Data processing: generic control systems or specific application – Specific application – apparatus or process
Reexamination Certificate
1999-07-09
2001-04-17
Grant, William (Department: 2786)
Data processing: generic control systems or specific application
Specific application, apparatus or process
C604S004010, C604S020000, C604S028000, C606S007000, C606S015000, C606S322000, C600S006000, C607S092000, C436S519000, C700S079000, C700S080000, C700S083000, C700S084000
Reexamination Certificate
active
06219584
ABSTRACT:
FIELD OF THE INVENTION
This invention generally relates to determining an amount of light energy to deliver to fluids, particularly partially transparent fluids, containing targets for the light energy, in order to deliver an effective amount of light energy to the targets. The invention particularly relates to phototherapy and photopheresis systems where an effective amount of light energy is desired to be delivered to targets in biological fluids.
BACKGROUND OF THE INVENTION
Light irradiation or phototherapy has been widely used in the chemical and biological sciences for many years. Ultraviolet (UV) light irradiation of blood was used in the 1930's, 40's, and 50's for the treatment of many conditions. These conditions included bacterial diseases such as septicemias, pneumonias, peritonitis, wound infection, viral infections including acute and chronic hepatitis, poliomyelitis, measles, mumps, and mononucleosis. Phototherapy or light irradiation also includes the processes of exposing photoactivatable or photosensitizable targets, such as cells, blood products, bodily fluids, chemical molecules, tissues, viruses, and drug compounds, to light energy, which induces an alteration in or to the targets. In recent years, the applications of phototherapy are increasing in the medical field. These applications include the inactivation of viruses contaminating blood or blood products, the preventive treatment of platelet-concentrate infusion-induced alloinmunization reactions, and the treatment of both autoimmune and T-cell mediated diseases. Light irradiation applications also include the irradiation sterilization of fluids that contain undesirable microorganisms, such as bacteria or viruses.
Numerous human disease states, particularly those relating to biological fluids such as blood, respond favorably to treatment by visible or UV light irradiation. Light irradiation may be effective to eliminate immunogenicity in cells, inactivate or kill selected cells, inactivate viruses or bacteria, or activate desirable immune responses. For example; phototherapy can be used as an antiviral treatment for certain blood components or whole blood. (See PCT Application WO 97/36634 entitled Photopheresis Treatment of Chronic HCV Infections). In this case, a pathogenic virus in a donated platelet concentrate can be inactivated by UV light exposure.
Indeed, certain forms of light irradiation may be effective by themselves, without the introduction of outside agents or compounds, while others may involve the introduction of specific agents or catalysts. Among the latter treatment techniques is the use of photoactivatable drugs. In a particular application, it is well known that a number of human disease states may be characterized by the overproduction of certain types of leukocytes, including lymphocytes, in comparison to other population of cells which normally comprise whole blood. Excessive abnormal lymphocyte populations result in numerous adverse effects in patients including the functional impairment of bodily organs, leukocyte mediated autoimmune diseases and leukemia related disorders many of which often ultimately result in fatality.
Uses of photoactivatable drugs may involve treating the blood of a diseased patient where specific blood cells have become pathogenic as a consequence of the disease state. The methods generally may involve treating the pathogenic blood cells, such as lymphocytes, with a photoactivatable drug, such as a psoralen, which is capable of forming photoadducts with lymphocyte DNA when exposed to UV radiation.
A specific type of phototherapy is extracorporeal photopheresis (ECP). An application of ECP is for the treatment of cutaneous T-cell lymphoma (CTCL). In an example of this therapy, 8-methoxypsoralen (8-MOP), a naturally occurring light-sensitive compound, is orally administrated to a patient prior to before ECP treatment. During the ECP treatment, blood is withdrawn from the patient, anticoagulated, and the white cells are separated by centrifugation and collected as a leukocyte enriched fraction, also known as the buffy coat. The 8-MOP molecules in the blood enter the white blood cell nuclei and intercalate in its double-stranded DNA helix.
In the extracorporeal circuit, UV light is directed at the leukocyte-enriched blood fraction and promotes the photoactivation of the target 8-MOP molecules. The photoactivated 8-MOPs alter the pathogenic leukocyte by cross-linking to the thymidine bases and prevent the unwinding of DNA during transcription. The fluid containing the altered leukocytes is then reinfused back into the patient. The reinfusion induces a therapeutically significant delayed immune attack that targets antigens on the surface of both irradiated and unirradiated leukocytes of the same pathogenic clones. See PCT Application WO 97/36581 entitled Photopheresis Treatment of Leukocytes, which is expressly hereby incorporated herein by reference in its entirety. This PCT Application discloses the UVAR® system for ECP. U.S. Pat. Nos. 4,321,919, 4,398,906, 4,428,744, and 4,464,166, each of which is expressly hereby incorporated herein by reference in its entirety, also describe, inter alia, methods for reducing the functioning lymphocyte population of a human subject using photopheretic techniques.
ECP also has been shown to be an effective therapy in a number of autoimmune diseases such as progressive systemic sclerosis (see A. H. Rook et al., A
RCH
. D
ERMATOL
. 128:337-346 (1992)), inflammatory bowel disease, rheumatoid arthritis (see S. Malawista, et al., A
RTHRITIS RHEUM
. 34:646-654 (1991)), and juvenile onset diabetes mellitus (see J. Ludvigsson, D
IABETES METAB. REV
. 9(4):329-336 (1993)), as well as other T-cell mediated phenomena including graft-versus-host disease (see Rosseti et al., TRANSPLANT 59(1):149-151 (1995)), and organ allograft rejection after transplantation (see A. H. Rook, et al., J. C
LIN
. A
PHERESIS
9(1):28-30 (1994)). The ECP treatment preferably results in a highly specific immune response against aberrant T-cells as well as removal of pathogenic antibodies and circulating immune complexes.
A difficulty inherent in light irradiation or phototherapy techniques when used in the irradiation of fluids and/or their target components, however, is that often times the fluid is not completely transparent to light, e.g., the fluid itself is not entirely transparent and/or the fluid contains material (e.g., non-target material) that is not entirely transparent to light. Material that is not completely transparent to light energy attenuates the irradiance of the light. This phenomenon is particularly undesirable in phototherapy or photopheresis applications since some targets in the fluid will receive light that is attenuated by the nontransparent material. This attenuation makes it difficult to predict how much light energy should be delivered to the fluid to provide a desired amount of light energy to targets in the fluid.
Another source of light attenuation in fluids is stacking. Stacking occurs in a fluid when material or targets in the fluid are not distributed uniformly on the fluid surface but rather are located at different depths throughout the fluid. Therefore, for instance, targets in the outer most layer of the fluid, closest to the irradiating light source, may be exposed to incident light intensity, while the targets below the surface layer may receive attenuated light energy.
Furthermore, the shapes of non-transparent material in the fluid and their alignment can be a cause of light attenuation. For example, in photopheresis applications, non-targets in he biological fluid may include red blood cells, which have discord shapes with depressions at the middle. When red blood cells are aligned parallel to the light energy source during irradiation, their attenuation of light is minimized. However, when red blood cells are aligned perpendicular to the light energy source during irradiation, their attenuation of light is maximized. Since the alignment of such fluid material is usually not predictable, it is present
Grant William
Marc McDieunel
McKenna & Cuneo LLP
Therakos, Inc.
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