MXPA98008019A - Treatment for photoferesis of chronic infections for hepatiti viruses - Google Patents
Treatment for photoferesis of chronic infections for hepatiti virusesInfo
- Publication number
- MXPA98008019A MXPA98008019A MXPA/A/1998/008019A MX9808019A MXPA98008019A MX PA98008019 A MXPA98008019 A MX PA98008019A MX 9808019 A MX9808019 A MX 9808019A MX PA98008019 A MXPA98008019 A MX PA98008019A
- Authority
- MX
- Mexico
- Prior art keywords
- blood
- treatment
- cells
- hcv
- patient
- Prior art date
Links
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Abstract
The present invention relates to a method for treating chronic HCV infections, the method involves the optional treatment of a patient with interferon-alpha and the treatment of the blood of a patient with a psoralen compound followed by activation with ultraviolet light of the compound of psoralen, the blood treated in such a way is returned to the patient in a procedure known as extracorporeal photopheresis
Description
TREATMENT FOR FOTQFEREBIS OF CHROMIC INFECTIONS FOR HEPATITIS C VIRUSES
BACKGROUND OF THE INVENTION
Extracorporeal photopheresis is a procedure whereby S-meto? Ipsoralen (8-MOP) »light-sensitive compound that is present in nature» orally is administered two hours before treatment; blood is then drawn from the patient * anticoagulant and the white blood cells are separated by centrifugation and collected as an enriched leukocyte fraction. These leukocytes containing 8-M0P are then irradiated with ultraviolet light A < UVA > which binds 8-MOP to bases of DNA pyridines and to intra- and extracellular proteins. These treated leukocytes are returned to the patient and the result is an immunomodulation that has been found to be clinically useful in a number of morbid states *. There are a number of diseases that are perceived to involve primarily T cells or that are mediated by T cells. It is thought that in diseases »such as cutaneous T-cell lymphoma» rejection of foreign grafts in organs after transplantation and diseases such as progressive systemic sclerosis ÍESP) »rheumatoid arthritis and diabetes mellitus with juvenile onset (DMIJ), which are mediated by T cells.
Cutaneous T-cell lm (TCCL) is a malignant disease that is progressive. The therapeutic options are limited. Edelson and others conducted a multi-center trial * which revealed that 24 of 29 (83%) erythrodermic patients experienced a significant improvement in their disease. These positive responses were seen at a mean time of 22.4 weeks after the initiation of therapy. Of clinical significance »these patients were those whose diseases were resistant to previous therapy who are perceived to be an insufficient predictor group. In addition »a decrease in the amount of peripheral blood involvement (Sezary cells) was observed. Statistical data had indicated that mean survival had been increased to more than o months after the start of treatment compared to a historical mean survival time of less than 30 months. In this original group of patients, remissions were experienced in 8 of the individuals who were leukemic. Adverse reactions associated with photopheresis were rare. Autoimmune diseases are characterized by a dysregulation of the immune system by specific cellular destruction and humoral mediation of specific organs or tissues in the patient. Some examples of such diseases are rheumatoid arthritis and progressive systemic sclerosis. Rheumatoid arthritis (RA) is an inflammatory disease that ultimately leads to the destruction of joints and is a generalized disease involving many organ systems. There are many agents in use for RA, however, well-tolerated agents with potential to modify the disease are needed because the disease is lifelong. In particular »a loss of efficacy and progression of the disease is observed in a large number of patients after initiating secondary line therapy for RA. Many of the second-line agents are immunosuppressive and are themselves the reason for the main side effects »such as infection. The need for the development of a more specific, non-toxic immunomodulation therapy3 is great. Progressive systemic sclerosis (ESP) is a connective tissue disease characterized by inflammatory and fibrotic changes in the skin and viscera. The treatment has been difficult. Anti-inflammatory drugs and corticoteroids have been useful in the early stages of the disease "but do not appear to influence the progress of the disease. Tests are underway »with D-penicillamine channel blockers» methotrexate »sislosporin» calcium and prostaglandins »but these agents do not seem to influence the total progress of the disease. Since it has been considered that this disease is mediated by T cells, Rock and colleagues have treated patients with ESP by photopheresis- *. In this trial »56 patients were enrolled in a randomized non-disguised clinical trial. A significantly higher response rate was observed in the group treated with photopheresis (685% response rate) compared to the group with D-penicillamine (control) (32% response rate). It is perceived that diabetes mellitus