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

The debate over the potential risk of tumorigenicity attributable to the use of CCL substrates for biologicals production has continued for over 30 years and may continue for some time to come. Manufacturers and regulatory agencies are developing scientifically based guidelines for such products. It is currently possible to follow these guidelines to prepare recombinant biologicals and monoclonal antibodies in CCLs which do not pose unreasonable risks. This chapter has attempted to describe the scientific tools available to evaluate the putative risk of tumorigenicity due to potential virus DNA and protein contaminants. No theoretical or experimental basis exists to hypothesize that residual cellular protein might present a significant risk of tumorigenicity. The tools are certainly adequate for characterization of putative risks due to viruses and DNA but are not sufficiently powerful by themselves to assure product safety. The subsequent chapter on process validation describes how adequate assurances of safety ultimately can be obtained for products of CCLs against theoretical risks of tumorigenicity due to putative viruses and DNA. In addition to these safeguards, no evidence of tumorigenicity has been found in human or livestock animal recipients of the products prepared in CCL substrates. Many patients have received inoculations of tissue plasminogen activator, erythropoeitin, factor VIII, soluble CD4, GM-CSF, hepatitis B surface antigen vaccine, and various monoclonal antibodies and other recombinant products of continuous cell lines in clinical trials. For tissue plasminogen activator, large doses of 100 mg per patient or more have been used. At the time of writing over 10 kg of CHO-derived tissue plasminogen activator has been sold since late 1987 for administration to over 100,000 human patients. For recombinant factor VIII, erythropoeitin, and soluble CD4 proteins, chronic administration has been employed. Millions have received polio and rabies vaccines prepared in continuous Vero cells. In addition to this human experience, livestock animals have received annual inoculations of foot-and-mouth virus vaccine prepared in BHK-21 (a highly tumorigenic CCL) for up to 14 years without effect (69). No effects have been reported which might be attributed to oncogenic factors. Thus, scientific tools of characterization and principles of process validation are available to protect patients from putative risks of tumorigenicity associated with products prepared in CCLs. Increasing clinical experience also supports this conclusion.
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PMID:Continuous cell substrate considerations. 137 28

Prevention against the transmission of the HIV must be universal today, which means that it applies to all patients. Blood, tissues, the CSF are infected, but nasal secreta, tears and saliva are not contaminated unless they contain blood. The statistical risk of an HIV serological conversion when making an injection is an estimate of 0.1 to 0.3%, one hundred times less than with the hepatitis B virus. The best protection for maxillofacial surgeons, who are very exposed by the manipulation of objects (needle, wires) and by considerable projections of blood (rotary motor) is not a systematic HIV serological test for all patients, but goggles with side screens, a double pair of gloves and the use of an antiseptic acting on the HIV in case of staining.
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PMID:[The maxillofacial surgeon faced with the HIV-positive patient: risks and prevention]. 150 50

To investigate whether an intravenously administered compound of the IgG class is able to penetrate the CSF barrier despite its high molecular weight, 12 hepatitis B surface antibody (anti-HBs)-negative patients received 20 ml each of a beta-propiolactone-treated IgG compound with a high anti-HBs titer (1:115,000) as a marker. 8 had an inflammatory CSF syndrome. In cases of inflammatory CSF syndromes, significantly more marked IgG crossed the blood-brain barrier, this could be of considerable clinical importance.
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PMID:Investigation of the blood-brain barrier for IgG in inflammatory syndromes of the central nervous system. 637 94

Injection of low doses of particulate hepatitis B surface Ag (HBsAg) into H-2d mice without adjuvants primes an Ld-restricted, S28-39-specific T cell response. This study indicates that dendritic cells (DC) and macrophages (M phi) both serve as APCs that support priming of CD8+ CTL precursors in vivo to exogenous HBsAg particles. After transfer into a syngeneic, naive host, HBsAg particle-pulsed DC, either freshly purified from skin or derived from a cloned DC line, efficiently primed class I-restricted, HBsAg-specific CTL precursors. M phi, either harvested from the peritoneal cavity or generated in macrophage-CSF-stimulated bone marrow cell cultures in vitro or derived from established, cloned M phi lines (PU5-1.8, J774A.1), pulsed with HBsAg particles in vivo or in vitro, elicited a class I-restricted, HBsAg-specific CTL response after adoptive transfer into naive hosts. The class I-restricted CTL response induced by HBsAg particle immunization was suppressed in carrageenan-treated mice, but was restored when carrageenan-treated mice were immunized with syngeneic, HBsAg-pulsed M phi. Selective elimination of M phi by liposome-incorporated dichloromethylene-diphosphonat did not suppress the induction of a CTL response of H-2d mice by HBsAg particle immunization. HBsAg-pulsed, freshly prepared DC are more potent than pulsed M phi in priming class I-restricted CTL in vivo. The relative importance of both types of APC in priming CTL remains to be resolved.
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PMID:Exogenous hepatitis B surface antigen particles processed by dendritic cells or macrophages prime murine MHC class I-restricted cytotoxic T lymphocytes in vivo. 756 Oct 24

