Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-09-11
2002-12-10
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S025000, C514S217000, C514S226200, C514S253030, C514S254060, C514S258100, C514S259500, C514S280000, C514S288000, C514S317000, C514S327000, C514S353000, C514S356000, C514S397000, C514S413000, C514S415000, C514S509000, C514S619000, C514S654000, C514S680000
Reexamination Certificate
active
06492332
ABSTRACT:
I. FIELD OF THE INVENTION
The present invention relates to methods of inhibiting tumor cell adhesion and/or invasion and/or local tumor cell metastasis while simultaneously treating pain, and/or inflammation, and/or smooth muscle spasm and/or restenosis during surgical procedures using perioperative, local delivery of a combination of therapeutic agents.
II. BACKGROUND OF THE INVENTION
Endooscopy is a surgical procedure in which a camera, attached to a remote light source and video monitor, is inserted into a body cavity (e.g., joint, peritoneal cavity, bladder, thorax, etc.) through a small portal incision in the overlying skin and body wall. Through similar portal incisions, surgical instruments may be placed in a body cavity, their use guided by arthroscopic visualization. As endoscopists' skills have improved, an increasing number of operative procedures, once performed by “open” surgical technique, now can be accomplished endoscopically. Such procedures include, for example, appendectomies, cholecystectomies and cardiac surgery. As a result of widening surgical indications and the development of small diameter endoscopes, pediatric endoscopy has become routine.
Throughout each endoscopic procedure, physiologic irrigation fluid (e.g., normal saline or lactated Ringer's) is flushed continuously through the joint, distending the body cavity removing operative debris, thereby providing clearer visualization. U.S. Pat. No. 4,504,493 to Marshall discloses an isomolar solution of glycerol in water for a non-conductive and optically clear irrigation solution for arthroscopy.
Irrigation is also used in other procedures, such as cardiovascular and general vascular diagnostic and therapeutic procedures, urologic procedures and the treatment of burns and any operative wounds. In each case, a physiologic fluid is used to irrigate a wound or body cavity or passage. Conventional physiologic irrigation fluids do not inhibit tumor cell adhesion and/or invasion and/or local tumor cell metastasis, nor do they provide analgesic, anti-inflammatory, anti-spasm and anti-restenotic effects.
Cell adhesion molecules are important in cell-cell interaction and interactions between cells and components of the extracellular matrix. While these adhesion molecules are fundamental to diverse biological processes and regulate intracellular signaling events, these molecules are particularly important in the earliest stages of tumor metastasis that require adhesion and/or invasion of tumor cells. Specific cell adhesion molecules and proteinases have been associated with the attachment and implantation of free tumor cells which occur during metastasis in a wide variety of human malignancies, including breast, prostate, liver, ovarian and bladder cancer. The diverse adhesion molecules, which mediate the adhesion interactions, are comprised of cellular surface receptor-ligand pairs. The cellular surface receptors constitute a group of transmembrane proteins that can be classified as members of related biological families or superfamilies based upon homologous structure and shared functional characteristics. Adhesion of cancer cells at secondary sites is known to be regulated by several families of adhesion proteins, including the CD44 proteoglycans, integrins and selecting. The primary functions of these receptors are to mediate cellular binding to the specific structural proteins that comprise the extracellular matrix (ECM) and to recognize membrane bound ligands mediating cell-cell adhesion. Cellular adhesion and invasion can also be facilitated by proteinases, such as the metalloproteinases (MMPs) and their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs).
