Chemical apparatus and process disinfecting – deodorizing – preser – Process disinfecting – preserving – deodorizing – or sterilizing – Using direct contact with electrical or electromagnetic...
Reexamination Certificate
1998-05-18
2001-02-20
Thornton, Krisanne (Department: 1744)
Chemical apparatus and process disinfecting, deodorizing, preser
Process disinfecting, preserving, deodorizing, or sterilizing
Using direct contact with electrical or electromagnetic...
C250S43200R, C422S028000, C422S044000, C435S283100, C604S004010
Reexamination Certificate
active
06190609
ABSTRACT:
The present invention relates to methods and apparatus for treating biological fluids such as blood and blood components. More particularly, the present invention relates to methods and apparatus for inactivating contaminants, such as viruses, in such biological fluids.
Human blood includes both cellular and non-cellular components. The cellular components in blood include red blood cells (RBC), white blood cells (WBC), and platelets. Plasma is a non-cellular component of blood and is the liquid medium in which the cellular components are suspended. Plasma also includes various other components such as proteins (e.g. fibrinogen, albumin and globulins), electrolytes and metabolites.
It is well known that viruses, such as hepatitis or HIV virus, may be resident within human blood. The viruses residing in blood may be “intracellular,” i.e. contained within one of the cellular components of blood, such as white blood cells, or they may be “extracellular” i.e. freely existing in the plasma. For example, the hepatitis virus is primarily an extracellular virus, the cytomegalovirus (the virus responsible for herpes) is primarily an intracellular virus, and the HIV virus (the virus responsible for AIDS) is found both intracellularly and extracellularly. Regardless of where the virus resides, the presence of the virus in the bloodstream poses the risk of infection and disease not only to the host, but also, if the blood or a blood component is collected and transfused, to a recipient.
Accordingly, the medical community has attempted to reduce the risk of transfusing blood that is tainted with active virus by developing methods and apparatus to remove virus from the blood stream or otherwise inactivate the virus. For example, one such attempt involves the filtration of blood and/or blood components to remove intracellular viruses entrained, for example, in white blood cells, Rawal et al., “Reduction of human immunodeficiency virus-infected cells from donor blood by leukocyte filtration,”
Transfusion,
pp. 460-462 (1989). Although filtration of blood and/or blood components has been somewhat effective in removing the intracellular viruses, it has been generally ineffective in the removal of extracellular viruses because such viruses are typically too small to be captured by currently commercially available filters.
Other methods for inactivating viruses and, in particular, extracellular viruses, in blood, include steam sterilization of blood plasma to inactivate virus. Still, other methods include the use of “detergents” to cleanse the blood and/or the blood component of any viruses, or procedures whereby the blood components are frozen, thawed and washed to remove the virus.
A more recent approach to viral inactivation is the treatment of blood or blood components with a photochemical agent and light. When activated by light of an appropriate wavelength, the photochemical agent either kills the virus directly or indirectly inhibits the ability of the virus to replicate and, thus, in either case “inactivates” the virus. As used herein, the term “inactivate” (and forms thereof) mean the actual destruction, eradication of a contaminant such as a virus, or a direct or indirect effect on the contaminant that inhibits its ability to replicate or otherwise to adversely affect a living recipient.
Several known photochemical agents have been used or disclosed for use in inactivating viruses in blood. They include, for example, psoralens (which have been used in the inactivation of viruses in collected platelets) as described in U.S. Pat. No. 5,459,030. Other photochemical agents that have been disclosed for the inactivation of viruses in blood include the family of light activated drugs derived from benzoporphyrin, as described in U.S. Pat. No. 5,536,238, which is assigned to the assignee of the present application and is incorporated by reference herein. Still other photochemical agents considered for use in the inactivation of viruses in biological fluids are compounds from the family of phenothiazine dyes, which include, but are not limited to toluidine blue O, azure A, azure B, azure C, thionine, methylene blue, and methylene green.
For the photochemical agents to inactivate viruses, the light applied to the photochemical agent must be of a wavelength that can be absorbed by the photochemical agent. As described in U.S. Pat. No. 5,527,704, also assigned to the assignee of the present application and incorporated by reference herein, in the case of methylene blue, it is known that methylene blue absorbs visible light having wavelengths of between about 550 and 700 nm.
As presently understood, a methylene blue molecule that has been activated by light becomes a catalyst for secondary and tertiary reactions that inactivate virus. More specifically, activation of the photochemical agent such as methylene blue is believed to result in the production of singlet oxygen which enhances the secondary and tertiary reactions. A detailed discussion of methylene blue, its photophysics, and photodynamic action on proteins, nucleic acid, viruses and bacteria is set forth in Tuite et al., “Photochemical interactions of methylene blue and analogues with DNA and other biological substrates,”
J. Photochem, Photobiol. B. Biol.,
21, (1993) which is incorporated by reference herein.
In addition to acting as a catalyst for viral inactivation reactions, photochemical agents (when activated by light), such as methylene blue may also result in damage to plasma proteins and, in particular, therapeutic proteins as described in European Patent No. 0196515 which is incorporated by reference. As set forth in European Patent No. 0196515 and as used herein, therapeutic proteins include any biologically active protein which has qualities which make it useful in the treatment of medical disorders. Examples of such proteins include human-blood plasma proteins such as Factor VIII, Von Willebrand Factor, Factor IX, Factor X, Factor XI, Hageman Factor, the activated forms of such factors, prothrombin, anti-thrombin III, fibronectin, plasminogen, immune serum globulin, modified immune globulin, albumin, 1-antitrypsin, and prekallikrein. Prior to the present invention, a system capable of providing maximum viral kill with minimal damage to therapeutic proteins has been considered unattainable because the increased production of singlet oxygen was also believed to be responsible for protein damage.
Various apparatus for using photochemical agents in viral inactivation have also been developed. For example, in U.S. Pat. No. 5,300,019, assigned to the assignee of the present application and also incorporated by reference herein, an apparatus for treating a fluid containing a biological contaminant with a photochemical agent is described. In U.S. Pat. No. 5,300,019, blood including a contaminant, such as a virus, and a photochemical agent is pumped from a source container through a treatment chamber to a collection container. While in the treatment chamber, the blood is exposed to a light source that activates the photochemical agent as the blood is processed within the treatment chamber. To ensure that the blood is sufficiently and uniformly exposed to the light source, the blood (with contaminants and photochemical agent) is continuously mixed within the treatment chamber. After treatment, the blood is collected in the collection container. The photochemical agent described in that patent is benzoporphyrin.
In U.S. Pat. No. 5,527,704, also incorporated by reference, a single container of blood or a blood component is placed between two facing arrays of light emitting diodes. The container includes a blood component (plasma), a viral contaminant and a quantity of methylene blue. The container is irradiated by the light emitting diodes which produce light having a wavelength of approximately 620-670 nm to activate methylene blue. The container of blood or blood component is subjected to light for a period of approximately five (5) minutes.
While the prior art methods and apparatus represent progress in the inactivation of contaminant
Chapman John R.
Larson Dale N.
Stark Peter R. H.
Swallow Michael V.
Baxter International Inc.
Kolomayets Andrew G.
Rockwell Amy L. H.
Serewicz Denise M.
Thornton Krisanne
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