MXPA00000419A - Treatment of inflammatory disorders of the bowel and urinary bladder - Google Patents

Abstract

A method of treating inflammatory disorders of the bowel and inflammatory disorders of the urinary bladder is disclosed. A method of modulating the function of monocytes is also disclosed. The method involves the treatment of a patient's blood with a photoactivatable compound followed by ultraviolet light-activation of the photoactivatable compound. The blood treated as such is returned to the patient in a process known as extracorporeal photopheresis.

Description

TREATMENT OF INFLAMMATORY BOWEL DISORDERS AND URINARY BLADDER BACKGROUND OF THE INVENTION Extracorporeal photopheresis is a procedure in which 8-methoxypsoralen (8-MOP), a light-sensitive compound that occurs naturally, is administered orally 2 hours before treatment; blood is then extracted from the patient which is anticoagulated, and the white blood cells are separated by centrifugation and collected as a fraction enriched with leukocytes. These leukocytes containing 8-MOP are then irradiated with ultraviolet light (UVA), which binds 8-MOP to the pyrimidine bases in the DNA, and to intra- and extra-cellular proteins. These treated leukocytes are returned to the patient, and the result is an immunomodulation, which has been found to be of clinical benefit in numerous disease states [Edelson RL. Photopheresis; a clinically relevant immunobiologic response modifier. [Revision] Ann NY Acad Sci. 191; 636: 154-64]. There are several diseases that are thought to involve mainly T cells, or are mediated by T cells. It is thought that T cell-mediated diseases such as cutaneous T-cell lymphoma, organ allograft rejection after transplantation, progressive systemic sclerosis ( PSS), inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and juvenile diabetes mellitus (JODM). Cutaneous T-cell lymphoma (CTCL) is a malignant disease that is progressive. The therapeutic options are limited. Edelson et al. carried out a test in multiple centers [Edelson R, Berger C, Gasparro F. et al. Treatment of cutaneous T cell lymphoma by extracorporeal photochemotherapy: Preliminary results. N Engl J Med 1987; 316: 297-303], which showed that 24 of 29 (83%) erythrodermic patients experienced a significant improvement in their disease. These positive responses were observed at an average time of 22.4 weeks after the start of therapy. Of clinical importance, these patients were those whose diseases were resistant to previous therapy, which is thought to be a poor prognosis group. In addition, a decrease in the degree of peripheral blood intervention (Sezary cells) was observed. Current data had indicated that average survival was increased to more than 60 months from the start of treatment, compared to a historical average survival time of less than 30 months. In this original group of patients, remissions were sustained in eight of the subjects who were leukemic. Adverse reactions associated with photopheresis were rare. Autoimmune diseases are characterized by a dysregulation of the immune system, characterized by cellular or humoral destruction mediated specific to specific organs or tissues in the patient.

Examples of such diseases are rheumatoid arthritis and progressive systemic sclerosis. Rheumatoid arthritis (R. A.) is an inflammatory disease that ultimately leads to the destruction of joints, and is a generalized disease that involves many organ systems. There are many pharmaceutical agents that are used to treat R. A .; However, well-tolerated agents are required with the potential to modify the disease as long as it is lifelong. In particular, loss of efficacy and progression of the disease is observed in a large number of patients after the initiation of secondary line therapy for RA Many of the secondary line agents are immunosuppressive, and are themselves the cause of the effects. major side effects such as infection. The need for the development of a more specific and non-toxic immumodulation therapy is great [Malawista S, Trock D, Edelson R. Treatment of rheumatoid arthritis by extracorporeal photochemotherapy: a pilot study. Arthritis Rheum 1991; 34: 646-54]. Progressive systemic sclerosis (PSS) is a connective tissue disease characterized by inflammatory and fibrotic changes in the skin and viscera. His treatment has been difficult. Corticosteroids and anti-inflammatory drugs are useful in the early stages of the disease, but they do not seem to influence the progression of it. Tests are under way with D-penicillamine, methotrexate, cyclosporine, calcium channel blockers and prostaglandins, but these agents do not seem to influence the overall progression of the disease. Since it has been considered that this disease is mediated by T cells, Rock and his colleagues have treated patients suffering from PSS with photopheresis [Rock AH, Freundlich B, Jegasothy BV, et al. Treatment of systemic sclerosis with extracorporeal photochemoterapy: Results of a multicenter trial. Arch Dermatol 1992; 128: 337-46]. In this trial, 56 patients were included in a randomized non-blinded clinical trial. A significantly higher response rate was observed in the group treated with photopheresis (response rate of 68%), compared to the group treated with D-penicillamine (control) (response rate of 32%). It is thought that juvenile diabetes mellitus (JODM) is mediated by the immune system and results in the destruction of cells in the pancreas, responsible for the production of insulin. Patients with this disorder not only have dysregulation of their blood sugar levels, but the disease is characterized by a vascular disease, which results in damage to specific organs, leading to significant morbidity and mortality. IBD is limited to the colon (ulcerative colitis) or affects the colon and small intestine. In addition, there are intraintestinal manifestations of the disease that include pyoderma gangrenosum, erythema nodosum, sclerosing cholangitis, ankylosing spondylitis, hepatitis, arthritis and uveitis. IBD involves a dysfunction of immunoregulatory mechanisms that sub-regulate immune responses to digestion products, while maintaining the ability to develop a specific immune response to pathogens. Exposure to methoxsalen, activated by UV light, modulates immunoregulatory function, allowing mucosal cells to prepare a lower proliferative response to common microbial antigens than peripheral T cells. Other phenomena mediated by T cells include rejection of tissues that are foreign to the host. In the case of organ allograft transplants, it is convenient to prevent rejection with respect to the transplanted organ, however, to otherwise maintain the competence of the immune system to allow the body to fight the infection and to allow other normal body defenses. . Standard treatments after transplantation are limited in that immunosuppression regimens are used to cause a state of generalized immunosuppression, which leads to opportunistic or microbial infection, the most common adverse reaction to this treatment. An immunomodulation that does not have broad immunosuppressive properties would be more convenient. It has been shown that photopheresis is effective, and researchers at Loyola University have been able to successfully treat with photopheresis, 13 out of 14 cases of cardiac rejection refractory to standard immunosuppressive agents. In a variation of this situation, photopheresis has been successfully used to treat a patient with chronic graft-versus-host disease [Rossetti et al., 1995, Transplant, 59: 1, pp. 149-151]. This disorder is characterized by an immunocompetent host introgenically induced, wherein competent immune cells (peripheral stem cells or bone marrow) are infused in a patient in situations such as treatment of various malignancies and leukemia. In this case, the transplanted immunocompetent cells attack the patient (the "host"), and the problem is to modulate the immunocompetent cells without causing further extensive immunosuppression and the side effects thereof. Photopheresis involves the extracorporeal exposure of peripheral blood leukocytes to 8-methoxypsoralen (8-MOP), photoactivated by ultraviolet light A, followed by reinfusion of the treated white blood cells. The 8-methoxypsoralen molecules in the blood enter the nuclei of the white blood cells, and are interspersed in the helix of the double-stranded DNA. In an extracorporeal circuit, long-wave ultraviolet light is directed to the blood fraction enriched with leukocytes within the UVAR® photopheresis system. The photoactivated drug, which responds to the energy of UVA light, binds to the thymidine base in the DNA helix. This results in a cross-linking of the thymidine bases, which prevents the unfolding of the DNA during transcription. The plasma and the altered leukocytes are then reinfused in the patient. The reinfusion of leukocytes damaged by photopheresis results in a delayed immune attack against these damaged leukocytes, as well as also of otherwise unmodified white blood cells that show the same cell surface antigens. Methoxsalen is a photoactive substance that occurs naturally present in the seeds of the species Ammi majus (umbelifera plant). It belongs to a class of compounds known as psoralens or furocoumarins. Its chemical name is 9-methoxy-7H-furo [3,2-g] [1] -benzopyran-7-one. The drug formulation is a sterile liquid at a concentration of 20 mcg / ml in a 10 ml container. The pharmacokinetic activity of methoxsalen is available in the researcher's brochure [Investigator's Brochure for A Comparison Study of the Use of Extracorporeal Chemotherapy (ECP) With and Without Alpha Interferon in Treatment of Patients with Chronic HCV. June, 1996]. Toxicological studies of extracorporeal photochemotherapy and different dosages of UVADEX® and ultraviolet light in beagle dogs are included in the researcher's brochure.