with juvenile onset (DMIJ) is mediated by the immune system resulting in the destruction of the 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 vasculopathy, resulting in damage to a specific organ that leads to significant morbidity and mortality. Other phenomena mediated by T cells include the rejection of tissues that are foreign to the host. In the case of graft transplantation alien to an organ "it is convenient to avoid this rejection with respect to the transplanted organ" to maintain otherwise the capacity of the immune system "in order to allow the body to fight the infection and allow other normal body defenses . Regular treatments after transplantation are limited as the suppressive regimens used to cause a state of general suppression »which leads to the most common adverse reaction to this treatment» again infection »which may be a bacterial or opportunistic infection. Immunomodulation that does not have immunosuppressive properties; This would be more convenient. It has been shown that photopheresis is effective; Researchers at the University of Loyola have successfully treated 13 of 14 cases of cardiac rejection reluctant to regular immunosuppressive agents by photopheresis. In a variant of this situation, photopheresis has been successfully used (Rossetti et al. And others) to successfully treat a patient with chronic graft disease against the host. This disorder is characterized by a hydrogenetically induced immunocompetent host »wherein the immune competent cells (peripheral bone or bone marrow cells) are infused into a patient in such situations as a treatment for various malignancies and leukemia. In this case »the transplanted immunocompetent cells attack the patient (the
"host"). In this case again, the solusifln is to modulate the immunosompetent cells without causing greater immunosuppression and side effects thereof. Photopheresis involves the extracorporeal exposure of peripheral blood leukocytes to 8-me oxypsoralen (8-MOP) photoactivated by ultraviolet light A "followed by reinfusion of the treated white blood cells. The S-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 extraorporal circuit »long-wave ultraviolet light is directed to a blood fraction enriched with leukocytes within the UVAR photopheresis system. The photoactivated drug »responding to the UVA energy» binds to the base of ti idina in the DNA helix. This results in the entanglement of thymidine bases which prevents the development of DNA during transcription. The plasma and altered leukocytes are then re-fused to the patient. The re-diffusion of leukocytes damaged by photopheresis results in a delayed immune attack against these damaged leukocytes "as well as" the otherwise unmodified BCs that deploy the same antigens on cell surfaces.
UVAR system The treatment consists of three phases including (1) the collection of a pigtail ration (enriched with leukocytes) »(2) irradiation of the fraction of collected coleint and < 3) the reinfusion of the treated white blood cells. The collection phase has 6 clicks of the extraction steps »centrifugation and blood reinfusion. During each cycle »whole blood is centrifuged and separated in a bowl of pediatric feresis. From this separation »are rescued in the plasma < the volume of each cycle is determined by an operator of the UVAR instrument) and 40 ml of pigtail in each collection cycle. The red cells and all the additional plasma are re-united to the patient before beginning the next cycle of withdrawal. Finally »a total of 240 ml of recollect and 300 ml of plasma is separated and recovered for UVA irradiation. The irradiation of the blood enriched with leukocytes within the irradiation circuit begins during the collecting of the first cycle of collection. The collected plasma and recollect are mixed with 200 ml of normal heparinized saline and 200 mg of UVADEX (water-soluble 8-methoxypsoraline). This mixture flows from a layer of 1.4 mm in thickness through the PHOTOCEPTOR photostreaming chamber which is inserted between two rows of UVA lamps of the PHOTOSETTE. The UVA lamps irradiate both sides of this PHOTOCEPTOR camera transparent to the UVA light »allowing an exposure of 180 minutes to the ultraviolet light A» producing an average exposure by limposite of 1-2J / cma. The final preparation of coleto contains from 20% to 25% estimated of the total peripheral blood mononuclear cell component and has a hematocrit of 2.5% to 7%. After the photoactivation period, the volume is reinfused to a patient for a period of 30 to 45 minutes. Systems employing these techniques are known by which extracorporeal treatment of a patient's blood is performed. For example »in the patent of E.U.A. No. 4 »573» 960-Goss »a patient is given a drug that requires photo-ablation and is extracted after the patient's blood and its components are divided. The untreated components (red blood cells »a little plasma» etc) are returned to the patient. The patient is then disconnected from the treatment apparatus and the separate components are exposed, eg, white blood cells, to ultraviolet light.
