The present invention comprises and utilizes methods and compositions for treating hyperimmune reactions in the eye. Compositions comprising antibodies to gamma interferon alone and in combination with other drugs are described. Also disclosed in the invention are methods of applying a composition comprising interferon gamma antibodies topically to the eye to treat hyperimmune reactions, such as transplant rejection, autoimmune diseases of the eye, and ocular disorders incidental to or connected with autoimmune diseases.

The ability of the mammalian immune system to recognize xe2x80x9cselfxe2x80x9d versus xe2x80x9cnon-selfxe2x80x9d antigens is vital to successful host defense against invading microorganisms. xe2x80x9cSelfxe2x80x9d antigens are those which are not detectably different from an animal""s own constituents, whereas xe2x80x9cnon-selfxe2x80x9d antigens are those which are detectably different from or foreign to the mammal""s constituents. A normal mammalian immune system functions to recognize xe2x80x9con-self antigensxe2x80x9d and attack and destroy them. An autoimmune disorder such as for example, rheumatoid arthritis, insulin-independent diabetes mellitus, acquired immune deficiency syndrome (AIDS), multiple sclerosis, and the like, results when the immune system identifies xe2x80x9cselfxe2x80x9d antigens as xe2x80x9cnon-selfxe2x80x9d, thereby initiating an immune response against the mammal""s own body components (i.e., organs and/or tissues). This creates damage to the mammal""s organs and/or tissues and can result in serious illness or death.
Predisposition of a mammal to an autoimmune disease is largely genetic; however, exogenous factors such as viruses, bacteria, or chemical agents may also play a role. Autoimmunity can also surface in tissues that are not normally exposed to lymphocytes such as for example, neural tissue and the eye (particularly the lens or the cornea). When a tissue not normally exposed to lymphocytes becomes exposed to these cells, the lymphocytes may recognize the surface antigens of these tissues as xe2x80x9cnon-selfxe2x80x9d and an immune response may ensue. Autoimmunity may also develop as a result of the introduction into the animal of antigens which are sensitive to the host""s self antigens. An antigen which is similar to or cross-reactive with an antigen in an mammal""s own tissue may cause lymphocytes to recognize and destroy both xe2x80x9cselfxe2x80x9d and xe2x80x9cnon-selfxe2x80x9d antigens.
It has been suggested that the pathogenesis of autoimmune diseases is associated with a disruption in synthesis of interferons and other cytokines often induced by interferons (Skurkovich et al., Nature 217:551-552, 1974; Skurkovich et al., Annals of Allergy, 35:356, 1975; Skurkovich et al., J. Interferon Res. 12, Suppl. 1:S110, 1992; Skurkovich et al., Med. Hypoth., 41:177-185, 1993; Skurkovich et al., Med. Hypoth., 42:27-35, 1994; Gringeri et al., Cell. Mol. Biol. 41(3):381-387, 1995; Gringeri et al., J. Acquir. Immun. Defic. Syndr., 13:55-67, 1996). In particular, interferon (IFN) gamma plays a significant pathogenic role in autoimmune dysfunction. IFN gamma stimulates cells to produce elevated levels of HLA class II antigens (Feldman et al., 1987, xe2x80x9cInterferons and Autoimmunityxe2x80x9d, In: IFN xcex3, p. 75, Academic Press). It is known that IFN gamma participates in the production of tumor necrosis factor (TNF), and it is also known that TNF also plays a role in stimulation of production of autoantibodies. In view of this, therapies to modulate these cytokines have been developed. Clinical success in treating several autoimmune diseases using antibodies to IFN gamma has been reported (Skurkovich et al., U.S. Pat. No. 5,888,511).
However, while an autoimmune response is considered to be typical in diseases such as multiple sclerosis and rheumatoid arthritis, one area of medicine where treatment of autoimmune or hyperimmune responses has not been fully explored is the area of transplant therapy. Autoimmunity arising from transplant rejection is typical in transplant patients. Rejection of a transplant is the organism""s normal reaction to invading foreign antigens. In particular, transplantation of tissues or organs such as the eye, which is not normally exposed to lymphocytes, skin, heart, kidney, liver, bone marrow, and other organs, have a high rate of rejection, which rejection is largely the result of a hyperimmune reaction.
Hyperimmune reactions including rejection of tissue transplants in the eye are of considerable concern. Corneal transplants, lens replacements, and the like, are frequently rejected when transplanted into a human patient. In addition, other diseases in the eye, such as for example, keratoconjunctivitis sicca (dry eye syndrome), episcleritis, scleritis, Mooren""s ulcer, ocular cicatricial pemphigoid, orbital pseudotumor, iritis, central serous retinopathy, Graves"" ophthalmopathy, chorioretinitis, Sjogren""s syndrome, and Stevens-Johnson syndrome may also be the result of a hyperimmune reaction in the eye. Systemic infections, such as tuberculosis, syphilis, AIDS, toxoplasmosis infection, and cytomegalovirus retinitis, may also cause eye diseases, including but not limited to, uveitis, enophthalmitis, retinitis, choroiditis, and retinal necrosis. These types of hyperimmune reactions typically result in blurred vision and eventually blindness. Current therapies to treat such hyperimmune responses include corticosteroid treatment, including dexamethasone, and treatment with an anti-inflammatory preparation. To date, there are no successful or long-term methods or compositions for effectively treating hyperimmune reactions in the mammalian eye and other organs. The present invention provides such methods and compositions.
The invention relates to a method of treating rejection of an eye-related tissue or organ transplant in a mammal. The method comprises administering to the eye of the mammal a composition comprising antibody to interferon gamma.
In one aspect, the composition is administered topically to the eye of the mammal.
In another aspect, the mammal is human.
In yet another aspect, the transplant is a corneal transplant.
In yet another aspect of the invention, the antibody is a polyclonal antibody, a monoclonal antibody, a humanized antibody, or a biologically active fragment of an antibody to interferon gamma.
In yet another aspect, the composition is suspended in a pharmaceutically acceptable carrier.
The invention comprises and utilizes the discovery that administration of antibodies to interferon (IFN) gamma to an animal having an autoimmune reaction in the eye is useful in alleviating or eliminating the autoimmune reaction. Such autoimmune reactions in the eye may occur as a result of transplants of eye tissue and eye diseases, including but not limited to Sjogren""s syndrome, multiple sclerosis, sarcoidosis, ankylosing spondylitis, keratoconjunctivitis sicca (dry eye syndrome), episcleritis, scleritis, Mooren""s ulcer, ocular cicatricial pemphigoid, orbital pseudotumor, iritis, central serous retinopathy, Graves"" ophthalmopathy, chorioretinitis, Stevens-Johnson syndrome, uveitis, enophthalmitis, retinitis, choroiditis, and retinal necrosis. Autoimmune reactions in the eye may also occur as a result of contracting an infectious disease, including, but not limited to AIDS, syphilis, toxoplasmosis infection, and tuberculosis. Autoimmunity may also occur as a result of transplantation of tissue into the eye.
It is immediately apparent from the Examples disclosed herein that antibodies to IFN gamma are also useful for treatment of eye diseases which are characterized by hemorrhage and exudate collection in the eye. Hemorrhage and/or exudate may collect in the anterior chamber of the eye and is a characteristic result of an inflammatory reaction. Typically, these symptoms occur during transplant rejection (i.e., a hyperimmune response). However, the invention should not be construed as being limited solely to the examples provided herein, as other autoimmune diseases of the mammalian eye which are at present unknown, once known, may also be treatable using the methods of the invention.