UVAR system The treatment consists of three phases that include: 1) the collection of a yellow cover fraction (enriched with leukocytes), 2) irradiation of the collected yellow cover fraction, and 3) reinfusion of the treated white blood cells. The collection phase has six cycles of extraction, centrifugation and blood reinfusion steps. During each cycle, the whole blood is centrifuged and separated in a bowl of pediatric pheresis. From this separation, each plasma collection cycle is saved (the volume in each cycle is determined by the operator of the UVAR® instrument), and 40 ml of the yellow cover. The erythrocytes and all the additional plasma are reinfused in the patient before starting the next collection cycle. Finally, a total of 240 ml of the yellow cover and 300 ml of plasma are separated and saved for irradiation with UVA light. The irradiation of the blood enriched with leukocytes within the irradiation circuit begins during the collection of the yellow cover of the first collection cycle. The plasma and the yellow cover collected are mixed with 200 ml of heparinized normal saline and 200 mcg of UVADEX® (water-soluble 8-methoxypsoralen). This mixture flows in a 1.4 mm thick layer through the PHOTOCEPTOR® photoactivation chamber, which is inserted between two banks of UVA light lamps of the PHOTOSETTE®. PHOTOSETTE® UVA light lamps irradiate both sides of this transparent PHOTOCEPTOR® UVA light camera, allowing 180-minute exposure to ultraviolet A light, producing an average exposure per lymphocyte of 1-2 J / cm2. The final yellow coat preparation contains an estimated percentage of 20% to 25% of the total peripheral blood mononuclear cell component, and has a hematocrit of 2.5% to 7%. After the photoactivation period, the blood volume is reinfused in the patient for a period of 30 to 45 minutes. Systems are known that use these techniques, by which the extracorporeal treatment of a patient's blood is carried out. For example, in the patent of E.U.A. No. 4,573,960-Goss, a patient is given a drug that requires photoactivation, and the patient's blood is then extracted and separated into its components. The untreated components (erythrocytes, a certain amount of plasma, etc.) are returned to the patient. The patient is then disconnected from the treatment apparatus, and the separate components, e.g. white blood cells, are exposed to ultraviolet light. After photoactivation, the treated cells are returned to the patient. In the patents of E.U.A. Nos. 4,321,919; 4,398,906; and 4,464,166, issued to Edelson, external treatment methods have been discussed for diseases in which there is a pathological increase in lymphocytes, such as occurs in cutaneous T-cell lymphoma. In these methods, the patient's blood in the presence of a compound chemical or an antibody, is irradiated with ultraviolet light. The ultraviolet light effects a union between the lymphocytes and the chemical compound or antibody, thus inhibiting the metabolic processes of the lymphocytes. Several human viruses are capable of infecting, and of replicating within, mononuclear cells, or infectious viral particles can remain inside mononuclear cells. Mononuclear cells can function as a source of viral replication and virus propagation, or as a reservoir of infectious viral particles which are difficult to eliminate by the immune system. The inability to eliminate these sources of infectious virus can lead to the establishment of a chronic condition. Viruses that can infect, replicate within, or reside in, mononuclear cells include, but are not limited to, viruses carried by arthropods, enteroviruses, paramyxoviruses (RSV), herpes viruses, cytomegalovirus (CMV), Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), hepatitis G virus (HGV) and retroviruses (such as HIV). A variety of non-viral human pathogens are capable of infecting and replicating within mononuclear cells, or infectious non-viral pathogens can remain within mononuclear cells. Mononuclear cells can function as a source of replication and propagation of non-viral pathogens, or as a reservoir of infectious non-viral pathogens, which are difficult to eliminate by the immune system. The inability to eliminate these sources of infectious non-viral pathogens can lead to the establishment of a chronic condition. Non-viral pathogens that can infect, replicate within, or reside in, mononuclear cells include, but are not limited to, bacteria such as bacteria carried by arthropods, mycoplasma species and mycobacteria species, and parasites such as species. of Plasmodium and other parasites carried by arthropods. Extracorporeal photopheresis (ECP) has been used successfully to treat infections caused by HIV (U.S. Patent No. 4,960,408), and it has been shown that psoralen compounds using long wavelength ultraviolet light, activate certain viruses in Vitro, such as HIV (Quinnan, GV et al., 1986, Transfusion, 26, pp 481; Bisaccia, A. et al., 1990, Am. Intern. Med., 113. pp 270; Bisaccia, A. et al., 1991, Ann. NY Acad. Sci., 636, pp 321) and the influenza virus and the herpes simplex virus (Redfield, D.C. et al., 1981; Infect. And Immun., 32, pp 1216). Bisaccia has studied ECP in a pilot test as therapy for patients with complex related to AIDS. The rationale was that a combination of psoralen with activation by UVA light could damage HIV in vitro, and that reinfusion of the damaged virus could initiate an immune response. The authors found that the ECP produced an increase in the production of Ab for HIV, an increase in CD8 (+) lymphocytes, a decrease in the titer of the p24 antigen, and the impossibility to culture HIV in 3 patients. Eleven of the 20 patients had improved their skin reaction to the test antigen. In addition, a reduced incidence of infection episodes was reported in patients receiving photopheresis treatment for immunosuppression following transplant surgery (Meiser, B. M. et al., 1994, Transplantation, 57, pp. 563). However, the results observed for transplant surgery patients did not correlate with photopheresis treatment, since episodes of infection were recorded in general, including patients who received a variety of treatments to prevent rejection of the transplanted organ.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to a method for treating inflammatory bowel disorders including, but not limited to, IBD, Crohn's disease and ulcerative colitis, using extracorporeal photopheresis. In addition, the present invention is directed to the treatment of inflammatory diseases of the urinary bladder including, but not limited to, cystitis, such as interstitial cystitis. In particular, patients with IBD, Crohn's disease, ulcerative colitis or interstitial cystitis, are treated by the method of the present invention. The present invention is also directed to the alteration or modulation of the function of monocytes in patients having inflammatory bowel disorders or inflammation of the urinary bladder, by using the photopheresis method. The method of treatment of the present invention involves treating the blood of a patient with a photoactivatable or photosensitive compound, which is capable of binding to nucleic acids in infected nucleated cells after activation of the compound by ultraviolet light. The photoactivatable or photosensitive compound can be administered to the patient's blood in vitro or in vivo by conventional administration techniques. A portion of the patient's blood is then treated extracorporeally using photopheresis, which comprises subjecting the blood to ultraviolet light, preferably long wavelength ultraviolet light on the wavelength scale from 320 nm to 400 nm, commonly referred to as light GRAPE. The treated blood, or a fraction thereof, is returned to the patient after extracorporeal photopheresis to modulate the function of the monocytes and / or stimulate an immune response by the patient's immune system. The cellular genetic material is damaged by this treatment, which may result in alteration or modulation of monocyte function, as described herein.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to the use of photopheresis to treat patients suffering from an inflammatory bowel disorder including, but not limited to, IBD, Crohn's disease or ulcerative colitis, or patients who have an inflammatory disorder of the urinary bladder including, but not limited to, cystitis, such as interstitial cystitis. Although the scope of the present invention is not intended to be limited by any specific theory of operation, inflammatory disorders of the intestine and inflammatory disorders of a patient's urinary bladder are thought to be treated by the use of a treatment. Photopheresis according to the present invention It is thought that extracorporeal photochemotherapy using methoxsalen (photopheresis), causes an immunization against abnormal T cells (cancerous, in the case of CTCL) During photopheresis, methoxsalen enters the nuclei of The white blood cells are interspersed in the double stranded DNA helix In an extracorporeal circuit, long wave ultraviolet light is directed to the blood volume enriched with leukocytes Methoxsalen, which responds to the energy of UVA light, binds to the thymidine base in the DNA helix, this results in the entanglement of the thymidine bases, which prevents the ddoblamiento of the DNA during the transcription. Ultraviolet A (UVA) light damages abnormal T cells, making them more immunogenic. After the cells are photoactivated, the reinfusion of these altered T cells causes an immunological reaction that targets the T cells that possess the same surface antigens [Edelson RL. Photopheresis: a clinically relevant immunobiologic response modifier. [Revision] Ann NY Acad Sci. 191; 636: 154-64]. This results in the production of a highly specific immune response against the abnormal cells (a clone of cancer or perhaps T cells expressing viral antigens on its surface). It is estimated that approximately 25 to 50% of the total peripheral blood mononuclear cell compartment are treated by