After photoactivation, the treated cells are returned to the patient. In the patents of E.U.A. No. 4 »321» 919; 4 »398» 906; and 4 »464» 166 issued to Edelson »external treatment methods have been considered for diseases in which there is a pathological increase of lymphocytes »such as cutaneous T-cell lymphoma. In these methods» the patient's blood is irradiated in the presence of a chemical substance or an antibody »with ultraviolet light. The ultraviolet light effects a link between the lifositos and the chemical substance or the antibody »thus inhibiting the metabolic processes of the lifositos. A variety of human viruses can infect and replicate within mononucleosis cells or infectious viral particles may be present within the mononucleosis cells. The mononuclear cells can astuar either as a source or for the viral replication and the propagation of the virus or as a deposit of viral infectious particles which is difficult to eliminate for the immune system. Failing 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 produced by arthropods» enteroviruses »paramyxoviruses (RSV)» herpes viruses »cytomegalovirus (CMV)» Epstein virus- Barr (VEB) »hepatitis B virus iVHB)» hepatitis C virus (HCV) »hepatitis D virus (VHD). Hepatitis S virus (VHG) and HIV. A variety of non-viral pathogenic human agents can infect and replicate within mononucleosis cells or infectious viral particles may be present within the mononuclear cells. Mononuclear cells can act either as a source or for viral replication and virus propagation or as a deposit of infectious viral particles which is difficult to eliminate for the immune system. Failing 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 »bacteria such as bacteria produced by arthropods» species of misoplasm »and species of misrobacteria» and parasites such as species of plasmodium and other parasites produced by arthropods. Extracorporeal photopheresis has been successfully used to treat HIV infection (U.S. Patent No. 4,960,408) and it has been shown that psoralen compounds with long wavelength ultraviolet light inactivate certain in vitro viruses. as HIV (Quinnan »GV and others» 1986 »Transfusion» 26 »pp 481; Bisacsia »A and others. 1990 »Ann Intern. Med. »113» pp 270í Bisaccia, A et al. 1991 »Am. NY Acad. Sci. »636» pp 321) »the influenza virus and the herpes simplex virus (Redfield, D.C. and others» 1981; Infect »and Immun.» 32 »pp 1216). Bisaccia of the University of Columbia has lO
studied the ECP of a reference test as therapy for patients with a complex related to AIDS. The rationale was that a combination of psoralen with UVA activation could damage the HIV virus in vitro and that the reinfusion of the damaged virus may initiate an immune response. The authors found that the ECP produced an increase in the production of HIV-Ab »increases the CD8 < +) lim ositos »decrease of the p24 titre and antigen and the inability to culture the HIV virus of three patients. 11 of the 20 patients had improvement in their reactivities of the antigens in skin tests. In addition », the reduced incidence of infection episodes in patients receiving photopheresis treatment for immunosuppression following transplant surgery was reported (Meiser, B.M. and others 1994, Transplantion, 57, pp. 563). However, "the results observed for patients with transplant surgery did not correlate with the treatment of photopheresis" since episodes of infection were generally recorded, including in patients who received a variety of treatment to avoid rejection of the transplanted organ.
