably produced within the patient's blood vessel upon provision of an appropriate diet.
Further, none of the above disclosures provides apparatus and method wherein the therapeutic agent is produced by means of biologically active agents such as enzymes immobilized to the apparatus.
There is thus a widely recognized need for, and it would be highly advantageous to have, intravascular apparatus and method which provide an effective local treatment of a patient's vessel for an extended period of time.
It would be further advantageous to have such apparatus and method wherein the amount of therapeutic agent provided by such apparatus is not limited by its physical dimensions.
It would be further advantageous to have such apparatus and method which enable to control the concentration of therapeutic agent at the site of treatment, and to produce trends in such concentration.
Further, it would be advantageous to have such apparatus and method which enable to use therapeutic agents having substantially short life-time in the systemic circulation.
Further, it would be advantageous to have such apparatus and method wherein a therapeutic agent is locally and controllably produced within the patient's blood vessel by providing an appropriate diet.
Further, it would be advantageous to have such apparatus and method wherein the therapeutic agent is produced by means of biologically active agents such as enzymes immobilized to the apparatus.
SUMMARY OF THE INVENTION
According to the present invention there is provided an intravascular apparatus for locally treating a patient's blood vessel, comprising: (a) an implantable carrier for insertion into the vessel; and (b) a biologically active agent immobilized to the carrier, the biologically active agent reacting with a first substance to produce a second substance. The second substance is preferably a therapeutic agent such as nitric oxide for locally treating the vessel. The biologically active agent is preferably an enzyme such as nitrogen oxide synthase. Preferably, the first substance is arginine and is introduced to the patient's body as part of a diet. Alternatively, the biologically active agent is a catalytic antibody specifically tailored to react with a specific substrate to give a desired therapeutic agent. Alternatively, the biologically active agent is a ribozyme.
According to still further features in the described preferred embodiments the biologically active agent is chemically attached to the implantable carrier. Alternatively, the biologically active agent is entrapped within a polymeric network covering the implantable carrier.
According to another embodiment the first substance is an undesirable agent at the site of treatment. The biologically active agent may be an enzyme having anti thrombogenic activity, such as Tissue Plasminogen Activator. Alternatively, the biologically active agent is a catalytic antibody. Alternatively, the biologically active agent is a ribozyme.
According to the present invention there is further provided a method for locally treating a patient's vessel, comprising: (a) introducing into a patient's vessel an implantable carrier including a biologically active agent immobilized thereto; and (b) reacting the biologically active agent with a first substance to locally produce a second substance. Preferably, the method further comprises introducing the first substance to the patient's body. Further, the method preferably comprises controlling the concentration of the second substance by changing the concentration of the first substance introduced to the patient's body. Preferably, the first substance is introduced to the patient's body as part of a diet.
The present invention successfully addresses the shortcomings of the presently known configurations by providing an intravascular apparatus and method which provide an effective local treatment of a patient's vessel for an extended period of time. Further, the present invention addresses the shortcomings of the presently known configurations by providing an intravascular apparatus and method wherein the total amount of therapeutic agent provided by such apparatus is not limited by its physical dimensions. Further, the present invention addresses the shortcomings of the presently known configurations by providing an intravascular apparatus and method which enable to control the concentration of therapeutic agent at the site of treatment, and to produce trends in such concentration. Further, the present invention addresses the shortcomings of the presently known configurations by providing an intravascular apparatus and method which enable to use therapeutic agents having substantially short life-time in the systemic circulation.
The present invention discloses a novel intravascular apparatus and method wherein a therapeutic agent is locally and controllably produced within the patient's blood vessel upon introducti
Dinnar Uri
Lotan Noah
Sivan Sarit
Counts Gary
G. E. Ehrlich Ltd.
Le Long V.
Technion Research & Development Foundation Ltd.
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