photopheresis session (2 consecutive days program). The works carried out by Vowels [Vowels BR, Cassin M, Boufal MH, et al. Extracorporeal photochemotherapy induces the production of tumor necrosis factor-alpha by monocytes: Implications for the treatment of cutaneous T cell lymphoma and systemic sclerosis. J. Invest Dermatol 1992; 98: 686-92], demonstrated that monocytes treated in an extracorporeal plasma circuit contained 8-methoxypsoralen, and exposure to ultraviolet light A (photopheresis) released tumor necrosis factor alpha, IL-1, IL-6, and possibly IL. -8. It is thought that photopheresis modulates the activity of peripheral blood monocytes / macrophages. In accordance with the claimed methods, a photoactivatable or photosensitive compound is first administered to the blood of a patient suffering from an inflammatory bowel disorder or an inflammatory disorder of the urinary bladder. The photoactivatable or photosensitive compound can be administered in vivo (eg, orally or intravenously), or it can be administered in vitro to a portion of the patient's blood, which has been removed therefrom using conventional blood draw techniques. In accordance with the present invention, the photoactivatable or photosensitive compound must be capable of binding nucleic acids after activation by exposure to electromagnetic radiation of a prescribed spectrum, eg, ultraviolet light. Next, the portion of blood of the patient to which the photoactive compound has been administered is treated by subjecting it to photopheresis using ultraviolet light. The photopheresis step is preferably carried out in vitro using an extracorporeal photopheresis apparatus. The step of photopheresis according to the present invention can also be carried out in vivo. An presently preferred extracorporeal photopheresis apparatus for use in the methods according to the present invention is currently manufactured by Therakos, Inc. under the trade name of UVAR®. A description of said apparatus can be found in the patent of E.U.A. No. 4,683,889. The exposure of blood to ultraviolet light in a photopheresis apparatus is within the skill of those skilled in the art. When the photopheresis step is carried out in vitro, at least a fraction of the treated blood is returned to the patient. Preferably, the method of treatment described herein is repeated at an interval from about once a week to about once every four weeks. Preferred photoactive compounds for use in accordance with the present invention are compounds known as psoralens (or furocoumarins), as well as psoralen derivatives such as those described in US Pat. No. 4,321,919 and the patent of E.U.A. No. 5,399,719. Alternatively, the patient's blood can be separated into a standard device of the apheresis type, and photoactivated in a separate device. Preferred photoactivatable or photosensitive compounds for use in accordance with the present invention include, but are not limited to, the following: psoralen and psoralen derivatives; 8-methoxypsoralen; 4,5'8-thmethylpsoralen; 5-methoxypsoralen; 4-methylpsoralen; 4,4-dimethylpsoralen; 4-5'-dimethylpsoralen; 4'-aminomethyl-4,5 ', 8-trimethylpsoralen; 4'-hydroxymethyl-4,5 ', 8-trimethylpsoralen; 4 ', 8-methoxypsoralen; and 4 '- (omega-amino-2-oxa) alkyl-4,5', 8-trimethylpsoralen including but not limited to 4 '- (4-amino-2-oxa) butyl-4,5', 8- trimethylpsoralen. The most particularly preferred photosensitive compound for use according to the invention is 8-methoxypsoralen. The photosensitive compound, when administered to the patient's blood in vivo, is preferably administered orally, but may also be administered intravenously and / or by other conventional routes of administration. The preferred oral dosage of the photosensitive compound is in the range of from about 0.3 to about 0.7 mg / kg, more preferably about 0.6 mg / kg. When administered orally, the photosensitive compound should preferably be administered at least about one hour before the photopheresis treatment, and no more than about three hours before said treatment. If administered intravenously, the schedules should be closer. Alternatively, the photosensitive compound can be administered to the patient's blood after removing the patient's blood, and before or contemporaneously with exposure to ultraviolet light. The photosensitive compound can be administered to whole blood or a fraction thereof, provided that the blood cells or components of the target blood receive the photosensitive compound. The treatment of photopheresis in the treatment methods according to the present invention is preferably carried out using long wavelength ultraviolet light (UVA) at a wavelength within the range of 320 to 400 nm. Exposure to ultraviolet light during the photopheresis treatment preferably lasts for a sufficient time to supply approximately 1 -2 J / cm2 to the blood. When the photopheresis treatment according to the present invention is carried out in vivo, special attention must be paid to controlling the maximum radiant exposure in order to avoid causing unnecessary harm to the patient. Methods for calculating the maximum radiant exposure to ultraviolet light are known in the art. First, a photosensitive compound as described above is administered to at least a portion of the blood of the donor before extracting it, either orally or intravenously, or after extracting it from the patient, in which case it is administered in vitro. . Optionally, a portion of the blood of the donor could be processed first using known methods to substantially remove the erythrocytes, and the photoactive compound is then administered to the resulting fraction enriched with leukocytes. In any case, the portion of blood (or fraction thereof enriched with leukocytes) to which the photosensitive compound has been administered is subjected to a photoactivation treatment using ultraviolet light, preferably UVA light in the manner described above. The treated blood or treated fraction enriched with leukocytes (as the case may be), is then administered back to the donor. Current treatment of inflammatory bowel disorders include chemotherapeutic agents such as aminosalicylates, corticosteroids and immunosuppressants. Significant side effects occur due to the use of these chemotherapeutic treatments. Many patients develop side effects from the use of aminosalicylates before reaching a therapeutic dose. Side effects of nausea, malaise, headache and myalgia, often result from the patient's non-compliance. Side effects of long-term use of corticosteroids (Cushingoid appearance, hypertension, cataract formation, osteoporosis and aseptic necrosis) are well documented. In addition, although corticosteroids may be effective in treating an exacerbation of the disease, the ability of these drugs to prevent recurrence has never been demonstrated. A higher risk of developing cancer, neutropenia and bone marrow suppression is well documented in the population of organ transplant recipients. A brief description of certain inflammatory bowel disorders which are discussed in the method of the present invention includes, but is not limited to: 1. Ulcerative colitis Ulcerative colitis is a disorder of the mucosa that affects the colon, and is associated with significant morbidity and mortality. There are associated extraintestinal manifestations of this disease that include arthritis, ankylosing spondylitis, hepatitis, uveitis, pyoderma gangrenosum, erythema nodosum and sclerosing cholangitis. Cancer can develop in areas of chronic inflammation. Specific symptoms of ulcerative colitis include diarrhea, intestinal bleeding, weight loss and cramping and abdominal pain. This disease can affect individuals of any age. Children with this disease do not grow or develop normally. 2. Crohn's disease Crohn's disease is characterized by focal, transmural and asymmetric inflammation that involves one or more segments of the alimentary canal, extending to other points from the mouth to the anus. The most commonly involved areas include the distal ileum and the right colon. Exclusive colonic intervention occurs in approximately 20%, and disease limited to the small intestine occurs in 15% to 20% in patients affected with Crohn's disease. The ulcerations associated with Crohn's disease extend linearly, often isolating cavities of normal mucosa, giving this disease a characteristic cobblestone appearance. A brief description of certain inflammatory disorders of the urinary bladder which are treated in the method of the present invention includes, but is not limited to: 1. Interstitial cystitis (IC) Interstitial cystitis (IC) is a severe chronic bladder disorder similar to IBD, in that it is an autoimmune disease that manifests itself as an attack on the wall of the bladder rather than on the wall of the intestine. Like IBD, HF can be identified histologically as a unifocal or multifocal inflammatory infiltration of the bladder wall with scarring and ulceration of the mucosa. It produces smooth muscle contraction, decreased urinary capacity, frequency symptoms, hematuha, urgency, nocturia, painful urination and suprapubic pelvic pain. Treatments such as amitriptyline, hydroxyzine, dimethyl sulfoxide, chlorpactin and heparin may improve symptoms, but do not alter the long-term course of the disease. The result of the method of treatment of the present invention of inflammatory bowel disorders including, but not limited to, IBD and Crohn's disease, and of inflammatory disorders of the urinary bladder including, but not limited to, cystitis, such as IC, is an elimination of the symptoms of the disease, reflected as a reduction in the rate of activity of the disease and / or a significant reduction in the dose of steroids (particularly for those who are dependent on steroids) and / or prevention of surgery (excision of affected tissue) and increasing free intervals of symptoms in these patients. The following examples are provided to illustrate the present invention, but should not be considered as a limitation thereof.

