Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-13
2004-01-13
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S912000
Reexamination Certificate
active
06677366
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to the field of pharmacotherapeutics and the use of photodynamic therapy (“PDT”) to reduce or prevent inflammation due to injured tissue, whether by intestinal injury, such as surgery, or by accidental injury, such as skin lacerations, injuries to joints and tendons, and the treatment of burn victims. In a preferred embodiment, the invention relates to the use of “low dose” PDT to treat ocular tissue where inflammation is due to the manipulation of eye tissue, especially when the inflammation presents a complicating factor in the patient's recovery from a necessary procedure. Common applications include inflammatory eye disease and various types of ocular surgery or laser treatment, such as transplantation and the filtration ocular surgery commonly used to treat glaucoma. In a particularly preferred embodiment, the invention relates to the extension of filtration bleb survival to improve the outcome of filtration surgery.
BACKGROUND ART
Inflammation in General
The four cardinal signs commonly associated with inflammation are: (1) redness, (2) swelling, (3) heat and (4) pain, with an optional fifth cardinal sign being loss of function of the affected part. While injury triggers a complex series of events, many of which occur simultaneously and are interrelated in a variety of ways, it is known that small blood vessels participate in an important way in the induction of inflammation. In fact, inflammation is one of the body's valuable defense mechanisms and is generally thought of as having three phases: the degenerative phase, the vascular phase, and the healing phase. See Klein, “Defense Reactions in Action”,
Immunology, The Science of Self
-
Nonself Discrimination
, Chapter 14, 577-84 (1982), the disclosure of which is hereby incorporated by reference.
Specifically, in the degenerative phase, the affected cells, primarily epidermal cells and fibroblasts become swollen, with their cytoplasms becoming vacuolized and their nuclei enlarging and fragmenting. Some of the platelets in the damaged blood vessels disintegrate and release serotonin and other mediators acting on sympathetic nerve endings.
The vascular phase is characterized by changes in the blood vessels, extensive migration and activity of the so-called inflammatory cells (granulocytes—particularly neutrophils, lymphocytes, monocytes and macrophages), and the clearing of degenerated cells and cellular debris. The capillary network and the postcapillary venules become flooded, congested and engorged by blood in active hyperemia. Because the number of capillaries also proliferate, one observes the reddish appearance of inflamed tissue, sometimes called “flare.” The increased blood flow also causes the temperature of the inflamed area to approach that of warmer aortic blood, as compared with the surrounding normal tissue, giving the sensation of heat.
Upon injury, the damaged tissue releases substances known to be related to histamine called H substances, which are a mixture of histamine and serotonin released by disrupted tissue mast cells. The H substances cause an active dilation of blood vessels, and the endothelial cells of the dilated vessel separate from one another, causing the gaps between them to enlarge. The endothelium lining the blood vessels gradually becomes paved with leukocytes, forcing some of the fluid out into the surrounding tissue. The protein-rich fluid that leaks out of the vessel into the surrounding tissue causes tissue swelling. The leakage of fluid also contains substances that neutralize bacterial toxins and aid in the destruction of the agent causing the inflammation.
The leukocytes, particularly neutrophils and monocytes, move about on the blood vessel wall until they find a suitable gap through which they can emigrate into the perivascular structures and tissue spaces. The leukocytes attack the dead and dying cells, digesting them intracellularly by phagocytosis or extracellularly by proteolytic enzymes released from their lysosomes when they themselves die. The stimuli for leukocyte emigration is believed to come from the injured tissue in the form of chemotactic factors.
Platelets are another cell type profoundly affected by tissue injury. Shortly after the injury, platelets, singly or in clumps, adhere to the vessel walls. Simultaneously, fibrin fibers begin to appear, forming a fine mesh that helps to trap cells. The resulting clot pulls the edges of the disrupted tissue together.
The intra- and extracellular digestion of necrotic tissue by neutrophils and monocytes produces a fluid that combines with the serous material being extruded from the blood vessels. If an abscess forms, the cavity is lined by a pyrogenic membrane that, in wounds infected with bacteria, prevents the dissemination and multiplication of pathogenic microorganisms into the blood.
In the first two phases of the inflammatory process, the foreign body is either destroyed, for example, if the foreign body is an organism, or the tissue around it is loosened, for example, if it is a splinter. In the healing phase, the inflammation begins to subside; individual blood vessels and vascular patterns become normal once again; and repair of the wound commences. The three main events in the repair process are (1) formation of new connective tissue by proliferating fibroblasts; (2) regeneration of epithelium; and (3) outgrowth of new capillaries.
Even before the inflammation subsides, fibroblasts begin moving into the injured area from the surrounding normal tissue, where they usually exist in a dormant state. They migrate by an ameboid movement along strands of fibrin and distribute themselves throughout the healing area. Once fixed into position in the injured tissue, they begin to synthesize collagen and secrete this protein, which arranges itself into fibers. The fibers orient themselves with their longitudinal axes in the direction of the greatest stress. As the collagen bundles grow in firmness, the fibroblasts gradually degenerate and attach closely to the bundles, and the injured area transforms into scar tissue.
Simultaneously with scar tissue formation, the intact epidermal cells on the edge of the wound begin to proliferate and move, as one sheet, toward the center of the injured area. As the inflammation subsides, a need for a direct supply of blood arises, and new vessels begin to grow into the wound.
It is known that, looking at inflammation on a molecular basis, a number of active compounds interact with one another in a complex manner. Among the cells damaged by injury are mast cells, which release mediators that trigger an early phase of vasodilation, accompanied by the separation of endothelial cells and exposure of collagen fibers in the subendothelial layer. Fibers in the intercellular gaps that form in blood vessels trap platelets and trigger the release of mediators from these cells.
In addition to platelets, the exposed collagen fibers also interact with proteins of the plasma that filter through the pores of the dilated vessel wall, including the triggering factor of the blood-clotting cascade. These proteins also initiate the kinin-bradykinin cascade, producing bradykinin, which becomes involved in vasodilation, the increase of blood vessel permeability, and chemotaxis.
A fourth molecular system, the complement cascade, can be activated by several stimuli: the injured blood vessels, the proteolytic enzymes released by the damaged cells, the membrane components of any participating bacteria, and antigen-antibody complexes. Some of the activated complement components act as chemotactic factors, responsible for the influx of leukocytes into the inflamed area. Others facilitate phagocytosis and participate in cell lysis.
Ocular Inflammation
Glaucoma is a disease of the eye in which high intraocular pressure causes damage to the individual's vision. In a normal eye, fluid is produced by the epithelial cells of the ciliary body, which is located around the inner circumference of the iris (toward the inside of the eyeball). The functions of this
Fsadni Mario G.
Hariton Claude A. A.
Huber Gustave
Levy Julia G.
Obochi Modestus O. K.
Fay Zohreh
QLT Inc.
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