Surgical trauma has been found to increase the frequency of tumor implantation at the sites of surgical injury and wound healing. One of the consequences of surgical trauma to malignant tissues is the dissemination of free tumor cells locally at the operative site. For example, patients with pancreatic cancer often exhibit peritoneal dissemination and hepatic metastasis after undergoing surgery. Adhesive molecules and receptors mediating the attachment of free-floating tumor cells and implantation at surgical sites and at sites of wound healing are frequently present on numerous other normal cell types. Surgical trauma also stimulates and potentiates the production and release of proteinases from tumor cells, inflammatory cells, and components of the extracellular matrix. Thus, a pharmaceutical approach aimed at interfering with the function of cell adhesion molecules to decrease tumor cell adhesion and inhibit the production and activation of proteinases is to deliver the therapeutic agents only to the tissues at risk for local tumor metastasis. Since the process of free tumor-cell attachment and invasion into the extracellular matrix or other cells during surgery is a dynamic process involving specific interactions temporally related to the operative trauma, the optimal time for pharmaceutical intervention is at the time of surgery. Discovery of the role of multiple adhesive proteins, adhesion receptors, and proteinases in the metastatic spread of cancer enables development of pharmaceutical compositions that block the attachment of tumor cells to extracellular matrix proteins and/or inhibit tumor cell invasion during surgical procedures.
Alleviating pain and suffering in postoperative patients is an area of special focus in clinical medicine, especially with the growing number of out-patient operations performed each year. The most widely used agents, cyclooxygenase inhibitors (e.g., ibuprofen) and opioids (e.g., morphine, fentanyl), have significant side effects including gastrointestinal irritation/bleeding and respiratory depression. The high incidence of nausea and vomiting related to opioids is especially problematic in the postoperative period. Therapeutic agents aimed at treating postoperative pain while avoiding detrimental side effects are not easily developed because the molecular targets for these agents are distributed widely throughout the body and mediate diverse physiological actions. Despite the significant clinical need to inhibit pain and inflammation, as well as vasospasm, smooth muscle spasm and restenosis, methods for the delivery of inhibitors of pain, inflammation, spasm and restenosis at effective dosages while minimizing adverse systemic side effects have not been developed. As an example, conventional (i.e., intravenous, oral, subcutaneous or intramuscular) methods of administration of opiates in therapeutic doses frequently is associated with significant adverse side effects, including severe respiratory depression, changes in mood, mental clouding, profound nausea and vomiting.
Prior studies have demonstrated the ability of endogenous agents, such as serotonin (5-hydroxytryptamine, sometimes referred to herein as “5-HT”), bradykinin and histamine, to produce pain and inflammation. Sicuteri, F., et. al.,
Serotonin
-
Bradykinin Potentiation in the Pain Receptors in Man
, Life Sci. 4, pp. 309-316 (1965); Rosenthal, S. R.,
Histamine as the Chemical Mediator for Cutaneous Pain
, J. Invest. Dermat. 69, pp. 98-105 (1977); Richardson, B. P., et. al.,
Identification of Serotonin M
-
Receptor Subtypes and their Specific Blockade by a New Class of Drugs
, Nature 316, pp. 126-131 (1985); Whalley, E. T., et. al.,
The Effect of Kinin Agonists and Antagonists
, Naunyn-Schmiedeb Arch. Pharmacol. 36, pp. 652-57 (1987); Lang, E., et. al.,
Chemo
-
Sensitivity of Fine Afferents from Rat Skin In Vitro
, J. Neurophysiol. 63, pp. 887-901 (1990).
For example, 5-HT applied to a human blister base (denuded skin) has been demonstrated to cause pain that can be inhibited by 5-HT
3
receptor antagonists. Richardson et al., (1985). Similarly, peripherally-applied bradykinin produces pain which can be blocked by bradykinin receptor antagonists. Sicuteri et al., 1965; Whalley et al., 1987; Dray, A., et. al.,
Bradykinin and Inflammatory Pain
, Trends Neurosci. 16, pp. 99-104 (1993). Peripherally-applied histamine produces
Demopulos Gregory A.
Herz Jeffrey M.
Pierce-Palmer Pamela
Tanelian Darrell L.
Christensen O'Connor Johnson & Kindness PLLC
Jarvis William R. A.
Omeros Corporation
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