EXAMPLE 1 Extracorporeal photochemotherapy in the treatment of patients with ulcerative colitis I. Description of the patient population Patients who show an acute propensity for their ulcerative colitis were the subjects of this clinical investigation. To be included in this protocol, the following inclusion / exclusion criteria had to be met: Patients must weigh 40 kg. Women with maternity potential must be negative to the urine pregnancy test within 24 hours before starting the test. study treatment. Effective birth control should be practiced from one month before the study treatment, until the end of the treatment phase of the protocol. Women may not be nursing. Laboratory values prior to the study of: White blood cell count greater than 3.0 cmm Hemoglobin greater than 6.5 mg / dL Platelet count greater than 75, 000 / UL Prothrombin time not greater than 3 seconds beyond the normal scale Able to provide informed consent Adequate venous access Capable and willing to comply with the study protocol and medication programs The diagnosis of ulcerative colitis must be confirmed by endoscopic and histological evaluation and through the clinical history and physical examination. The extent of the disease should be at least 10 cm from the anal edge. To qualify for the study: The patient must be experiencing acute, moderate to severe recurrence of their UC, and will meet at least three of the seven criteria mentioned: Diarrhea > 6 / day Dense blood in feces Fever > 37.7 Heart rate > 90 / min Anemia less than 75% of normal ESR > 30 Dependent on steroids or Candidate for surgical intervention.