The invention includes a method of treating an eye disease characterized by a hyperimmune response in the eye of a mammal. Briefly, the method comprises applying antibodies to gamma interferon directly to the affected eye. The method can be used to treat an autoimmune eye disease in any mammal; however, preferably, the mammal is a human.
The antibodies to interferon gamma useful in the methods of the invention may be polyclonal antibodies, monoclonal antibodies, synthetic antibodies, such as a biologically active fragment of an antibody to interferon gamma, or they may be humanized monoclonal antibodies. Methods of making and using each of the types of antibodies useful in the methods of the invention are now described. In addition, human antibodies to interferon gamma, obtained from human donors, may be employed in the invention.
When the antibody used in the methods of the invention is a polyclonal antibody (IgG), the antibody is generated by inoculating a suitable animal with interferon gamma or a fragment thereof. Antibodies produced in the inoculated animal which specifically bind interferon gamma are then isolated from fluid obtained from the animal. Interferon gamma antibodies may be generated in this manner in several non-human mammals such as, but not limited to goat, sheep, horse, rabbit, and donkey. Methods for generating polyclonal antibodies are well known in the art and are described, for example in Harlow, et al. (1988, In: Antibodies, A Laboratory Manual, Cold Spring Harbor, N.Y.). These methods are not repeated herein as they are commonly used in the art of antibody technology.
When the antibody used in the methods of the invention is a monoclonal antibody, the antibody is generated using any well known monoclonal antibody preparation procedures such as those described, for example, in Harlow et al. (supra) and in Tuszynski et al. (1988, Blood, 72:109-115). Given that these methods are well known in the art, they are not replicated herein. Generally, monoclonal antibodies directed against a desired antigen are generated from mice immunized with the antigen using standard procedures as referenced herein. Monoclonal antibodies directed against full length or peptide fragments of interferon gamma may be prepared using the techniques described in Harlow, et al. (supra).
When the antibody used in the methods of the invention is a biologically active antibody fragment or a synthetic antibody corresponding to antibody to interferon gamma, the antibody is prepared as follows: a nucleic acid encoding the desired antibody or fragment thereof is cloned into a suitable vector. The vector is transfected into cells suitable for the generation of large quantities of the antibody or fragment thereof. DNA encoding the desired antibody is then expressed in the cell thereby producing the antibody. The nucleic acid encoding the desired peptide may be cloned and sequenced using technology which is available in the art, and described, for example, in Wright et al. (1992, Critical Rev. in Immunol. 12(3,4):125-168) and the references cited therein. Alternatively, quantities of the desired antibody or fragment thereof may also be synthesized using chemical synthesis technology. If the amino acid sequence of the antibody is known, the desired antibody can be chemically synthesized using methods known in the art.
The present invention also includes the use of humanized antibodies specifically reactive with IFN gamma epitopes. These antibodies are capable of neutralizing human IFN gamma. The humanized antibodies of the invention have a human framework and have one or more complementarity determining regions (CDRs) from an antibody, typically a mouse antibody, specifically reactive with IFN gamma. Thus, the humanized gamma IFN antibodies of the present invention are useful in the treatment of eye diseases and diseases of other organs which are characterized by an autoimmune reaction which includes overproduction of interferon gamma.
When the antibody used in the invention is humanized, the antibody may be generated as described in Queen, et al. (U.S. Pat. No. 6,180,370), Wright et al., (supra) and in the references cited therein, or in Gu et al. (1997, Thrombosis and Hematocyst 77(4):755-759). The method disclosed in Queen et al. is directed in part toward designing humanized immunoglobulins that are produced by expressing recombinant DNA segments encoding the heavy and light chain complementarity determining regions (CDRs) from a donor immunoglobulin capable of binding to a desired antigen, such as human IFN gamma, attached to DNA segments encoding acceptor human framework regions. Generally speaking, the invention in the Queen patent has applicability toward the design of substantially any humanized immunoglobulin. Queen explains that the DNA segments will typically include an expression control DNA sequence operably linked to the humanized immunoglobulin coding sequences, including naturally-associated or heterologous promoter regions. The expression control sequences can be eukaryotic promoter systems in vectors capable of transforming or transfecting eukaryotic host cells or the expression control sequences can be prokaryotic promoter systems in vectors capable of transforming or transfecting prokaryotic host cells. Once the vector has been incorporated into the appropriate host, the host is maintained under conditions suitable for high level expression of the introduced nucleotide sequences and as desired the collection and purification of the humanized light chains, heavy chains, light/heavy chain dimers or intact antibodies, binding fragments or other immunoglobulin forms may follow (Beychok, Cells of Immunoglobulin Synthesis, Academic Press, New York, (1979), which is incorporated herein by reference).
Human constant region (CDR) DNA sequences from a variety of human cells can be isolated in accordance with well known procedures. Preferably, the human constant region DNA sequences are isolated from immortalized B-cells as described in WO87/02671. CDRs useful in producing the antibodies of the present invention may be similarly derived from DNA encoding monoclonal antibodies capable of binding to human IFN gamma. Such humanized antibodies may be generated using well known methods in any convenient mammalian source capable of producing antibodies, including, but not limited to, mice, rats, rabbits, or other vertebrates. Suitable cells for constant region and framework DNA sequences and host cells in which the antibodies are expressed and secreted, can be obtained from a number of sources such as the American Type Culture Collection, Manassas, Va.
In addition to the humianized IFN gamma discussed above, other xe2x80x9csubstantially homologousxe2x80x9d modifications to native IFN gamma antibody sequences can be readily designed and manufactured utilizing various recombinant DNA techniques well known to those skilled-in the art. Moreover, a variety of different human framework regions may be used singly or in combination as a basis for humanizing antibodies directed at IFN gamma. In general, modifications of genes may be readily accomplished using a variety of well-known techniques, such as site-directed mutagenesis (Gillman and Smith, Gene, 8, 81-97 (1979); Roberts et al., 1987, Nature, 328, 731-734).
Substantially homologous sequences to IFN gamma antibody sequences are those which exhibit at least about 85% homology, usually at least about 90%, and preferably at least about 95% homology with a reference IFN gamma immunoglobulin protein.
Alternatively, polypeptide fragments comprising only a portion of the primary antibody structure may be produced, which fragments possess one or more functions of IFN gamma antibody. These polypeptide fragments may be generated by proteolytic cleavage of intact antibodies using methods well known in the art, or they may be generated by inserting stop codons at the desired locations in vectors comprising the fragment using site-directed mutagenesis.
DNA encoding antibody to IFN gamma are expressed in a host cell driven by a suitable promoter regulatory sequence which is operably linked to the DNA encoding the antibody. Typically, DNA encoding the antibody is cloned into a suitable expression vector such that the sequence encoding the antibody is operably linked to the promoter/regulatory sequence. Such expression vectors are. typically replication competent in a host organism either as an episome or as an integral part of the host chromosomal DNA. Commonly, an expression vector will comprise DNA encoding a detectable marker protein, e.g., a gene encoding resistance to tetracycline or neomycin, to permit detection of cells transformed with the desired DNA sequences (U.S. Pat. No. 4,704,362).
