Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Guidelines have been prepared by the National Hemophilia Foundation, USA, for treating patients with haemophilia, these are: 1. General recommendations. The risks of withholding treatment far outweigh risks of treatment. Patients should however be educated to use appropriate clotting factor doses to minimize overuse and contain costs. 2. Factor VIIIC-deficient patients. DDAVP should be used whenever possible by patients with mild or moderate factor VIIIC deficiency. When feasible, an alternative to concentrates may be the use of cryo-precipitate prepared from one well-screened donor or from a small number of such donors. (a) Prevention of hepatitis. Hepatitis B vaccination is essential for uninfected patients. Preliminary data suggest that products that are pasteurized, solvent/detergent-treated or monoclonal antibody-purified are at a reduced risk of transmitting hepatitis viruses. (b) Prevention of HIV-1. Concentrates pasteurized, treated with solvent/detergent, purified with monoclonal antibody, heated in suspension with organic solvents, or dry heat-treated for long periods are preferred. These products carry a substantially reduced risk of transmitting HIV-1. 3. Factor IX deficiency. For patients with severe deficiency the use of virus-inactivated Factor IX concentrate is recommended. For mild to moderate patients when feasible an alternative would be fresh, frozen plasma prepared from one well-screened and repeatedly-tested donor or from a small number of such donors. In the past few years, significant progress has been made in understanding the nature of the defect in haemophilia both at the molecular and structural levels, such a foundation is necessary for definitive treatments in the future. For now, however, the dark side of replacement therapy must be accepted along with its benefits.
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PMID:HIV-1 infection in haemophilia. 210 39

Blood coagulation factor IX (Christmas factor) is a plasma protein which is required for normal haemostasis. A functional deficiency of factor IX results in haemophilia B, a bleeding disorder which is generally treated by infusions of factor IX concentrates prepared from pooled human plasma. The use of human blood products is connected with the risk of transmitting viral agents responsible for diseases such as hepatitis B and AIDS. Recombinant DNA techniques may provide the means to produce the required proteins without exposing the patients to these risks and at lower costs. One of the problems which has to be overcome before recombinant factor IX can be used for therapeutical purposes is related to the vitamin K-dependent carboxylation of its 12 NH2-terminal glutamate residues. In cell cultures this carboxylation, which is required to render the protein its procoagulant activity, is far from complete, especially at high expression levels. In this paper we describe the in vitro carboxylation of non and/or partly carboxylated recombinant factor IX produced by transformed Chinese hamster ovary cells. The identity of the newly formed Gla residues was verified and it could be demonstrated that all carboxyl groups had been incorporated into the recombinant factor IX.
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PMID:In vitro carboxylation of a blood coagulation factor IX precursor produced by recombinant-DNA technology. 274 97

In a long term surveillance study hemophilia A and B patients were treated with a Factor VIII HS and Factor IX HS concentrate respectively, both pasteurized by heating in solution: 10 hours at 60 degrees C. None of 31 virgin hemophiliacs treated with Factor VIII HS Behringwerke developed hepatitis B during a follow up between 6 to 60 months. One patient who received 379.280 IU Factor VIII by 977 applications showed a seroconversion after 961 days of treatment. Passive/active immunisation is suggested. 4 patients had moderate elevations of transaminases (less than 120 U/l) without clinical signs of liver disease. 2 patients suffered a non-icteric NA NB-hepatitis two months after synovectomy in the same hospital. 6 virgin hemophilia B patients who had been treated with Factor IX concentrate HS Behringwerke remained serologically negative and did not develop any symptoms indicative of a hepatic disease during a follow up between 11-29 months. The HTLV-III safety of Factor VIII HS and Factor IX HS Behringwerke is presently under investigation by determination of the corresponding antibody.
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PMID:Virus safety of pasteurized factor VIII and factor IX concentrates: study in virgin patients. 303 38

Pasteurization (heat treatment at +60 degrees C for 10 hours in solution) during the production of human plasma protein preparations has proved useful 1. to inactivate a broad spectrum of viruses and 2. in combination with stabilizers to leave the nativity of the products unaffected. Their efficacy has been experimentally tested for HTLV-III/LAV, Hepatitis B and non-A/non-B viruses. The following preparations were tested: with HTLV-III/LAV: Factor VIII, Factor IX, AT III, AHC and PPSB; with Hepatitis B virus: Factor VIII, Factor XIII, AT III, PPSB and Fibrinogen; with Hepatitis non-A/non-B virus: Factor VIII and AT III.
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PMID:Inactivation of HTLV-III/LAV, hepatitis B and non-A/non-B viruses by pasteurization in human plasma protein preparations. 311 11