BRIEF DESCRIPTION OF THE INVENTION
The present invention is directed to a method for treating chronic HCV infections using extracorporeal photopheresis. In particular, it is treated in patients who have chronic HCV infections by the method of the present invention and the level or presence of genetic material of HCV is reduced or identifiable in patients thus treated. The method of the present invention involves treating the blood of a patient with a photo-passivable or photosensitive compound that is capable of binding to nucleic acids in infected, nuselled cells by activating 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 consists of subjecting the blood to ultraviolet light" terribly long wavelength ultraviolet light in wavelength ranges of 320 to 400 nanometers »commonly called UVA light. The treated blood "or a fraction thereof" is returned to the patient following extracorporeal photopheresis to stimulate an immune response of the patient's immune system against the infected cell population and / or against
HCV to inhibit the progress of viral infection. The viral genetic material is also damaged by this treatment "making the virus incapable of replication" thereby interrupting the spread of the virus and the neutralizing infectious viral particles residing in the cell.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 »Panel A» Panel B and Panel C show the results of patients from group 1 »group 2 and group 3 treatment» respectively.
DESCRIPTION DETAG ^ A? A t? E THE INVENTION
The present invention is directed to the use of photopheresis to inactivate HCV and / or kill blood cells that have been infected with HCV. Although the scope of the present invention is not intended to be limited by any specific theory of operation, it is believed that HCV infections that are not controlled by the normal immune response of a patient can be treated by damaging infected nuclear blood cells (such as mononusal cells) using photopheree treatment according to the invention. The treated cells as well as the annihilated and / or attenuated viruses "peptides" native subunits of the virus itself (which are released are disintegrated and / or discharged into the blood) and / or pathogenic non-infested viruses are then used for generate an immune response. HCV is capable of infecting and replicating with mononuclear cells »or infectious viral particles may be present within mononuclear cells. Mononuclear cells can act as a source of viral replication or spread from the virus »or as a deposit of infectious viral particles, which is difficult to eliminate for the immune system.
Failure to eliminate these sources of infectious diseases can lead to the establishment of a chronic condition. According to the claimed methods, "a photoactivable or photosensitive compound" was made to the first of the blood of a patient who is chronically infected with HCV. The photoactivatable or photosensitive compound can be administered in vivo (for example orally or intravenously) or it can be administered in vitro to a portion of the patient's blood that has been extracted from the patient using conventional blood extraction techniques. According to the present invention, the photoactivatable or photosensitive compound may be linked to nucleic acids by activation by exposure to electromagnetic radiation of a prescribed spectrum, eg, ultraviolet light. Next, the portion of the blood of the patient to whom the photoactive compound has been registered is treated by subjecting the portion of the blood 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 invention is currently manufactured by Therakos »Inc.» estchester »Pa under the name of UVAR. A description of such an apparatus can be controlled in the US patent. No 4 »683» 889 on August 14, 1987. Exposure of ultraviolet light blood in a photopheresis device is within the capacity of people who have ordinary skill in the technique. When the photopheresis step is carried out in vitro, at least a fraction of the treated blood is returned to the patient to increase the patient's immune response to the infected cell population and to the HCV itself.