Escherichia coli is an example of a prokaryotic host which is particularly useful for expression of DNA sequences encoding the antibodies of the present invention. Other microbial hosts suitable for use include but are not limited to, Bacillus subtilis, and other enterobacteriaceae, such as selected member of Salmonella, Serratia, and various Pseudomonas species. It is possible to generate expression vectors suitable for the desired host cell wherein the vectors will typically comprise an expression control sequence which is compatible with the host cell. A variety of promoter/regulatory sequences are useful for expression of genes in these cells, including but not limited to the lactose promoter system, a tryptophan (trp) promoter system, a beta-lactamase promoter system, or a promoter system derived from phage lambda. The promoter will typically control expression of the antibody whose DNA sequence is operably linked thereto, the promoter is optionally linked with an operator sequence and generally comprises RNA polymerase and ribosome binding site sequences and the like for initiating and completing transcription and translation of the desired antibody.
Yeast is an example of a eukaryotic host useful for cloning DNA sequences encoding the antibodies of the present invention. Saccharomyces is a preferred eukaryotic host. Promoter/regulatory sequences which drive expression of nucleic acids in eukaryotic cells include but are not limited to the 3-phosphoglycerate kinase promoter/regulatory sequence and promoter/regulatory sequences which drive expression of nucleic acid encoding other glycolytic enzymes.
In addition to microorganisms, mammalian tissue cell culture may also be used to express and produce the antibodies of the present invention (Winnacker, 1987, xe2x80x9cFrom Genes to Clones,xe2x80x9d VCH Publishers, New York, N.Y). Eukaryotic cells are preferred for expression of antibodies and a number of suitable host cell lines have been developed in the art, including Chinese Hamster Ovary (CHO) cells, various COS cell lines, HeLa cells, preferably myeloma cell lines, and transformed B-cells or hybridomas. Expression vectors which express desired sequences in these cells can include expression control sequences, such as an origin of DNA replication, a promoter, an enhancer (Queen et al., 1986, Immunol. Rev., 89, 49-68), and necessary processing sequence sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcriptional initiation and terminator sequences. Preferred expression control sequences are promoters derived from immunoglobulin genes, Simian Virus (SV) 40, adenovirus, cytomegalovirus, bovine papilloma virus and the like.
The vectors containing the DNA segments of interest can be transferred into the host cell by well-known methods, which vary depending on the type of cellular host. For example, calcium chloride transfection is commonly utilized for prokaryotic cells, whereas calcium phosphate treatment or electroporation may be used for other cellular hosts. (Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual, Cold Spring Harbor, N.Y.).
Once expressed, whole antibodies, dimers derived therefrom, individual light and heavy chains, or other forms of antibodies can be purified according to standard procedures known in the art. Such procedures include, but are not limited to, ammonium sulfate precipitation, the use of affinity columns, routine column chromatography, gel electrophoresis, and the like (see, generally, R. Scopes, xe2x80x9cProtein Purificationxe2x80x9d, Springer-Verlag, N.Y. (1982)). Substantially pure antibodies of at least about 90% to 95% homogeneity are preferred, and antibodies having 98% to 99% or more homogeneity most preferred for pharmaceutical uses. Once purified, the antibodies may then be used therapeutically.
The antibodies of the invention may be used in a therapeutic setting in a pharmaceutical acceptable carrier either alone, or they may be used together with a chemotherapeutic agent such as a non-steroidal anti-inflammatory drug, a corticosteroid, or an immunosuppressant. The antibodies, or complexes derived therefrom, can be prepared in a pharmaceutically accepted dosage form which will vary depending on the mode of administration.
The invention thus embodies a novel composition comprising antibodies that bind with IFN gamma for use in treatment of eye disease. As stated above, the antibodies can be monoclonal antibodies, polyclonal antibodies, humanized monoclonal antibodies, or monoclonal chimeric antibodies, or a biologically active fragment of any type of antibody herein recited. Generation of each type of antibody is discussed herein and applies to generation of antibodies for use in the novel methods of the invention. Generally, it is preferred that monoclonal humanized antibodies are used because they are non-immunogenic, and thus, will not elicit an immune response. However, any type of antibody may be used in the present invention.
The method of the invention is not intended to be limited to use of antibodies to IFN gamma. Inhibitors to IFN gamma are also useful in the method of the invention. Such inhibitors include, but are not limited to, peptides which block the function of IFN gamma, IFN gamma receptor, antibodies to IFN gamma receptors, IFN beta, interleukin-10 (IL-10), and any combination thereof.
The pharmaceutical composition useful for practicing the invention may be administered to deliver a dose of between one microgram per kilogram per day and one hundred milligrams per kilogram per day.
Pharmaceutical compositions that are useful in the methods of the invention may be administered topically or systemically in ophthalmic, injectable, or other similar formulations. In addition to the antibodies to IFN gamma, such pharmaceutical compositions may contain pharmaceutically-acceptable carriers and other ingredients known to enhance and facilitate drug administration. Other possible formulations, such as nanoparticles, liposomes, resealed erythrocytes, and immunologically based systems may also be used to administer the gamma IFN antibodies according to the methods of the invention.
Compounds comprising antibodies to IFN gamma that can be pharmaceutically formulated and administered to an animal for treatment of autoimmune reactions in the eye are now described.
The invention encompasses the preparation and use of pharmaceutical compositions comprising antibodies to IFN gamma as an active ingredient. Such a pharmaceutical composition may consist of the active ingredient alone, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise the active ingredient and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these. The active ingredient may be present in the pharmaceutical composition in the form of a physiologically acceptable ester or salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art.
As used herein, the term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d means a chemical composition with which the active ingredient may be combined and which, following the combination, can be used to administer the active ingredient to a subject.
As used herein, the term xe2x80x9cphysiologically acceptablexe2x80x9d ester or salt means an ester or salt form of the active ingredient which is compatible with any other ingredients of the pharmaceutical composition, which is not deleterious to the subject to which the composition is to be administered.
The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.
Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation.
A pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a xe2x80x9cunit dosexe2x80x9d is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient.
In addition to the active ingredient, a pharmaceutical composition of the invention may further comprise one or more additional pharmaceutically active agents. Particularly contemplated additional agents include IFN gamma receptor, antibodies to IFN gamma receptors, IFN beta, interleukin-10 (IL-10), and any combination thereof.
Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology.
Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or suspensions. Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein. lonophoretic administration of the pharmaceutical composition of the invention is considered a form of topical administration herein.
The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1,3-butane diol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer""s solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides. Other parenterally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer systems. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.
A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1% to 1.0% (w/w) solution or suspension of the active ingredient in an aqueous or oily liquid carrier. Such drops may further comprise buffering agents, salts, or one or more other of the additional ingredients described herein. Other administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form or in a liposomal preparation.
As used herein, xe2x80x9cadditional ingredientsxe2x80x9d include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials. Other xe2x80x9cadditional ingredientsxe2x80x9d which may be included in the pharmaceutical compositions of the invention are known in the art and described, for example in Genaro, ed., 1985, Remington""s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., which is incorporated herein by reference.