Inactivation of Hepatitis B virus associated DNA polymerase was studied in factor IX concentrate (coagulation factors II, VII, IX and X) by heat pasteurization (60 degrees C, 10 hr) and by alkylating agents iodoacetic acid and iodoacetamide. DNA polymerase appeared to reach a residual level which occurred in human serum albumin at 60 degrees C, 10 hr under comparable spike level of hepatitis B virus. Of the four coagulation factors, factor IX activity was most susceptible to inactivation procedures with 40-50% recovery across heat pasteurization and approximately 70% recovery across iodoacetic acid treatment. Factor IX specific activities of the treated concentrates were greater than or equal to 70% of the untreated controls with no appreciable change of corresponding NAPTT values. Factor IX concentrates subjected to such inactivation procedures should reduce the potential for hepatitis B virus transmission.
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PMID:Hepatitis B virus associated DNA polymerase inactivation in factor IX concentrates. 370 11

Plasma derivatives can be separated into those with either a low or a high risk of transmitting viral hepatitis. Low-risk products, with few exceptions, will remain low-risk irrespective of the plasma from which they are manufactured because they are heated at 60 degrees C for 10 hours (Albumin, Plasma Protein Fraction) or because they contain protective antibodies (Immune Globulin). This would appear to be the case not only for hepatitis B but also for non-A, non-B hepatitis. The risk of hepatitis B associated with plasma derivatives is reduced but not eliminated by HBsAg screening of donors. Further decreasing the risk of hepatitis B associated with AHF or Factor IX lots, as well as newer products like AT-III, alpha-1 antitrypsin, Fibronectin, C-1 Inactivator, and Factor XIII, may be accomplished either by the combination of stabilization and heating or by assuring that these products contain an excess of anti-HBS. For highly-purified products with little residual immunoglobulin it may be necessary to add anti-HBs. The addition of antibodies against non-A, non-B hepatitis agents when they are identified, could prevent transmission of both forms of viral hepatitis by plasma derivatives. Methods to stabilize and heat high-risk plasma derivatives to inactivate hepatitis viruses have the potential to remove both hepatitis B and non-A, non-B hepatitis infectivity.
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PMID:Plasma derivatives and viral hepatitis. 681 45

To evaluate the safety of a beta-Propiolactone/Ultraviolet (BPL/UV), irradiated Factor IX complex preparation we inoculated 8 chimpanzees with 25 units Factor IX/Kilo from a pool of 5 production lots which had been treated in this manner. These lots were derived from approximately 1,000 donors. Animals were followed with weekly tests for hepatitis B serologic markers and transaminases, and biweekly liver biopsies, for 6 months. No evidence of transmission of hepatitis B, or non-A, non-B viruses was observed. To further evaluate the BPL/UV procedure a plasma pool was intentionally contaminated with hepatitis B virus and one half of the pool treated with BPL/UV. Factor IX complex was isolated from the treated and untreated pools and each was inoculated into 4 chimpanzees. The Factor IX derived from untreated plasma infected all four animals with an average incubation period of 10.5 weeks, whereas that prepared from PBL/UV treated plasma infected only one of four animals with an incubation period of 21 weeks. These results were interpreted as suggesting that BPL/UV can inactivate approximately 99.9% of hepatitis B virus infectivity.
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PMID:Evaluation of the effect of betapropiolactone/ultraviolet irradiation (BPL/UV) treatment of source plasma on hepatitis transmission by factor IX complex in chimpanzees. 746 40