Preferably, the method of treatment described herein is repeated over an interval of about once a week to about once every four weeks. Preferred photo-active compounds for use in accordance with the present invention are compounds known as subalens (or furocoumarins) and are described in US Pat. Do not
4 »321» 919. Alternatively, the blood can be separated from the patient in a regular device of the photopheresis type and can be photoactivated in a separate device. Preferred photosensitive or photosensitive compounds for their use as a solvent with the present invention include the following: psoralen »8-methoxyipeoralen» 4 »5f8-trimethyl-soralen; 5-methoxypsoralen; 4-methylpsoralen; 4 »4-dimethylpsoralen; 4-5 * -dimetilpsoralen; 4'-aminomethyl-4 »5r» 8-trimethylpsoralen; 4'-hydroxymethyl-4 »5 '> 8-trimethylpsoralen; and 4 »» 8-methoxypsoralen. The most particularly preferred photosensitive compound for use according to the invention is 8-ethoxypsoralen. The photosensitive compound "when administered to the patient's blood in vivo is preferably administered orally" but can 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 about 0.3 to about 0.7 mm / Kg, most preferably about 0.6 mm / 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 3 hours before the photopheresis treatment. If administered intravenously »times should be shorter. Alternatively, the photosensitive compound can be administered to the patient's blood immediately after subtraction of the patient and prior to exposure * or simultaneously with it "in ultraviolet light" the photosensitive compound can be administered to the whole blood or a fraction thereof. same »provided that the blood cells or the components target blood cells receive photosensitive compounds. The photopheresis treatment in the treatment methods according to the 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 has a duration of sufficient magnitude to release approximately 1-2 J / cm 5 * to the blood. When the photopheresis treatment according to the invention is carried out in vivo »careful attention must be paid to control the maximum radiant exposure» in order to avoid unnecessary harm to the patient. Methods for calculating maximum radiant exposure to ultraviolet light are known in the art. The invention also provides methods for making vaccines against HCV. According to the invention, a donor who is infected with HCV can be used to produce a vaccine against his viral infection as follows. First »a photosensitive compound as described hereinabove is administered to at least a portion of the blood of the donor either from the extraction of the blood» either orally or intravenously »or after the extraction of the patient in which case it is administered in vitro. Optionally, a portion of donor blood could be processed first using known methods to substantially remove erythrocytes and then administered after the photoactive compound to the resulting enriched leukocyte fraction. In any case, the portion of blood (or the fraction of leukocytes enriched thereof) to the sual was administered the photosensitive compound is subjected to a photo-etivation treatment using ultraviolet light, preferably UVA in the manner previously described. The treated blood or the treated leukocyte fraction treated (as the case may be) is administered back to the donor. The following examples are provided to illustrate the present invention and not to be construed as limitation thereof.
EXAMPLE 1
Reduction of HCV in chronic patients infected with HCV The fundamental defects that allow the establishment of chronic hepatitis C following acute HCV infection are not known. Several researchers have suggested that impaired cellular immunity may have its share - either T cells or natural killer cells. Weiner and collaborators of the Chiron Corporation have demonstrated the existence of a hypervariable region of the DHC genome in the E2 / NS1 ß segment. This area encodes the linear epitopes that bind to B-cell antibodies specific for "isolated units" that are expressed on the envelope surface of the HCV particle. The characteristics of this domain are similar to those of the V3 loop of the pg 120 protein of human immunodeficiency virus 1. The rapid mutation within this region may explain a lack of immune recognition and disappearance of the hepatitis C virus. Other authors postulate that they may see other possibilities of resisting interferon treatment. There is evidence that the genotype of the virus may be just as important in influencing the outcome of the therapy. It seems that some genotypes (subtypes) of the hepatitis C virus may be persistent to interferon-alpha therapy than other types. Other researchers found a correlation with the viral titer of previous treatment of the hepatitis C virus and the outcome after treatment with interferon-alf. But the basic immune mechanisms that result in the disappearance of the hepatitis C virus are not yet known. Shirai of the National Cancer Institute has shown that the CDS (- * -> &sot; sitotosytic limotocytes) recognizes a monostructural protein with homology to an RNA polymerase expressed in association with V antigen of HLA ICs on the surface of hepatosites "> This results in the procedure of antibody-dependent sitotoxic destruction and damage by virally