II. Description of treatment frequency and efficacy parameters Photopheresis treatments were carried out on two consecutive days for four weeks (8 photopheresis treatments), and then carried out on two consecutive days per week for the following eight weeks (8 additional treatments) for a total of 16 photopheresis procedures for 12 weeks (defined as the period of treatment I). The objective of treatment period I was to evaluate the primary parameters of efficacy (index of disease activity [DAI], assess the need for surgical intervention, evaluate the ability of patients to stop steroids or other immunosuppressive drugs used for the control of the symptoms of UC, and evaluate the response to treatment at an endoscopic / histological level). For the purpose of this protocol, a successful response to treatment was defined as: A 50% decrease in the rate of disease activity (IAD), prevention of surgery or reduction / elimination of steroids and improvement in the extent of endoscopy and histology, are considered clinically significant. After the treatment phase I ended, the patient was followed for nine months after discontinuing treatment. The exacerbations (evidenced by an increase in the symptoms of ulcerative colitis [diarrhea, hemorrhage and pain]) during this follow-up period were treated with photopheresis, at the discretion of the investigator. The objective of this follow-up protocol was to calculate: (1) disease-free intervals, (2) determine if exacerbations in the disease can be controlled by photopheresis, and (3) provide data on weaning from photopheresis therapy. lll. Description of the efficacy evaluations During the treatment and the follow-up periods, the patient underwent the following efficacy evaluations: A. disease activity index: This is a modified scale of Truelove and Witts, as described by Lichtiger, et.al. (picture 1). This scale evaluates the number of bloody bowel movements, presence of nocturnal diarrhea, incontinence, abdominal pain, general well-being and abdominal sensation. The minimum score is 0. The maximum score is 21. It is considered that scores of 12 or more are in the severe category. A significant improvement indicates a decrease in the DAI by 50%. Scores lower than 4 indicate clinical remission.