In the last few years, plasma fractionation has been subjected to major technological changes which have contributed to improve the viral safety and overall purity of plasma derivatives. New viral inactivation treatments, primarily solvent-detergent and pasteurization, have been introduced in the manufacturing processes of plasma derivatives to ensure the inactivation of major plasma-borne viruses, including HIV and hepatitis B and C viruses. Concurrently, new highly purified products obtained by chromatographic methods (mainly ion exchange and/or immunopurification) have been developed in the last five years and have replaced former preparations, providing a significantly higher safety level in terms of purity and viral risks. For an example, the new generation of Factor VIII and Factor IX concentrates (to treat hemophilia A and hemophilia B, respectively), which have been introduced in the last five years, are purified over 10,000- to 20,000-fold from plasma, as compared to only 50- to 100-fold for the former products. Similarly, new, standardized, clotting factor or protease inhibitor concentrates have been made available, thus permitting to carry out selective hemotherapy of specific diseases. Examples include the development of von Willebrand factor, factor XI, protein C, or alpha 1-antitrypsin concentrates for the substitutive therapy of congenital or acquired deficiencies. In addition, the concept of good manufacturing practices has been implemented, whereas carefully controlled, validated processes are contributing to the consistency in the quality of those products. Current major problems in plasma fractionation relate to the potential occurrence of new pathogenic agents that could resist present viral inactivation treatments and to the potential effect of given purification technologies on the development of immunogenic properties of proteins. Current trends indicate that significant progress in viral safety of plasma derivatives (for example through the introduction of new concept such as viral filtration) are to be expected very soon. Further research in this very important field is mandatory as plasma should remain the starting material of important therapeutic products in the coming years.
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PMID:[Plasma fractionation. Progress, problems and perspectives]. 799 59

The efforts to reduce the risk of viral disease due to clotting factor concentrates have been quite successful. However, additional steps need to be taken to protect the users of these products. First, all patients should be vaccinated against hepatitis B. Second, vaccines against other viruses need to be developed. There is a great deal of interest in an HIV vaccine, and a vaccine against hepatitis C would also be a great boon to the "at risk" population. Third, more effective inactivation procedures need to be implemented in the manufacturing of concentrates other than Factor VIII, including Factor IX Complex, Coagulation Factor IX (Human), and Anti-Inhibitor Coagulant Complex. Despite the advances that have been made, it should be remembered that none of these procedures is perfect and the risk will never be reduced to zero. This is because the plasma pools will always contain infectious virus and the manufacturing process, regardless of how carefully controlled, cannot be made fail-safe. Errors will be made that result in contamination or inadequate treatment of products. For this reason, strict adherence to standard operating procedures and good manufacturing practices is essential. The investments of time, money, and hard work that have been made toward improving the safety of clotting factor concentrates have yielded a handsome return thus far. It is hoped that continued efforts in this direction will result in even greater benefits.
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PMID:Viral safety of clotting factor concentrates. 845 24

Haemophilia is a bleeding disorder characterised by a deficiency in Factor IX. Replacement therapy in the form of a Factor IX concentrate is a widely accepted practice. In this paper we describe a double virus inactivated chromatographic process for producing a high purity Factor IX product, MonoFIX((R))-VF. The process involves separation of the prothrombin complex by cryoprecipitation, fraction I precipitation and DEAE-cellulose adsorption, further ion-exchange chromatography of crude Factor IX, followed by solvent/detergent treatment. Heparin affinity chromatography is then used to further purify Factor IX. Final nanofiltration is sequential through 35 nm then 15 nm membrane filters. The principal virus inactivation/removal steps are solvent/detergent treatment and nanofiltration and the partitioning of relevant and model viruses provides further reduction in virus load through the production process.Solvent/detergent treatment was shown to achieve log reduction factors of 4.5 for HIV-1, 5.1 for Sindbis virus, 6.1 for vesicular stomatitis virus (VSV), 5.1 for bovine viral diarrhoea virus (BVDV) and 5.3 for pseudorabies virus (PRV). BVDV is a model for hepatitis C virus (HCV), and pseudorabies virus (PRV), like hepatitis B virus (HBV) is an enveloped DNA virus. Using scaled down models of the production process, we have also demonstrated the neutralization/partitioning of at least 6 logs of hepatitis A virus (HAV) during cryoprecipitation, Fraction I precipitation, and the DEAE adsorption and elution step, and a further 1.6 log reduction in HAV load as a result of heparin affinity chromatography. The log reduction factors for HAV as a result of the second ion-exchange chromatography step and as a result of enhanced neutralisation associated with solvent/detergent treatment were not significant. Nanofiltration was shown to contribute a further log reduction factor of 6.7 for HAV and 5.8 for BVDV indicating that log reduction factors of this order would be obtained with other viruses of a similar or larger size, such as HIV, HBV and HCV.Overall, these studies indicate that MonoFIX-VF is a product with an extremely high level of viral safety.
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PMID:Inactivation and clearance of viruses during the manufacture of high purity factor IX. 1096 39


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