The compound may be administered to an animal as frequently as several times daily, or it may be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less. The frequency of the dose will be readily apparent to the skilled artisan and will depend upon any number of factors, such as, but not limited to, the type and severity of the disease being treated, the type and age of the animal, etc.
Preferably, the composition of the invention is administered topically. The composition may be administered as an ointment to the lower eyelid. Preferably, the composition is administered in the form of eye drops. However, the composition comprising antibody to IFN-gamma may also be administered parenterally.
The antibodies to IFN-gamma may be present in a composition to be administered to the affected eye at a range of concentrations.
A composition comprising an antibody to IFN gamma can be administered to the affected eye several times per day. Preferably, the composition is administered from one to five times per day, and more preferably, the composition is administered from one to three times per day. Most preferred is administration of the composition three times per day.
IFN gamma antibodies can be administered to the affected eye of a patient for as long as necessary to remedy the effects of the autoimmune reaction. Preferably, the patient receives treatment for about 5 to about 10 days. More preferably, the patient receives treatment for about 5 to about 7 days. The entire treatment of administering IFN gamma antibodies can be repeated.
As evidenced by the Examples, the present invention is particularly useful in treating a hyperimmune response resulting from rejection of an eye-related tissue or organ transplant. The invention is also useful in preventing an expected rejection of a transplanted tissue or organ when the composition of the invention is administered about one day before, during, and immediately after transplant surgery. The preferred treatment period is about seven days.
Administering IFN gamma antibodies to the an affected eye is also effective against damage of eye and optic nerve cells caused by hyperproduction of IFN gamma. Hyperproduction of IFN gamma can also induce an autoimmune response in the eye. Thus, the administration of IFN gamma antibodies to an eye affected with a disease that causes hyperproduction of IFN gamma is well within the purview of the present invention.
Definitions
The articles xe2x80x9caxe2x80x9d and xe2x80x9canxe2x80x9d are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, xe2x80x9can elementxe2x80x9d means one element or more than one element.
The term xe2x80x9cantibody,xe2x80x9d as used herein, refers to an immunoglobulin molecule which is able to specifically bind to a specific epitope on an antigen. Antibodies can be intact immunoglobulins derived from natural sources or from recombinant sources and can be immunoreactive portions of intact immunoglobulins. Antibodies are typically tetramers of immunoglobulin molecules. The antibodies in the present invention may exist in a variety of forms including, for example, polyclonal antibodies, monoclonal antibodies, Fv, Fab and F(ab)2, as well as single chain antibodies and humanized antibodies (Harlow et al., 1999, Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY; Harlow et al., 1989, Antibodies: A Laboratory Manual, Cold Spring Harbor, N.Y.; Houston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; Bird et al., 1988, Science 242:423-426).
By the term xe2x80x9csynthetic antibodyxe2x80x9d as used herein, is meant an antibody which is generated using recombinant DNA technology, such as, for example, an antibody expressed by a bacteriophage as described herein. The term should also be construed to mean an antibody which has been generated by the synthesis of a DNA molecule encoding the antibody and which DNA molecule expresses an antibody protein, or an amino acid sequence specifying the antibody, wherein the DNA or amino acid sequence has been obtained using synthetic DNA or amino acid sequence technology which is available and well known in the art.
By the term xe2x80x9cbiologically active antibody fragmentxe2x80x9d is meant a fragment of an antibody which retains the ability to specifically bind to IFN gamma.
A xe2x80x9cdiseasexe2x80x9d is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal""s health continues to deteriorate. Use of the term disease throughout the application is meant to encompass the terms diseases, disorders, and conditions.
xe2x80x9cTreatmentxe2x80x9d of a disease occurs when the severity of a symptom of the disease, the frequency with which such a symptom is experienced by a patient, or both, is reduced or eliminated. xe2x80x9cTreatmentxe2x80x9d also encompasses prevention of an anticipated disease state. For example, treatment of a transplant rejection includes use of a composition comprising antibodies to IFN gamma after rejection has already occurred, and also within a period of post-transplant surgery to prevent an anticipated rejection. The preferred period post-surgery is about seven days.
By the term xe2x80x9cspecifically binds,xe2x80x9d as used herein, is meant an antibody which recognizes and binds IFN gamma, but does not substantially recognize or bind other molecules in a sample.
xe2x80x9cAutoimmune responsexe2x80x9d refers to an alteration in the immune system wherein the immune response mounted during a disease state is detrimental to the host. Typically, cells of the immune system or other immune system components such as antibodies produced by the host, recognize xe2x80x9cselfxe2x80x9d antigens as foreign antigens.
A xe2x80x9chyperimmune responsexe2x80x9d refers to an autoimmune response characterized by an overexpression of one or more cytokines of the immune system.
As used here, xe2x80x9can eye-related tissue or organxe2x80x9d refers to the tissues and organs that constitute the eye. These include all parts of the eye as would be classified in an anatomy textbook, for example, Williams et al., eds., 1980, Gray""s Anatomy, 36th ed., W. B. Saunders Co., Philadelphia.
A xe2x80x9ccorneal transplantxe2x80x9d refers to the insertion of a cornea into the eye of a mammal, where the cornea being inserted is not the natural cornea of the mammal. The cornea being inserted may be from a cadaver.
A pharmaceutical composition is said to be xe2x80x9ctopically administeredxe2x80x9d when it is applied directly to the affected area. Eye drops, for example, are applied topically, as are creams and ointments. lonophoresis is also included as a form of topical administration.
xe2x80x9cRecombinant DNAxe2x80x9d refers to a polynucleotide having sequences that are not naturally joined together. An amplified or assembled recombinant polynucleotide may be included in a suitable vector, and the vector can be used to transform a suitable host cell. A recombinant DNA polynucleotide may serve a non-coding function (e.g., promoter, origin of replication, ribosome-binding site, etc.) as well.

Compositions and methods for treating hyperimmune response in the eye


Convective heat traps are installed at the cold water inlet and hot water outlet of a water heater. Each heat trap has a tubular body with two axially spaced apart resilient flapper members transversely extending across the interior of the body and being hinged on opposite sides thereof. The heat trap at the cold water inlet is coaxially disposed within a dip tube. In one alternate structure, flapper members are mounted directly on the dip tube, and in another alternate structure an external annular seal element is mounted on the dip tube or heat trap body, with a flapper member being integrally formed with the seal element.

The present invention generally relates to water flow control apparatus and, in illustrated embodiments thereof, more particularly relates to specially designed water heater convective heat trap constructions.
Water heaters of both the fuel-fired and electrically heated types typically have a tank portion in which pressurized, heated water is stored for on-demand delivery to various types of hot water-utilizing plumbing fixtures such as, for example, sinks, bath tubs and dishwashers. During standby periods in which discharge of stored hot water from the tank is not required, it is desirable to substantially reduce heat loss from the stored hot water to cooler areas outside the tank. For this reason it is customary practice to externally insulate the tank.
While this technique is effective in reducing undesirable heat loss from the tank body, stored water heat may also be lost by thermal convection flow of heated water from the tank through its cold water inlet and hot water outlet openings to piping connected thereto. In order to minimize this convective heat loss, various convective heat trap devices have been previously proposed for connection to the tank at or adjacent these inlet and outlet openings. These heat trap devices are basically check valve-type structures which freely permit water to flow through the tank inlet and outlet in operational directions during water supply periods, but substantially inhibit convective water outflow through the inlet and outlet during non-demand storage periods of the water heater.