TABLE 1 activity index of the disease B. Endoscopic findings: They were evaluated according to a modified scale determined by Blackstone, et. al., which evaluates the severity of granularity, vascular pattern, friability, ulceration and mucous membrane of the mucosa. The analysis of the endoscopic findings was carried out separately from the scores of the evaluation of symptoms (Table 2). Included in the endoscopic evaluation were the determination of the duration of the endoscopic disease and the corresponding severity of its mucosa.

TABLE 2 Endoscopic score of mucosal severity C. Histology: It was evaluated by a pathologist. The histological classification score is a system that classifies the activity and severity of the disease. The histological index (or score) was expressed by adding the values of the five criteria, and this total was expressed as the total of a maximum total score of 15. 1. ACTIVITY INDEX Criterion # 1: NEUTROFILLO LEUKOCYTES IN INTACTA PROPIA Method: The number of neutrophils was counted in a high magnification field (40 x) of the most actively inflamed area of the intact mucosa. The granulation tissue and the ulcer residues were excluded. 0 = no neutrophils 1 = 1 -10 / hpf 2 = 1 1 -20 / hpf 3 = > 21 / hpf Criterion # 2: ACUTE CRYPTTITIS Method: Infiltration of crypts by neutrophils, including crypt abscesses and destruction of crypts by acute inflammation. 0 = no cryptitis 1 = infiltration of crypts by neutrophils; no abscesses from crypts; without active destruction of crypts 2 = abscesses of crypts +; without active destruction of crypts 3 = active destruction of crypts.

Criterion # 3: EROSION / ULCERATION 0 = no erosion or ulceration 1 = only mucosal erosion of partial focal thickness 2 = presence of acutely inflamed necrotic tissue lacking in mucosa (= superficial ulcer) 3 = presence of acutely inflamed granulation tissue ( = deep ulcer). 2. INDEX OF CHRONICITY OF THE DISEASE Criterion # 4: CRYPT ARCHITECTURE 0 = normal 1 = slight deformation 2 = moderate deformation with defined branch 3 = severe deformation.

Criterion # 5: CHRONIC INFLAMATION OF THE OWN PLATE Method: The number of lymphocytes, plasma cells and eosinophils was evaluated (subjective, without counting) 0 = normal 1 = slight increase 2 = moderate increase 3 = severe disease.

Adverse events were evaluated as follows: The frequency and severity of adverse events were classified by their relation to the device, drug and disease. The frequency of the abnormal laboratory parameters and the new symptomatology at each treatment visit were classified.

IV. Program of sample evaluations A. Baseline assessments (within 48 hours of the first photopheresis treatment) CBC Chemistry sedimentation rate index of disease activity (DAI) List of concomitant medication Endoscopy with histological evaluation Quality of the life questionnaire.

B. Before each two-day photopheresis session CBC List of concomitant medication.

C. Every two weeks during the treatment phase Panel of chemistry Sedimentation rate index of disease activity (DAI).

D. Pre-tx # 5 Quality of the life questionnaire.

E. Monthly Urine pregnancy test (if applicable).

F. At weeks 6 and 12 of the photopheresis treatment Endoscopic and histological evaluation Quality of the CD4 / CD8 life questionnaire (week No. 12 only) G. Post-treatment evaluation One month after the last treatment in period I CBC Sedimentation rate Chemical disease activity index (DAI) CD4 / CD8 Quality of the life questionnaire List of concomitant medication Months 3, 6 and 9 CBC Sedimentation rate Chemistry index of disease activity (DAI) Quality of the life questionnaire List of concomitant medication Months 2, 4, 5, 7 and 8 index of activity of the disease (DAI) V. Results Patient # 1/1 Patient UC 1/1 Summary: A 26-year-old woman with endoscopic and histologically confirmed diagnosis of ulcerative colitis.

Baseline assessment: Entered the protocol for having diarrhea greater than 7 to 9 times per day, fecal incontinence, heavy blood in the stool and fever over 37.7 ° C. The colonoscopy showed changes of the mucosa from 20 to 0 cm. The findings included an erythematous appearance, superficial erosions, aphthous erosions, and areas of frank hemorrhage. The histological activity score was 6, the UC chronicity score was 3, and the endoscopy score was 2. The patient's disease activity index was 8 out of 20, and the quality of the The patient's life questionnaire gave a total score of 151 out of 224 possible points. The patient reported in the patient's diary feeling "good" and experiencing "moderate" pain.

Two-week evaluation: The patient's disease activity index decreased to 5 out of 20, with the main areas of improvement being noted as a reduced number of episodes of diarrhea 3 to 4 times per day, and without fecal incontinence. The patient's quality of life increased to 169 out of 224 possible points. The patient reported in the patient's diary feeling "fine" with only "mild" pain, and still reported the presence of blood in his stool.

Six-week evaluation: The patient's disease activity index decreased to 2 out of 20, with the main areas of improvement being noted as a reduced number of episodes of diarrhea from 0 to 2 times per day, and without fecal incontinence. The patient's quality of life increased to 208 out of 224 possible points. The patient reported in the patient's diary feeling "very well" "without" pain, and reported many more days without blood in his stool. The sigmoidoscopy showed changes in the mucosa in the rectum, with erythematous and granular changes. The visualized colon (up to 30 cm) was more or less normal. The UC histological score decreased from 6 to 1, the UC chronicity score decreased from 3 to 2, and the endoscopy score decreased from 2 to 1. Patient # 3, RJK Patient UC 1/3 Summary: A 42-year-old man with a history of more than 5 years of steroid dependence to control the symptoms of his ulcerative colitis.

