RESUMO
The interferons (IFN) act too slowly to arrest acute viral infections, but interferon-alpha (IFN alpha) preparations have proved useful in some chronic infections and will clearly be used increasingly in these in the future. In the preparations derived from human leucocytes or cultured B lymphoblastoid cells, which are in routine clinical use, mixtures of a number of distinct subtypes of human IFN alpha have been identified. There are also 3 slightly different versions of the same single subtype, IFN alpha-2, made by recombinant DNA procedures in bacteria. IFN alpha preparations are injected intramuscularly or subcutaneously. Dose-related side effects are common but usually tolerable, but prolonged treatment may cause increasing fatigue and depression. Some patients form neutralising antibodies which block the effects of the IFN; these appear to be relatively more common after recombinant IFN alpha-2 than after IFN derived from human cells. Given intranasally, IFN alpha can prevent a subsequent experimental rhinovirus infection, or the spread of natural colds within a family. Repeated administration progressively damages the nasal mucosa, so that long term prophylaxis is not possible. IFN alpha has proved useful in patients with papillomavirus warts of the larynx, ano-genital region (condyloma acuminata) and skin (common warts). Treatment regimens remain to be optimised and are likely to include surgery or other treatments. IFN alpha and zidovudine (azidothymidine) synergistically inhibit the growth of HIV in vitro, and combination are on trial in patients with early AIDS. Very large doses of IFN alpha are effective against Kaposi's sarcoma in some AIDS patients. In chronic hepatitis B, continuing virus replication may lead to cirrhosis or primary liver cancer. Earlier clinical trials with IFN alpha gave inconclusive results, but recent large studies have confirmed that 25 to 40% of patients obtain benefit; this probably results from both the antiviral and the immunomodulatory effects of IFN alpha. In patients with chronic hepatitis C, the biochemical markers usually improve rapidly during IFN alpha administration, but relapse if treatment is stopped after only a few months; to increase the chances of sustained cure, the treatment period is now being prolonged.
Assuntos
Interferon Tipo I/uso terapêutico , Interferon-alfa/uso terapêutico , Viroses/terapia , Infecções por HIV/terapia , Hepatite B/terapia , Hepatite C/terapia , Humanos , Interferon Tipo I/administração & dosagem , Interferon Tipo I/efeitos adversos , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Papillomaviridae/efeitos dos fármacos , Proteínas Recombinantes , Infecções Respiratórias/terapia , Infecções Tumorais por Vírus/terapiaRESUMO
Since 1959, The Wellcome Foundation Ltd. has been involved in research to develop interferon for practical use. A brief historical perspective is presented on the development and production of interferon alfa-n1.
Assuntos
Interferon Tipo I , Linfoma de Burkitt/análise , Criança , DNA de Neoplasias/isolamento & purificação , Herpesvirus Humano 4 , Humanos , Interferon Tipo I/biossíntese , Interferon Tipo I/isolamento & purificaçãoAssuntos
Interferons/farmacologia , Viroses/tratamento farmacológico , Animais , Antivirais/uso terapêutico , Embrião de Galinha , Varicela/terapia , Haplorrinos , Humanos , Interferons/administração & dosagem , Interferons/biossíntese , Interferons/líquido cefalorraquidiano , Interferons/uso terapêutico , Interferons/urina , Ceratite Dendrítica/tratamento farmacológico , Sarampo/terapia , Vírus da Febre Amarela/efeitos dos fármacosAssuntos
Interferons/análise , Animais , Técnicas de Cultura , Humanos , Imunoensaio , Microquímica , Radioimunoensaio/métodos , Padrões de ReferênciaAssuntos
Interferons/análise , Animais , Linhagem Celular , Chlorocebus aethiops , Rim , Vermelho Neutro , Espectrofotometria/métodosRESUMO
There are three main types of interferon, now designated alpha, beta and gamma. Human interferons-alpha exist as many subtypes, probably more than 26. These are chemically quite closely related, but each has a unique chemical composition and biological properties. Preparations of interferon-alpha derived from stimulated peripheral blood leukocytes or lymphoblastoid cell lines contain mixtures of these sub-types; individual sub-types can be obtained by expression of the human gene concerned in bacteria. Human interferon-beta shows about 30% chemical homology with the interferons-alpha. The natural product is glycosylated, and there is only one molecular species. Natural interferon-gamma, also a glycoprotein, has the same non-specific antiviral properties as other types of interferon, but shows little, if any, chemical homology. Recombinant interferons-beta and -gamma have also been prepared by application of gene cloning techniques and expression in E. coli. These proteins are not glycosylated, and differ in their pharmacokinetic behaviour from the natural human proteins. In nature, interferons are normally formed and act locally. If relatively large amounts are administered in order to produce systemic effects, there are dose-related side effects which resemble an attack of influenza.