A 43-year-old male with 2 episodes of sensory impairments in four extremities and liver dysfunction, developed an acute exacerbation of both sensory impairments and liver dysfunction after administration of interferon-alpha. On admission, neurological examination revealed a mild distal weakness of four extremities, moderate impairment of superficial sensation in hands and severe impairment of deep sensation and areflexia in all extremities. Routine laboratory tests were normal except for a mild liver dysfunction. His serum was positive for antinuclear antibody, but negative for anti-DNA antibody and LE-test. Since he was seropositive for hepatitis B (HB) c antibody but seronegative for HBs antigen and antibody, HBe antigen and antibody, he was considered to be a seroconverted carrier of HB virus. Liver biopsy revealed chronic active hepatitis with marked lymphocytic infiltration. CSF examinations were within normal limits. Sensory conduction studies of median and sural nerves showed no response, but motor conduction studies of median and peroneal nerves were within normal limits. Light and electron microscopic examination of biopsied sural nerve disclosed a moderate decrease in large myelinated fibers, but not in either small myelinated or unmyelinated fibers. Thin-layer chromatography with immunostaining showed the presence of anti-GQ1b antibody in his serum. The anti-GQ1b antibody did not react with GT1a. Oral administration of prednisolone alleviated liver dysfunction, muscle weakness and superficial sensory impairment of four extremities, but not in deep sensation.
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PMID:[Acute relapsing sensory-dominant polyneuropathy associated with anti-GQ1b antibody and autoimmune hepatitis]. 782 Sep 62

The uses of GM-CSF as an immunomodulator and vaccine adjuvant are reviewed. GM-CSF has a variety of effects on immune responses: it induces class II major histocompatibility complex antigen expression on the surface of macrophages; it enhances dendritic cell maturation and migration; it results in a localized inflammation at the injection site; and it has marked effects on maturation of haematopoietic progenitor cells in the bone marrow. Animal and human studies suggest that administration of GM-CSF can increase antibody titres to foreign antigens. Monkeys injected with human interleukin (IL)-3 plus GM-CSF, at a different injection site, developed peak antibody titres which were 8- to 30-fold higher than those in monkeys injected with IL-3 alone. In a study of ovarian cancer patients receiving GM-CSF to prevent chemotherapy-induced neutropenia, two patients who had demonstrated a low titre of antithyroid antibodies prior to the study showed an increase in antibody titre and transient thyroiditis after administration of GM-CSF. Recently a GM-CSF/antigen fusion protein has been tested. An antibody corresponding to a specific idiotype expressed on B-cell lymphomas was fused to GM-CSF and injected into mice with B-cell lymphoma xenografts. The mice developed antibodies to the lymphoma and there was a protective effect against disease progression. Preliminary results of clinical trials using GM-CSF in humans suggest that it enhances antibody responses to hepatitis B vaccine. On the basis of these preliminary results, several clinical trials are being planned and it would appear that GM-CSF has potential as a vaccine adjuvant.
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PMID:Potential role of granulocyte-macrophage colony-stimulating factor as vaccine adjuvant. 787 53

Gene/biotechnology products can be either physiological peptides for the purpose of substitution of deficiencies or for therapeutic purposes in superphysiological concentrations, or nonphysiological peptides, or newer biotechnology products like monoclonal antibodies. The rules for clinical trials developed so far are also valid for clinical trials with gene/biotechnology products. Nevertheless, a major challenge for the clinical pharmacologist is the species specificity of many reactions induced by gene/biotechnology products in man. In general, animal experiments may be less predictive, so there is a greater demand for human pharmacology studies. Gene/biotechnology products offer more chances for treatment of many diseases, but during the clinical trials the clinician has to always be aware of unexpected side effects. Several newer gene technology products offer superior safety as compared to older biological products like Factor VIII preparations and human growth hormone. More than 19 therapeutics produced by gene/biotechnology have already been approved by health authorities all over the world. Major clinical benefit could be shown with hepatitis B vaccine, insulin, human growth hormone, TPA, erythropoietin, GM-CSF, G-CSF, and monoclonal antibodies for immune suppression. There is also good evidence of efficacy of interferon alpha in chronic hepatitis. So far, our knowledge about cytokines is still limited. In several cancer diseases, interferons show efficacy as well as in several autoimmune diseases. Well designed clinical pharmacology studies will be important to elaborate the therapeutic potential of drugs arising from gene/biotechnology.
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PMID:Clinical trials of gene/biotechnology products. 788 81