One common type of convective heat trap utilizes a movable ball to block or impede undesirable convective water flow through its associated water inlet or outlet opening in the tank. While this ball type of heat trap typically eliminates or at least substantially reduces outward convective water flow, it also is prone to create undesirable noise (namely, xe2x80x9crattlingxe2x80x9d) during its operation. This has led to many complaints from water heater purchasers over the Years and corresponding repair or replacement costs for water heater manufacturers.
In response to this well-known problem typically associated with ball-type heat traps various xe2x80x9cflapperxe2x80x9d type heat trap constructions have been previously proposed as alternatives to movable ball-type heat traps. In this design, a flexible blocking member (or xe2x80x9cflapperxe2x80x9d) is appropriately positioned in each path of potential convective outflow currents of water from the tank (i.e., at or adjacent the cold water inlet and hot water outlet of the tank) and serves as a barrier to undesirable convective outflows of heated tank water during non-demand periods of the water heater. However, when one or more of the plumbing fixtures connected to the water heater is operated to draw hot water from the tank, the flappers resiliently deflect to freely permit cold water supply to the tank and hot water discharge from the tank. Because of the resilient nature of the flappers their operation is typically silent.
However, compared to ball type heat traps flapper type convective heat traps present their own types of problems, limitations and disadvantages including potentially higher cost and greater complexity, installation difficulties, additional shipping volume and less than optimal reductions in convective heat loss from their associated water heater. A need accordingly exists for improved water heater convective heat trap designs. it is to this need that the present invention is directed.
In carrying out principles of the present invention, in accordance with an illustrated embodiment thereof, a water heater is provided which includes a tank adapted to store a quantity of water and having water inlet and outlet openings; heating apparatus for heating water stored within the tank; and first and second specially designed heat traps respectively associated with the water inlet and outlet openings and operative to inhibit convective water outflows therethrough.
Each heat trap includes a tubular body extending along an axis; and first and second axially spaced apart resilient flapper structures carried by the body and having axially deflectable portions transversely extending across the interior of the body. Preferably, the deflectable flapper structure portions in each heat trap body are axially deflectable about circumferentially offset hinge locations adjacent the interior side surface of the body. Representatively, the hinge locations are circumferentially offset from one another by about 180 degrees. Additionally, when the resilient flapper portions are in undeflected orientations within their associated heat trap body they preferably define circumferentially extending gaps with the interior side surface of the body.
In an illustrated embodiment of the heat traps, each tubular body representatively has an outwardly projecting integral end flange with a noncircular driving recess formed in an outer side thereof. Axially spaced exterior annular grooves are formed in the body side wall, with circumferentially offset slots extending radially through the body at such grooves. Each resilient flapper member has a circular outer ring portion received in one of the grooves, and a generally circular interior portion received within the interior of the body and connected to the ring by a hinge tab portion extending outwardly through the associated slot and being formed integrally with the outer ring.
The heat trap at the cold water inlet of the tank is coaxially received in an upper end portion of a cold water inlet dip tube extending downwardly into the interior of the tank. Alternatively, the tubular body of the heat trap at the cold water inlet of the tank is eliminated, and the flapper members are incorporated directly into the dip tube to form a combination dip tube/heat trap structure.
Representatively, tubular connection spuds are externally secured to the tank over its cold water inlet and hot water outlet openings, and dip cup members extend downwardly through these openings. Tubular seal members circumscribe the hot water side heat trap body and the dip tube and sealingly engage the associated spuds and dip cups. Illustratively, these external seal structures are separate elements, but may alternately be formed integrally with the internal flapper portions. The non circular driving recesses in the flange portions of the heat traps are used to thread the flange edges into threaded interior portions of the connection spuds.
The specially designed neat traps substantially inhibit undesirable convective water flow outwardly through the cold water and hot water tank openings, with the circumferentially offset, axially spaced interior flapper portions forcing tank water to take a generally serpentine path outwardly through the traps. The heat traps operate very quietly, are of a simple construction, are easy to install, are inexpensive to manufacture, and operate in a reliable manner to materially reduce undesirable convective outflow of water from the tank during standby periods of the water heater.


A slide heater for use in a slide processing apparatus in which an interface surface between the slide heater and the slide has a plurality of slots or channels terminating in an edge thereof, for gathering and venting gas bubbles.

Immunostaining and in situ DNA analysis are useful tools in histological diagnosis and the study of tissue morphology. Immunostaining relies on the specific binding affinity of antibodies with epitopes in tissue samples, and the increasing availability of antibodies which bind specifically with unique epitopes present only in certain types of diseased cellular tissue. Immunostaining requiring a series of treatment steps conducted on a tissue section mounted on a glass slide to highlight by selective staining certain morphological indicators of disease states. Typical steps include pretreatment of the tissue section to reduce non-specific binding, antibody treatment and incubation, enzyme labeled secondary antibody treatment and incubation, substrate reaction with the enzyme to produce a fluorophore or chromophore highlighting areas of the tissue section having epitopes binding with the antibody, counterstaining, and the like. Each of these steps is separated by multiple rinse steps to remove unreacted residual reagent from the prior step. Incubations typically are conducted at around 40° C., while cell conditioning steps typically are conducted at somewhat higher temperatures, e.g. 90-100° C. In-situ DNA analysis relies upon the specific binding affinity of probes with unique nucleotide sequences in cell or tissue samples and similarly involves a series of process steps, with a variety of reagents and process temperature requirements.
Automated systems have been proposed to introduce cost savings, uniformity of slide preparation, and reduction of procedural human errors. Stross, W. et al, J. Clin. Pathol. 42: 106-112 (1989) describes a system comprising a series of baths positioned under the circumference of a circular, rotatable disc from which slide trays are suspended. The disc is lifted to lift slide trays from their baths, turned to position the slide trays above the next consecutive bath, and lowered to immerse the slide trays in the baths. This operation can be automated with suitable timers and switches. This system exposes each of the slides to the same treatment and relies on dipping for application of reactants and rinsing.
Stark, E. et al, J. Immunol. Methods. 107: 89-92 (1988) describes a microprocessor controlled system including a revolving table or carousel supporting radially positioned slides. A stepper motor rotates the table, placing each slide under one of the stationary syringes positioned above the slides. A predetermined volume of liquid, determined by a dial, is delivered to a slide from each syringe. Microprocessor controls are provided.
Cosgrove, R. et al, ACL. pp 23-27 (December, 1989) describe an immunostaining apparatus for auto-pipetting reagents into a slide well from a carousel holding up to 18 reagent vials. Below each well, a coverplate spaced from the surface of each slide provides cover and defines a reagent flow channel. The slides are suspended at a steep angle. Reagent from the well flows downward over the slide surface. A row of slides are suspended for sequential treatment. Washing is accomplished by a 3 to 4 minute continuous running wash over the sample, yielding an estimated 20:1 wash/reagent ratio.