Evaluation of the baseline: He entered the protocol with bloody stools and colonoscopy showing changes of the mucosa from 0 cm to 40 cm. The endoscopic findings included edema, an erythematous and friable appearance, aftoid erosions (an edge of erythema, a yellow-gray central crater and absence of a raised border) and a confused / frank vascular pattern. The ICD was 3, and the patient was receiving 20 mg of prednisone every other day. The quality of life of the baseline was 188 out of 224 possible points.

Two-week evaluation: ICD still 3, but the patient had had the dose of prednisone reduced to 10 mg every third day, without an increase in symptoms. The quality of life has increased from 188 to 212.

EXAMPLE 2 Extracorporeal photochemotherapy in the treatment of patients with Cro n disease I. Description of the patient population Patients who have an acute propensity for Crohn's disease are the subjects of this clinical investigation. For inclusion in this protocol, the following inclusion / exclusion criteria were met: A. Inclusion criteria - Age between 18 and 65 years - Diagnosis of Crohn's disease according to the Malchow criteria and the Crohn's activity index (CDAI) - Radiological and / or endoscopic and / or sonographic location documented within the last twelve months before the start of the study - Course of steroid-dependent disease with a documented treatment of at least 10 mg of prednisone per day for at least the last 3 months necessary to achieve remission (remission is defined as a CDAI < 200 for 2 successive weeks). Steroid dependence should be confirmed by a history of at least one recurrence (CDAI> 200) in an attempt to reduce the dose of steroids to < 10 mg - Written or oral consent in the presence of a witness after the patient has been informed in detail by the attending physician - Before starting treatment, all women of childbearing age should be given a beta-HCG pregnancy test in negative serum documented within 24 hours before the first treatment. In addition, they must agree to follow an adequate form of contraception during the study - No known allergy to heparin or 8-methoxypsoralen B. Exclusion criteria - Patients unable to cooperate with selection or treatment procedures - Patients with a high probability of requiring surgical intervention due to hemorrhage, abscess or peritonitis - Patients with clinically relevant stenosis of the gastrointestinal tract - Patients with intestinal stoma - Previous or concurrent exposure within the last 3 months of treatment with ciclosporin A - No previous exposure (within the last 3 months) or a stable dose of azathioprine within the last 3 months - More than 3 phases of antibiotic treatment, namely with ciproxin or metronidazole during a period of 14 days within the last 3 months with confirmed identification of the pathogen - Wet or pregnant women - Patients with serious concomitant disease - Cardiovascular instability that would not allow to extract the volume of blood required during photopheresis - Treatment with drugs with known photosensitizing potential - Patients with reduced venous access - Patients with HIV, Hbs antigen or HCV positivity - Patients with the following findings of Laboratory: • Hemoglobin of 10.5 g / dl • Platelets in amounts less than 100 x 109 / l • White blood cells <; 4000 x 109 / l • Bilirubin in serum > 3 mg / dl • Creatinine in serum > 2 mg / dl • PT < 60%, PTT > 50 sec II. Description of treatment frequency and efficacy parameters A. Frequency of treatment and effectiveness evaluations Preliminary phase 0 In the preliminary phase of the study, patients were selected who met the inclusion criteria or who could cover them in future observation. The retrospective documentation of the disease course of the steroid-dependent patient should be guaranteed. The CDAI of each patient was determined 6 weeks before the start of the study. In the following 6 weeks, the patient was stabilized at the maintenance dose, which was the lowest dose of steroids that ensures inactivity of the symptoms of Crohn's disease (defined as a CDAI <200 for two successive weeks) . The patients were incorporated into the study at the maintenance dose, which must be greater than 10 mg of prednisone per day. Additional monitoring of patients occurred within the first week before the start of the study (week 1).

Evaluation per week (-1): - Demography - History of Crohn's disease - Location of Crohn's disease - Previous surgical history - Previous treatment of Crohn's disease - Documentation of evidence of steroid dependence, according to the definition of inclusion criteria - clinical history and physical examination - laboratory evaluation (CBC with differential, ESR, CRP, acid glycoprotein 1, serum electrolytes, creatinine, BUN, SGOT, SGPT, bilirubin,? -GT, serum glucose , PTT, PT and urinalysis - Frozen serum for future study - CDAI - Documentation of extraintestinal manifestations of Crohn's disease - List of concomitant medication - Test of ß-HCG in urine (when applicable) - Supervision of compliance - Triple permeability test: sucrose, lactulose, mannitol - Quality of life index Preliminary phase 1 Patients who met the inclusion criteria were entered into the study during the preliminary six-month phase. Prospective documentation of the activity of the disease and the cumulative dose of steroids in the preliminary phase should be guaranteed. In the preliminary phase, continuous attempts were made to reduce the steroid dose according to a fixed schedule of steroid reduction. Repeated attempts were made to reduce the dose to a level lower than the maintenance dose according to the respective program. The maintenance dose was permanently reduced in the acute treatment phase. The clinical activity of the patient, measured by the CDAI, was used as a criterion to decide if the steroids would have been abandoned due to the steroid weaning program. Steroid reduction began with the first day of treatment in phase 1. Dosage was reduced by alternating the initial dose of steroids with the next lower dose level of a series of standard dosages (ie, 50 mg, 37.5 mg, 25 mg, 15 mg, 10 mg and 5 mg) for two weeks. For the next two weeks, an attempt was made to reduce the dose to this level. If clinical remission is maintained (no increase in CDAI> 60 above baseline or> 200 after the second week), the dose of steroids is reduced by an additional dose level for four weeks, as described above. . A recurrence of the primary disease was treated (increase in CDAI> 60 during baseline or> 200 for two weeks), with the dose of steroids returning to the next higher dose level of the series of dosages for two previous weeks to the exacerbation. If clinical remission can not be achieved with this dose (CDAI <200 for two weeks), the dose of steroids is increased to 50 mg per day for one week with subsequent dose reduction, according to the standard program of weaning. Steroids However, the dose was only reduced to the dose at which clinical remission was most recently observed. This dose may be different from the maintenance dose, and is referred to as the "remission stabilization dose"; the dose is reduced again according to the steroid weaning program. The possibility that the maintenance dose at the end of the treatment phase differs from that of the preliminary phase of the study can not be excluded. The patient's clinical course of Crohn's disease was stable during the last two weeks before the start of the photopheresis treatment phase. In the last two weeks before the start of the photopheresis treatment phase, the patient was given a Crohn's disease diary to document the symptoms associated with his disease. In the preliminary phase, blood samples were obtained every four weeks for CBC with differential, chemistry, CRP and acid glycoprotein 1.PI.