Ten patients with chronic hepatitis B received increasing doses of nIL-2 (30,000 U, 100,000 U, 300,000 U, 1.0 million U) subcutaneously in a phase I trial. Each dose was applied once per week over 3 weeks. Serum samples were taken before and 2, 12, 24, 48 and 72 h after the first application of each dose level. Serum concentrations of interleukin-1 (IL-1), IL-2, IL-6, interferon-alfa (IFN-alpha), IFN-gamma, tumor necrosis factor-alpha (TNF-alpha) and GM-CSF as well as the cytokine-dependent serum components neopterin, beta-2-microglobulin (B2M), C-reactive protein (CPR), soluble IL-2-receptor (sIL-2R) and 2'-5'-oligoadenylate synthetase (2-5 OA) were assayed using ELISAs and RIAs. None of the samples tested contained measurable cytokine levels other than IL-2. A low and non-toxic dose of 300,000 U nIL-2 was already biologically active with induction of neopterin, B2M and sIL-2R. Dose-dependent changes peaked 24-48 h after application. The same patients were then enrolled in a phase II trial. Treatment in five of the patients was continued twice per week for 3 months with a biologically active dose of 300,000 U nIL-2 subcutaneously. Two of these patients as well as another five patients from the original group were treated with 1.0 million U nIL-2 subcutaneously, twice weekly for 3 months. Neither a biologically active but non-toxic dose of 300,000 U nIL-2, nor a toxic dose of 1.0 million U resulted in permanent clearance of hepatitis B early antigen (HBeAg).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pilot study of natural human interleukin-2 in patients with chronic hepatitis B. Immunomodulatory and antiviral effects. 830 Oct 59

Recombinant human granulocyte-macrophage colony-stimulating factor is being used to improve the immunological function of patients with various diseases and to ameliorate hematological disorders. We investigated the tolerance and possible antiviral effect of the administration of daily doses of recombinant human granulocyte-macrophage colony-stimulating factor (3, 1 or 0.5 micrograms/kg body wt) to nine patients with chronic hepatitis B, alone or in combination with 5 MU interferon-alpha 2b. Recombinant human GM-CSF reduced significantly (p < 0.02) hepatitis B virus DNA levels. The three doses used were equally effective. Of the eight patients who completed the study, four became negative for HBV DNA and HBeAg; two of them seroconverted to HBe antibody. These four patients showed improvement in the histological activity of their liver disease. Ultimately, two patients regained normal ALT values. 2',5'-Oligoadenylate synthetase activity increased significantly (p < 0.01) in cell lysates of mononuclear cells cultured in vitro, coinciding with the reductions in hepatitis B virus DNA levels. Recombinant human granulocyte-macrophage colony-stimulating factor was well tolerated but produced a dose-dependent increase in white blood cell counts. It became intolerable at doses of 3 micrograms (and was reduced to 1.5 microgram); this effect was reversible after cessation of recombinant human granulocyte-macrophage colony-stimulating factor treatment. No remarkable variations occurred in other parameters. In conclusion, recombinant human granulocyte-macrophage colony-stimulating factor administration is safe and tolerable at doses of 0.5 to 1 microgram/kg body wt and may exert an antiviral effect in chronic hepatitis B.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pilot study of recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of chronic hepatitis B. 840 50

Recent advances in basic science and clinical trials have demonstrated that IFNs and myeloid hematopoietins play crucial roles in host defense against pathogens and immune surveillance. Here we have reviewed the biologic functions of GM-CSF, G-CSF, IFN-alpha and IFN-gamma. For patients with neutropenia resulting from cytotoxic chemotherapy, bone marrow transplantation, congenital agranulocytosis and cyclic neutropenia, therapeutic uses of GM-CSF and G-CSF were reviewed. Application of these growth factors to patient management represents a major contribution of biotechnology to a difficult area of therapeutics in febrile, neutropenic patients. Because IFN-alpha plays crucial roles in antiviral responses, its clinical applications in hepatitis B and C, human papilloma virus, HIV infection and malignancy were discussed. The use of IFN-gamma in bacterial prophylaxis in patients with chronic granulomatous disease was also presented. Advances in clinical applications of IFNs and hematopoietic growth factors serve as a paradigm for further development to investigate the use of other important cytokines in modern therapeutics.
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PMID:Biology and therapeutic uses of myeloid hematopoietic growth factors and interferons. 904 17


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