Brigati, D. et al, J. Histotechnology 11: 165-183 (1988) and Unger, E. Brigati, D. et al, et al, J. Histotechnology. 11: 253-258 (1988) describe the Fisher automated work station using capillary gap technology. A coverplate is placed over the slide, forming a capillary gap. Liquid is introduced into the capillary gap by placing the lower edge of the plate-slide pair in a liquid. Liquid is removed by placing the lower edge of the plate-slide pair on a blotter. The system is further described in U.S. Pat. Nos. 4,777,020, 4,798,706 and 4,801,431. The previously known devices are listed in their performance and unable to satisfy the needs for automated, high precision immunohistology.
The foregoing discussion of the prior art derives in large part from U.S. Pat. No. 5,654,200 to Copeland et al., who describe an automated biological processing system comprising a reagent carousel cooperating with a sample support carousel to apply a sequence of preselected reagents to each of the samples with interposed mixing, incubating, and rinsing steps cooperating therewith. This patented automated biological processing system, which is available from Ventana Medical Systems, Inc. of Tucson, Ariz. includes a slide support carousel having a plurality of slide supports thereon and drive means engaging the slide support carousel for consecutively positioning each of a plurality of slide supports in a reagent receiving zone. The reagent carousel has a plurality of reagent container supports thereon and drive means engaging the reagent carousel for rotating this carousel and positioning a preselected reagent container support and associated reagent container in a regent supply zone. The apparatus has a reagent delivery actuator means positioned for engaging a reagent container positioned on a container support in the reagent supply zone and initiating reagent delivery from the reagent container to a slide supported on a slide support in the reagent receiving zone.
FIG. 1, which largely corresponds to FIG. 3 of U.S. Pat. No. 5,654,200 is a partial exploded isometric view of an automated biological processing system, with the cabinet, liquid and air supply tubing and electrical wiring omitted in the drawings for the purposes of clarity.
The apparatus has an upper section 2, intermediate section 4 and lower section 6. In the upper section 2, reagent bottle support carousel 10 is mounted for rotation about its central axis on upper support plate 8. Reagent bottles 12 required for the immuno-histochemical reactions to be conducted during slide treatment cycle are supported by the carousel 10, mounted in reagent bottle receptors 11. These receptors 11 are configured to receive volumetric pump outlet tubes (not shown). The receptors 11 are preferably equally spaced in a circular pattern axially concentric with the carousel axis. The number of receptors 11 provided should be sufficient to accommodate the number of different reagent bottles 12 required for a cycle or series of cycles. The carousel 10 is rotated by the stepper motor 14 and drive belt 16 to a position placing a selected reagent bottle 12 in the reagent delivery position under an air cylinder reagent delivery actuator 18 over a slide to be treated with reagent. Reagent tray motor driver 20 is connected to stepper motor 14.
The intermediate section 4 comprises support plate 22 upon which the slide support carousel 24 is rotatably mounted. The carousel 24 supports slide supports 26. In the intermediate section 4, a stepper motor 48 rotates the slide support carousel 24, engaging drive belt 25 engaging the perimeter of the slide support carousel 24. Splash guard 50 is a wall which surrounds the sides, back and part of the front of the carousel 24, and contains liquid spray and droplets produced in the processing. Splash guard 50 extends upward from the intermediate plate 22 to a position adjacent the upper plate 8, leaving an air flow gap between the upper edge of the splash guard 50 and the underside of the plate 8. Lower section 6 includes slide carousel stepper motor driver 72 and relay 74, power supplies 76 and 78, and control systems all mounted on plate 40.
Referring to FIGS. 2 and 3, slide support 26 comprises a molded plastic base 80 on which is mounted a metal plate 82. An electrical resistance heater shown in phantom at 84 is mounted in direct contact to the underside of metal plate 82. Corner pins 86 locate a specimen carrying glass slide 88 on the surface of metal plate 82. Metal plate 82 has a top surface that is essentially flat and smooth. Flatness and smoothness facilitates glass plate position stability and thermal conduction uniformity.
In practice, water and other fluids employed in the slide processing may spill over the edges of the slides, and work their way under the slides where the fluids may boil, causing the slides to "pop" or dislocate. Moreover, since heater surfaces are not perfectly flat, in order to insure good thermal contact between metal plate 82 and glass slide 88, a thin layer 90 of oil may be applied to the top surface of metal plate 82. However, using oil as an interfacial heating medium, may exacerbate the problem of slide popping or dislocation due to gas formation from water or other fluid getting under the slide, mixing with the oil and then boiling off in an uncontrolled fashion. Dislocation of a slide may cause that slide to set up on a post, thereby compromising the processing of that one slide, or in a worse case scenario result in a domino or train wreck effect where the one dislocated slide hits a neighboring slide causing that slide to dislocate, and so forth.


Canoe and kayak mid-point sponsons attach to the canoe or kayak only at the mid-point of the sponsons, to enable the sponsons to rotate around the midpoint in order to reduce drag in waves and simplify attachment and detachment to the canoe or kayak, while also permitting much greater sponson buoyancy volume than any other type of sponson, without interfering with normal paddling to safety. They are attached to any canoe or kayak by material such as only one adjustable strap and two clips, extending to kayak deck fittings adjacent the cockpit or a canoe middle thwart, in such a manner as to facilitate normal paddling of the stabilized craft in life threatening emergencies. They can be directly attached to both sides of the hull near the waterline. The mid-point sponsons can be solid buoyant material, waterproof and airtight stowage bags containing bulky lightweight items such as sleeping bags, orally inflatable sponson floats, and gas cartridge inflatable sponson floats. A particular feature is permanent or semi-permanent attachment to the hull above the waterline to eliminate drag unless inflated, in which case the inflated sponsons are forced to immerse in the water. When not inflated each midpoint sponson would be neatly stowed in a small and rescue-emergency marked stowage bag or covering that holds sponsons upward from the waterline. Such an arrangement ensures that the sponsons rest sleekly and unobtrusively along the hull side when not deployed.

1. Field of the Invention
The invention relates to canoe and kayak safety derived from mid-point sponsons that permit greater buoyancy volume than normal sponsons, for higher stability from both a larger righting arm as well as more buoyancy force. This buoyancy force is most important when people with poor strength or fitness, sudden illness or in capsizing conditions require a sling to help them re-enter from the water. Mid-point sponsons, attached by only one point, can be pushed away from the hull upon re-entry, further immersing the sponson for greater buoyancy as well as creating a longer righting arm away from the hull side. The mid-point sponsons attach to the canoe or kayak only at the mid-point of the sponsons, to enable the sponsons to rotate around the midpoint in order to reduce drag in waves and simplify attachment and detachment to the canoe or kayak.
A particular feature is permanent or semi-permanent attachment to the hull above the waterline to eliminate drag unless inflated, in which case the inflated sponsons are forced to immerse in the water as shown in FIG. 2 of drawings, creating a massive stability arm instantly by gas cartridge, or in two minutes using a two foot long oral inflation tube, whether inflated from the water or the cockpit. When not inflated each midpoint sponson would be neatly stowed in a small and rescue-emergency marked stowage bag or covering that would hold sponsons upward from the waterline. Such an arrangement ensures that the sponsons rest sleekly and unobtrusively along the hull side when not deployed, each protected by an emergency stowage bag or covering and the midpoint sponson attachment point to the strap, shown in FIG. 2 as slightly below the waterline 13, would be instead somewhat above the waterline to eliminate drag almost entirely. Likewise an attachment point directly to the hull would be above the design waterline to eliminate all drag.