infected hepatocyte cells.This would be similar to the procedure used to eliminate the hepatitis B virus. The hepatitis C virus is a positive chain virus. which replicates by producing a negative-strand RNA as a template During active viral replication of HCV »these negative-strand RNA templates are present in the patient's liver.The inventors have also discovered the presence of active viral hepatitis C particles replicates in the mononuclear cells of the peripheral blood of patient ß. r that mononuclear cells »acrophages» T cells and B cells contain negative chain HCV RNA. During therapy with interferon-alpha, the hepatitis C virus of the liver and the patient's blood may disappear as measured by RT-PCR. Despite this apparent disappearance of the virus in some patients, there is a very high relapse rate (80-85%) after interferon therapy. Researchers have shown that the (few) patients who do not have HCV replission detected in PBMCs at the end of therapy "do not relapse after interferon therapy and are obvious cures" or "." - It would seem that the mononuclear cell It can serve immunologically protected that protects hepatitis C against the recognition and attack of the immune system Once the therapy is removed they are interferon-alpha »the viruses can leave the PBMCs and reinfest the blood and the liver of the patient. Ideally, the hepatitis C virus would disappear from the liver and the blood cells and the mononuclear cells infected simultaneously.The mechanism of action of the extraorporal photopresis causes an immunization against the abnormal T cells making them more immunogenic. Altered T cells cause an unological reaction that orients non-irradiated T cells which carries the same antigens on the surface xss. This results in the production of a highly specific immune response against these abnormal cells (either the cancer clone or perhaps the T cells expressing the viral antigens on their surface). In addition »the ideal therapy would not be effected by retendensia utuar of the hypervariable E2 / NS1 region of hepatitis C. This change in the enveloping viral antigens of particles causes an escape of neutralizing antibodies from B cells. Photophresis can also induce damage to any free viral particle in the irradiated blood. This form of therapy will also guide any newly formed hepatitis C escape mutants. In 1986 »Hoofnagle and others xa? published the first report of successful interferon-alpha therapy of chronic hepatitis C in an uncontrolled trial. Ten patients with chronic hepatitis C received subcutaneous injections of interferon for up to one year. Six patients still have normal LFT and non-abhorrent HCV RNA by RT-PCR seven years later. To date, the "interferon-alpha-2b" (intron A) is the only treatment approved by the FDA for chronic hepatitis in the United States. Davis and others reported that a six-month procedure with interferon-alpha-2b at a dose of 3 million units three times a week "resulted in a sustained 18% response to treatment A >; Other multiple tests have reproduced this response rate. Biochemical relapse occurs in most patients following the suspension of AS therapy. It has been shown that the detection of DHC RNA in serum by RT-PCR correlates with the normalization of serum amenases in the treatment and has also been shown that despite biochemical relapse once therapy has been discontinued * • * • * • ». Researchers continue to devise new therapies to improve low response rates. Higher interferon doses ß »longer treatment duration-» »different species of interferon ao 'aa- and auxiliary therapeutic phlebotomy to remove iron in excess» have been tried with several success rates. Other forms of therapy are even less effective and are associated with frequent side effects. It has been shown that corticosteroids and acislovir have posa utility. Fifteen (15) patients were randomly chosen either for monotherapy with ECP alone (5 patients) or for therapy in combination with ECP and interferon-alpha 3 MIU TIW (5 patients) or for ECP interferon-alpha 6 MIU TIW (5 patients) . All patients received ECP treatment at the Clinical Research Center (CRC) at the University Hospital of Pennsylvania.
Group I (ECP only) Patients randomly chosen to receive ECP only had two treatments - two consecutive days every two weeks. The patients received 24 ECP treatments during a period of 6 months.
Group II (ECP V IFN-O MIU) Three months after group I begins the ECP »patients randomly chosen to receive the ECP of interferon-alpha 3 MIU began therapy. Patients started ECP treatments two consecutive days every two weeks. Two weeks after the start with ECP, patients received interferon-alpha 3 MIU three times a week, subcutaneously. If they are well tolerated, patients will continue ECP treatments for two consecutive days every two weeks for an additional six months in combination with interferon-alpha. The patients received 24 ECP treatments during a period of six months.
rupo * X? < * > VA and IFN-? 6 M? U > Three months later group II started the ECP »patients randomly chosen to receive ECP and interferon-alpha 6 MIU began therapy. The patients started with ECP treatments two consessional days every two weeks. Two weeks after the onset of ECP, patients received interferon-6-MIU three times a week subcutaneously.