Treatment phase Photopheresis treatments were carried out on two consecutive days on a monthly basis for six months.

Before the first day of treatment in each of the monthly visits, the following evaluations were carried out: Evaluation of the clinical status CDAI Documentation of extraintestinal symptoms of Crohn's disease Documentation of the dose of steroids and other concomitant medications Laboratory evaluation: blood samples for CBC with differential, chemistry, CRP and acid glycoprotein 1 Assessment of adverse events Quality of life index Permeability test (only months 0 and 6) Colonoscopy with biopsy is optional Steroid reduction started on the first day of treatment. The reduction of the dose amounts to 5 mg of prednisone in four weeks according to the standard program of weaning of steroids. Recurrences of Crohn's disease with CDAI values of more than 450 led to the end of the study. > o Results Effect of photopheresis in 5 patients with Crohn's disease (standard deviation of arithmetic mean, mean and range) During this treatment phase, the steroids were that the patient has been informed in detail or the treating doctor - No allergy known to heparin or 8-methoxypsoralen - The patient must have pain when filling his bladder, and feel relief after emptying it and 5 - The patient must have suprapubic, pelvic, urethral, vaginal or perineal pain and - The patient must have urination frequency on alert > 5 times per day and nocturia > 2 times per night 10 and - The patient must have glomerulation after hydrodistension during cystoscopy or - Hunner's ulcer. 15 B. Exclusion criteria - Patients unable to cooperate with selection or treatment procedures - Patients with benign or malignant bladder tumors 20 - Patients with bacterial or radiation-induced cytoplasm or cyclophosphamide - Patients with vaginitis - Patients with symptomatic urethral diverticulum - Patients with uterine, cervical, vaginal or urethral cancers - Patients with active herpes - Patients with calculi of the lower urethra or bladder - Symptoms of cystitis are relieved by antibiotics, urinary antiseptics and analgesics - The duration of symptoms has been less than 12 months - The patient has involuntary contractions of the bladder through urodynamics - At a capacity of 400 ml of the bladder, there is absence of sensory urgency - Nursing mothers or pregnant women - Patients with concomitant disease would be - Cardiovascular instability that would not allow to extract the volume of blood required du for photopheresis - Treatment with drugs with known photosensitizing potential - Patients with reduced venous access - Patients with HIV, Hbs antigen or HCV positivity - Patients with the following laboratory findings: • Hemoglobin less than 10.5 g / dl • Platelets in smaller quantity of 100 x 109 / l • White blood cells < 4000 x 109 / l • Bilirubin in serum > 3 mg / dl • Creatinine in serum > 2 mg / dl • PT < 60%, PTT > 50 sec II. Description of the frequency and effectiveness of the treatment 5 Photopheresis treatments are carried out for two days - ^ consecutive every week for four weeks (8 photopheresis treatments), and then they are carried out for two consecutive days every third week for the next eight weeks (8 additional treatments) for a total of 16 photopheresis procedures for 12 weeks Photopheresis is abandoned after 12 weeks at a monthly and higher frequency, depending on the patient's long-term response. The treatment can be restarted to treat an exacerbation of the disease. A significant reduction is expected in pain, hematuria and The frequency of urination results from the method of treatment of this invention. The type and amount of concomitant medications that patients require for the treatment of HF is reduced, resulting in a general increase in quality of life and reduction of the disease.

Claims (9)

1. NOVELTY OF THE INVENTION CLAIMS 5 1.- The use of a photoactivable compound for the manufacture of A composition for treating an inflammatory bowel disorder in a patient, wherein said compound is administered to the blood of said patient, and wherein at least a portion of said patient's blood is treated with light at a wavelength that activates said compound 10 photoactivable.
2. 2. The use according to claim 1, wherein said inflammatory bowel disorder is selected from the group consisting of IBD, Crohn's disease and ulcerative colitis.
3. 3. The use according to claim 1, wherein said photoactivatable compound is a psoralen or psoralen derivative.
4. 4. The use according to claim 3, wherein said psoralen or psoralen derivative is 8-methoxypsoralen.
5. 5. The use of a photoactivatable compound for the manufacture of a composition for treating an inflammatory disorder of the urinary bladder in a patient, wherein said compound is administered to the blood of said patient, and wherein at least a portion of the blood of said patient is treated with light at a wavelength that activates said photoactivatable compound.
6. 6. - The use according to claim 5, wherein said inflammatory disorder of the urinary bladder is cystitis.
7. 7. The use according to claim 5, wherein said inflammatory disorder of the urinary bladder is interstitial cystitis.
8. 8. The use according to claim 5, wherein said photoactivatable compound is a psoralen or psoralen derivative.
9. 9. The use according to claim 8, wherein said psoralen or psoralen derivative is 8-methoxypsoralen.