2. Prior Art
Canoes and Kayaks are dangerous in capsizing conditions such as winds and waves. Winds can occur suddenly without clear warning. Canoes and kayaks cannot be paddled fast enough to escape these natural threats. Capsized kayaks and canoes are flooded and cannot be reliably rescued except by larger craft such as Coast Guard Rigid Inflatable boats, with large air-filled sponsons on a rigid hull. These are the most stable small powercraft in the world, and Coast Guards use them around the world.
Kayaks cannot be rescued reliably by Eskimo rolling because experts are left in the same capsizing conditions as before capsize, if they successfully roll up (after their bracing skills have just been inadequate to prevent capsize in the first place.) Most experts admit they do not roll with 100 per cent reliability since they normally do not practise rolls in all capsizing conditions, or they are paddling kayaks loaded differently from practice, perhaps using different paddles or suffering from seasickness or other ailments that are only a few of dozens of different circumstances that make rolls unreliable, such as capsizing conditions. Few experts are fortunate to roll repeatedly in capsizing conditions when water intrudes under sprayskirts with each roll, making kayaks increasingly less stable, and rolls less reliable. Kayak rolling is not at all possible for most of the public, let alone with any degree of reliability as required for safety. Canoe rolling is not normally possible except in specially equipped open canoes with massive internal flotation and young and fit experts highly practised in this refined technical skill. Only normal sponsons now provide reliable rescues due to normal sponsons providing high secondary stability coupled with the inevitable flooded kayak cockpit upon capsize. The weight of water is stabilized by sponsons, not sloshing transversely to destabilize kayaks and canoes, and creates ballast stability coupled with the righting arm of sponson buoyancy in capsizing conditions. Sponsoned kayaks and canoes are much more stable than before capsize. Rolling is practised by some groups with great enthusiasm and enjoyment, no matter how unreliable in capsizing conditions. There is a cult belief in the safety of rolls and ritualized practice, no matter how unreliable.
Some groups recognize that rolls need back-up safety and use a paddlefloat, while recognizing that paddlefloat rescues are less reliable than the rolls they backup. The paddlefloat rescue uses a float on the end of a paddle as a lever to assist on re-entry of kayaks. This does not stabilize the kayak upon reentry and is condemned as a xe2x80x9ccalm water rescuexe2x80x9d by the British Canoe Union and others world wide. The one-side lever recapsizes paddlers by rising on waves or submerging and tripping the kayak in waves, and it regularly breaks the most expensive lightweight paddles when used as a lever for a load weight that paddles are not designed to carry. The kayaker is not stabilized adequately while pumping out cockpit water, a long and tiring task using a pump that requires 2 hands through an opening in the spray skirt that attempts to prevent more water from flooding in. But even small one foot waves wash over any flooded, or loaded kayak and refill it. Calm water avoids this problem. Sprayskirts are awkward and permit gradual intrusion of water in normal situations apart from emergencies. Finally the paddle must be retrieved from behind the seated paddler and the paddlefloat removed in capsizing conditions. This is a precarious procedure and usually results in recapsize since the capsized victim is less stable than before capsize when a paddle was available for bracing strokes, to stabilize the kayak.
Open canoes cannot be paddled to safety while flooded due to insufficient buoyancy and stability, although optimistic and misleading instruction states the contrary. Flooded canoes without sponsons simply roll over when re-entry attempts are made. Dozens of well documented coroner inquests into canoeing deaths confirm this reality. Expert canoeists without sponsons die of hypothermia in wilderness areas after capsize, when winds build in strength without clear warning, or river waves flood canoes. Sponsoned canoes survive descents of large rivers without capsize due to high secondary stability in rapids.
Assisted rescues for canoes and kayaks are highly circumstantial and risk the lives of would-be rescuers in emergency conditions. Some experts agree to xe2x80x9csuicide pactsxe2x80x9d, not attempting to rescue one-another in emergencies lest the rescuers capsize too. Loaded canoes cannot be lifted and emptied over the gunwale of a rescuing canoe in capsizing conditions, any more than many hundreds of pounds of loaded kayak can be lifted out of the water. Even unloading heavy packs from open canoes will risk the group due to exposure from lost clothes, food, tents. (Such heavy packs are usually waterproofed and will provide interior flotation if secured within, since they do float and prevent the same volume of heavier water from occupying the space and sinking the craft lower in the water. Heavy packs cannot be retrieved in capsizing conditions without capsizing open canoes and all of these futile emergency operations leave victims in the cold water too long to avoid hypothermia. They cannot work hands after only a few minutes, although it may be hours before the body core temperature is low enough to kill. Even if these operations were remotely possible, canoes and kayaks simply reflood in the same waves and wind that have not mysteriously disappeared, in reality.) Sponsoned canoes and kayaks do not depend on removal of water inside but use it as ballast stability. All kayaks and canoes must have sufficient internal flotation in the ends or they are death traps.
All of the above information has been well-documented in major canoe and kayak publications, although not in a logically consistent fashion. Authors and instructor groups contradict each others"" emphases on particular safety techniques, increasing the safety risks for the public. The quick and reliable transformation of all canoes and kayaks into life rafts, that can reliably rescue victims from cold water (and even be paddled or towed, so stabilized, to a safe shore), is the most strategic and comprehensive safety possible. In comparison all other rescues are highly circumstantial, dependent on magical thinking that conditions leading to emergency capsizes have suddenly disappeared or that highly practised technical skills will be reliable, and even repeatedly reliable (although apparently not reliable enough to avoid capsize in the first place.) Sponsons replace irrational safety opinions with scientifically proven strategic stability that can be replicated anywhere, anytime, according to scientific method, in minutes or even seconds. Mid-point sponsons create a much more powerful stability equation than normal sponsons, to dramatically change the irrational safety climate that instructors and manufacturers have created, both unintentionally and from habit, to make money from repeated lessons. Instruction based on realistic paddling skills, judgment skills, weather reading etc, is extremely worthwhile. Specious and inconsistent instruction is confusing and ultimately kills the public.
It is desirable to create mid-point sponsons because midpoint sponsons can provide greatly increased stability, more than double the stability of normal sponsons, while permitting normal paddling with only a small drag penalty over normal sponsons (U.S. Pat. No. 4,838,196). Mid-point sponsons can provide a dramatic righting arm to permit a disabled paddler to step into a sling, using large leg muscles to get back into a kayak or canoe. Normal sponsons cannot provide as great a lever arm while still permitting normal paddling or sailing.
Mid-point sponsons dramatically, by simple observation, refute the unscientific opinions of some poorly educated xe2x80x9cnaval architectsxe2x80x9d who do not understand secondary stability; since the midpoint sponsons are not fully immersed except upon re-entry, and otherwise float almost entirely out of the water unless the kayak or canoe is leaned, whereupon the massive righting arm acts impressively, like the massive air sponsons on Coast Guard Rigid Inflatable Rescue Boats.