Selection Period The measurements of the selection period include a history and a physical examination "for the evaluation of the symptoms" weight and blood pressure. Laboratory tests include: complete blood test with differential index »thyroid function tests» prothrombin type »chemistry chart and HCG serum (if indicated). HCG of serum abundance was performed within 24 hours after the start of treatment. Complete blood analysis included hematocrit »hemoglobin» platelet and total WBC analysis with differential index including neutrophils »lymphocytes» mononuclear cells »eosinophils and basophils. A chemical table included total protein »albumin» total bilirubin »ALT» AST »alkaline phosphothase» gamma GT »sodium, potassium chloride» content of C02 »urea nitrogen» creatinine »glusosa» salsium »phosphate» cholesterol »tigliserides and uric acid . Serum and blood mononuclear cells per ferules (CMSPs) were collected for the determination of HCV RNA titers by RT-PCR and for the analysis of HCV genotypes. The serum of 7 ml of whole blood was collected and frozen at -70 ° C for future studies.
Treatment period An assessment of the symptoms »the weight» the blood pressure »the complete analysis of the blood and the ALT in week two and every four weeks during the treatment was made. The HCV RNA titre was measured in CMSPs at the end of treatment. The serum of 7 ml of whole blood was collected every eight (8) weeks and frozen at -70 ° C for future studies. A history and follow-up physical examination was done »chemistry table» thyroid portion tests and prothrombin type »at the end of the treatment.
Follow-up period The assessment of symptoms, "weight", blood pressure, "complete analysis of serum HCV blood and RNA" was followed every eight weeks during the visits and the last of the follow-up period. The HCV RNA titre was measured in CMSPs at the last follow-up visit. The ALT was measured every four weeks and the last follow-up visit. The serum of 7 ml of whole blood was collected every eight (8) weeks during the follow-up and frozen at -70 ° C for future studies. A history and follow-up physical examination was done »chemistry table» thyroid portion tests and prothrombin type »in the last visit of the follow-up period.
Collection of serum The blood was collected in serum separator tubes (BD SST). In the course of 2 hours of blood extraction, the blood tubes were centrifuged at 1500 x g for 20 minutes. The serum was collected immediately and stored at -70 ° C.
Preparation of mononuclear cells The blood was collected in a vacuum vessel CPT »8 ml capacity mononuclear cell preparation tube (Becton Dickinson). The tubes were centrifuged for 20 minutes at 1500 x g 18-5 ° C. The plasma was removed without altering the cell layer and frozen in 1 ml of alisotas at -70 ° C. A capillary aapa was introduced into a 15 ml sonic tube and 10 ml of PBS (saline regulated at its phosphate pH) was added. The tube was mixed gently 5 times and then centrifuged at 300 x g for 15 minutes. Once the cells were reduced to pellets at the bottom of the tube, the supernatant was removed and discarded. The pellet was resuspended in 2 ml of PBS and then divided into 1 ml of aliquots in 1.5 ml Sarstedt tubes. The Sarstedt tubes were rotated in a microcentrifuge continuously overhead for 10 minutes. The supernatant was removed and stored at -70 ° C until the PCR analysis was performed. PCR analysis was performed using an Amplicor assay (see below).
Ammonia assay for mononuclear cell serum or HCV The HCV RNA assay is a PCR-based prototype assay using a single pair of primers (biotinylated primer to the 3 'end) of the 5"untranslated region of HCV A uracil-N-glycosylase was incorporated to avoid amplicon contamination, HCV-oriented RNA was reverse transcribed and amplified in a single-tube reaction using the DNA RTTH polymerase enzyme in the presence of Mn ++. The products were denatured as alkaline and hybridized to a specific HCV probe.The detessation was sampled in a format of 96 misroreseptures using avidin horseradish peroxidase The result of the assay was expressed in A45 units detected at a regular reading of microcephalic plates.
gr?, 1: erJ.og of 9 jj-qfrsia Response to treatment was measured using the following virological and biochemical criteria:
Virological criteria (main criteria) HCV RNA in serum was monitored before the study "during therapy to determine the response and during the 24-week follow-up period to determine the stability of the response. The response to treatment was assessed according to the following criteria: (a) No response: HCV RNA remains detectable by PCR during treatment and follow-up periods. ib) Concrete response: HCV RNA is not detectable by PCR in therapy at the end of the treatment period and becomes detectable before the end of the follow-up period. (c) Cure: the HCV cRNA by PCR is not detectable at the end of the treatment period and remains non-abhorrent at the end of the follow-up period. The results of this study show that photopheresis alone or in conjunction with interferon treatment substantially reduces the level of the genetic material of HCV. The use of photopheresis alone produced at the viral level in the past srónisos by HCV that have fraasted previously with other treatments. Table I (and Figure I panel A) represents the HCV level of each patient in the baseline and after 8 weeks in therapy (region enclosed in figure I »panel A). The combination of photopheresia and interferon to eliminate the virus presensia, as detested by RT-PCR »in the peripheral blood of patients infected with HCV. Figures IB and 1C represent HCV levels for patients before, during and after the end of treatment. The effect of the treatment is foreseen after the photopheresis was discontinued.
TABLE I
HEPATITIS ,,,, C Group 1: Photopheresis only
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321: 1506-1510. 16.- Farsi P »Alter HJ» Wong D »Miller RH» Shih JW, Jett B »Purcell RH. A long term study of hepatitis C virus replisation in non-A »non-B hepatitis. N Engl J Med 1991; 325: 98-104. 17.- Shindo M »Dibisseglie AM Cheung L» Shih JW »Christian K. Feinstone SM» Christian K »Hoofnagle JH. Decrease in serum hepatitis C viral RNA during alpha-interferon therapy for shronis hepatitis. Ann Intern Med 1991; 115: 700-704. 18.- Watson »AR» Bartlome P. High-dose interferon-alpha-2A for the treatment of chronic hepatitis C. Specialized publication! Ann Phar Acotherapy 1994; 28: 341-2. 19.- Gómez-Rubio M. Porres JC »Castillo I» Quiroga JA »Moreno A» Carreno V. Prolonged treatment (18 months) of chronic hepatitis C with recombinant alpha-interferon in co-parison with a control group. J Hepatology 1990; 11: 363-7. 20.- Saez-Royuela F »Porres JC» Moreno A »Castillo I» Martínez ß »Galiana F and others. High doses of recombinant alpha-interferon or gamma-interferon for chronis hepatitis C: a randomized. controlled trial »Hepatology 1991; 13: 327-31.
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Claims (9)
1. - A method for treating HCV infected blood »comprising: (a) contacting said infected blood with a photoactivatable compound; and (b) treating at least a portion of the infected blood from step (a) with light at a wavelength that activates said photoactivatable compound.
2. The method according to claim 1 »sarasterized also because said photoactivatable compound is a psoralen.
3. The method according to claim 2, further characterized in that said psoralen is 8-methoxypsoralen.
4. A method for treating blood infected with HCV, said blood having been previously treated with interferon-alpha, comprising: (a) putting in bloodstain with a photoactivatable compound; and (b) treating at least a portion of the infected blood from step (a) with light at a wavelength that activates said photoactivatable compound.
5. The method according to claim 4 »further characterized in that said photoactivatable compound is a psoralen.
6. The method according to claim 5 »further characterized in that said psoralen is 8-methoxypsoralen.
7. A method for treating HCV infected blood »comprising: (a) contacting said HCV-infected blood with interferon-a; (b) exposing the infected blood to a photoactivatable compound; and (c) treating at least a portion of the infected blood from step (a) with light at a wavelength that activates said photoactivatable compound.
8. The method according to claim 7 »further characterized in that said photoactivatable compound is a psoralen.
9. The method according to claim 8 »is also sarasterized because said psoralen is 8-methoxypsoralen.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US60/014,612 | 1996-03-29 |
Publications (1)
Publication Number | Publication Date |
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MXPA98008019A true MXPA98008019A (en) | 1999-09-01 |
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