The unfortunate habits of safety instruction die hard, even among the most well-intentioned instructor organizations. The most powerful demonstration of mid-point sponsons is required, to change safety instruction. This most powerful demonstration would appear to be permanent or semi-permanent attachment to the hull above the waterline to eliminate drag unless inflated, in which case the inflated sponsons are forced to immerse in the water as shown in FIG. 2 of drawings, creating a massive stability arm instantly by gas cartridge, or in two minutes using a two foot long oral inflation tube, whether inflated from the water or the cockpit. When not inflated each midpoint sponson would be neatly stowed in a small and rescue-emergency marked stowage bag or covering that would hold sponsons upward from the waterline. Such an arrangement ensures that the sponsons rest sleekly and unobtrusively along the hull side when not deployed, each protected by an emergency stowage bag or covering, and the midpoint sponson attachment point to the strap 13, shown in FIG. 2 as slightly below the waterline, would be somewhat above the waterline to eliminate drag almost entirely. Likewise an attachment point directly to the hull would be above the design waterline to eliminate all drag. Clearly the instant inflation by gas cartridge of such powerful stability and seaworthiness, could not be easily dismissed.
The present invention reduces some of the problems of the prior art by providing much greater stability than normal sponsons (at least double) while still permitting normal paddling to safety with only slightly more drag than normal sponsons. Canoe and kayak mid-point sponsons attach to the canoe or kayak only at the mid-point of the sponsons, to enable the sponsons to rotate around the midpoint in order to reduce drag in waves and simplify attachment and detachment to the canoe or kayak, while also permitting a much greater sponson buoyancy volume without interfering with normal paddling to safety. This buoyancy force is most important when people with poor strength, health, or fitness require a sling to help them reenter from the water. Mid-point sponsons, attached by only one point, can be pushed away from the hull upon re-entry, further immersing the sponson for greater buoyancy as well as creating a longer righting arm away from the hull side. Sponsons normally extend from the lines of the hull along the waterline on both sides and do not float independently of the incline of the hull when paddled into waves, as is the case of mid-point sponsons. Sponsons are normally not as short as mid-point sponsons, but are longer and much thinner to facilitate paddling. Mid-point sponsons are much thicker but are also shorter to facilitate normal paddling. Mid-point sponsons permit a much greater buoyancy volume while also permitting normal paddling. The sponsons are connected below the waterline by material such as a strap that can be adjusted in length to fit canoes and kayaks of differing widths. The sponsons are connected to the canoe or kayak above the waterline by material such as a strap and two secure clips or snap hooks extending to kayak deck fittings adjacent the cockpit or a canoe middle thwart, in such a manner as to facilitate normal paddling of the stabilized craft in life threatening emergencies. Alternatively the mid-point sponsons can be directly attached to both sides of the hull near the waterline. The sponsons can be any buoyancy system including solid buoyant material, waterproof and airtight stowage bags containing bulky lightweight items such as sleeping bags, orally inflatable sponson floats, and gas cartridge inflatable sponson floats.
The mid-point sponsons, according to the invention consist two buoyant sponson floats, shorter and thicker than normal sponsons (U.S. Pat. No. 4,838,196). The sponsons are thick enough that they can be inflated by a paddler sitting in the cockpit of a kayak while leaning forward, without needing a long inflation tube to orally inflate from the cockpit. The sponsons are thick enough to inflate from the water after capsize without the victim""s head coming too close to the hard boat hull while orally inflating the sponsons. Alternatively the midpoint sponsons can be secured on the rear deck of a kayak, already inflated, or within an open canoe. The mid-point sponsons might consist of two sealed, waterproof and watertight stowage bags that contain only large, lightweight bulky items like a sleeping bag and stowed on deck or within as above, ready to deploy. Deployment of such sealed, already inflated floats, or floats made from buoyant material is normally accomplished from the water after capsize by attaching the nearest sponson to the deck hardware of a righted but flooded kayak by means of a secure clip or snap hook, etc. On open canoes the nearest sponson is normally attached to the middle thwart. The remaining float is pushed under the canoe or kayak to the other side and clipped. This is easily accomplished by pushing with an arm or leg, the buoyant force insufficient to impede this operation, although this same buoyant force is multiplied when in place as a righting lever arm. The remaining clip is attached to the deck hardware or middle thwart on the other side. Alternatively floats can attach directly to fastening points on the hull, near the waterline. In this case it may be easier to clip the floats directly to the hull of an overturned kayak or canoe, then gripping one float, lean back to use body weight to submerge other float and flip canoe or kayak upright. This is easier than flipping a righted sponsoned canoe or kayak over (i.e. capsize) because water ballast and paddler body weight are coupled with sponson righting arm for much greater secondary stability and body core out of cold water to avoid hypothermia.
The mid-point sponsons have great enough righting arm to be used with a simple stirrup or sling to assist disabled victims back into the boat. The mid-point sponsons may be clipped to deck hardware adjacent the kayak cockpit aft of the cockpit because the deck is lower and flatter aft to make re-entry easier. Mid-point sponsons are always clipped between the cockpits on a double kayak because this is the widest point of beam, (as is the middle thwart of any open canoe), to create the greatest stability arm from any given sponson float. Alternatively, mid-point sponsons may be preferred forward of the kayak cockpit as they may interfere less with paddling strokes, particularly steering strokes. Also they are visible to the paddler there and may be reached easily by leaning forward, to deflate slightly to decrease drag, or to unclip and deflate entirely, to stow when an emergency is passed. (Or when sailing, swimming, sunbathing, napping, snorkelling or swimming is passed. You may want a much more stable canoe or kayak for recreational uses, as well as safety.) The forward sponsons can be deployed from the cockpit by leaning forward to orally inflate, then sliding them forward and clipping to the deck hardware forward of the cockpit.
Finally the mid-point sponsons can be clipped to the canoe or kayak and then inflated immediately by means of a gas cartridge. This would be similar to Coast Guard approved inflatable lifejackets for people, but stabilizing instead kayaks and canoes in a most impressive, fast, and failsafe manner. And at much less cost than drysuits that are causing extreme discomfort to paddlers to the point of heatstroke. Overheated paddlers have died by not wearing dry suits properly zipped up, that become flooded with water inside and make it impossible to swim or get out of the water without outside help. Mid-point sponsons can guarantee that they can get out of cold water and live without risk of heatstroke, at a cost as little as $20 U.S. in large economies of scale, sponsons for every kayak and canoe. This compares to more than $400 U.S. per drysuit, retail.
A particular feature is permanent or semi-permanent attachment to the hull above the waterline to eliminate drag unless inflated, in which case the inflated sponsons are forced to immerse in the water as shown in FIG. 2 of drawings, creating a massive stability arm instantly by gas cartridge, or in two minutes using a two foot long oral inflation tube, whether inflated from the water or the cockpit. When not inflated each midpoint sponson would be neatly stowed in a small and rescue-emergency marked stowage bag or covering that would hold sponsons upward from the waterline. Such an arrangement ensures that the sponsons rest sleekly and unobtrusively along the hull side when not deployed, each protected by an emergency stowage bag or covering, and the midpoint sponson attachment point to the strap 13, shown in FIG. 2 as slightly below the waterline, would be somewhat above the waterline instead, to eliminate drag almost entirely. Likewise an attachment point directly to the hull would be above the design waterline to eliminate all drag. It should be noted that material such as a single strap running under the hull of a kayak or canoe near the mid-point cannot cause any significant drag at all, due to the fact that water is in turbulent flow at this point of the hull anyway, unlike the area of laminar flow.
The invention, as exemplified by a preferred embodiment, is described with reference to the drawings.

Canoe and kayak mid-point sponsons safety