Assuntos
Interferons/fisiologia , Animais , Glicosilação , Humanos , Interferons/classificação , Proteínas RecombinantesRESUMO
There are now published guidelines dealing with the production of cytokines, monoclonal antibodies and other therapeutic proteins made by applying biotechnological procedures. Strict conformity with these guidelines will undoubtedly yield safe products, but the question can be asked whether all the tests now specified are really essential in relation to the actual risks involved. During many years of experience with some of these biopharmaceutical products, problems which might on theoretical grounds have occurred have in practice not been encountered. Should biopharmaceuticals still be subjected to a much more intense scrutiny than is given to most other medicinal products? Has the time come to review current control procedures? Unnecessary tests increase the cost of products, and may make them too expensive to be available to millions of people who would benefit from their use.
Assuntos
Produtos Biológicos , Células Cultivadas/virologia , Qualidade de Produtos para o Consumidor , Humanos , Interferon-alfa/biossíntese , Vírus/isolamento & purificaçãoRESUMO
The interferon (IFN) system consists of both the formation of the various IFN proteins, and the diverse cellular responses which these induce: these result from the intracellular changes which follow their binding to a specific cell surface receptor. There is only a single human gamma, omega and beta IFN; in contrast, there are 13 closely related chemical species ("subtypes") of human alpha IFN, which are nevertheless chemically and biologically distinct. IFN preparations made from mass cultured human cells or by using recombinant DNA techniques are now readily available for clinical use. IFN have a major role in the defence of the body against virus infections. In acute virus infections, preformed exogenous IFN cannot be given soon enough to be of value. However, IFN-alpha and IFN-beta have proved of considerable value in some chronic virus infections, particularly chronic virus hepatitis and chronic papillomavirus infections. The doses routinely used are associated with both acute and chronic toxic side effects. Also, some patients form specific neutralising antibodies against the particular IFN preparation injected, which may abrogate all the benefits of the treatment. Nevertheless, IFN are now established as agents for use in routine medical practice.
Assuntos
Citocinas/uso terapêutico , Viroses/terapia , Animais , HumanosRESUMO
Any interferon assay essentially measures the potency of unknown samples relative to each other or to a standard. The reliability of such measurements of relative potency, i.e. the precision of the assay, is a key feature of any method. In contrast, sensitivity is seldom a characteristic of great importance in an assay. Nevertheless, relatively high sensitivity can often be achieved quite readily by a suitable choice of cells and challenge virus.
Assuntos
Interferons/análise , Animais , Células Cultivadas , Células Clonais , Humanos , Métodos , Camundongos , Padrões de Referência , Fatores de Tempo , Replicação ViralRESUMO
The Type I interferons are a family of closely related cytokines that have antiviral and immunostimulatory properties. There has been prolonged debate regarding the different interferon-alpha subtypes: with some authorities suggest that the different interferons have essentially similar properties but others argue that there are significant differences between them. Recent work has shown that the various interferon-alpha subtypes can interact with the interferon receptor components in different ways and can activate a number of different signalling pathways. Recent studies on the immunomodulatory properties of the Type I interferons indicate that there are profound differences between the subtypes. The clinical significance of all these differences remains to be determined.
Assuntos
Interferon Tipo I/imunologia , Interferon-alfa/imunologia , Interferon beta/imunologia , Animais , Anticorpos/imunologia , Humanos , Transdução de Sinais , Viroses/imunologiaRESUMO
A vaccine stored strictly according to the manufacturer's instructions can be used with confidence up to the designated expiry date. However, problems with transport, refrigeration plant, or electricity supply may lead to the exposure of a vaccine under field conditions, and particularly in tropical countries, to high or fluctuating temperatures. We have therefore studied the stability of the standard formulations of our live yellow fever virus, poliovirus and rubella virus vaccines, when they were deliberately exposed to high temperatures, or to alternating cycles of high and low temperatures, intended to simulate such conditions. Our results suggest that with these vaccines, the consequences of adverse storage are not likely to be serious.
Assuntos
Armazenamento de Medicamentos , Vacinas Virais/normas , Temperatura Baixa , Eletricidade , Liofilização , Temperatura Alta , Vacina Antipólio de Vírus Inativado/normas , Vacina contra Rubéola/normas , Meios de Transporte , Clima Tropical , Vírus da Febre AmarelaRESUMO
Interferons have considerable antitumour effects in animals, and have been used with encouraging results in patients with osteocarcomas and certain other tumours. So far only relatively small amounts of material suitable for use in man have been prepared, and almost all of this has come from human white blood cells [buffy coats]. Human fibroblast cell lines are now increasingly being used as an alternative source, but the resultant interferon differs in its chemical and biological properties from leucocyte interferon. Lymphoblastoid cells can also be induced to form an interferon which appears identical to buffy coat interferon. These cells can be grown in suspension in large tanks, and could provide large amounts of relatively inexpensive interferon. The advantages of this type of production system and the problems associated with it will be discussed.
Assuntos
Interferons/metabolismo , Linfócitos/metabolismo , Animais , Linhagem Celular , Fibroblastos/metabolismo , Humanos , Técnicas In Vitro , Interferons/uso terapêutico , Camundongos , Neoplasias/tratamento farmacológicoRESUMO
150 lymphoblastoid cell lines derived from normal individuals or from subjects with various clinical conditions were induced to form interferon by treatment with Sendai virus. Irrespective of the status of the donor, most of the lines produced some interferon and 22 produced considerable amounts (more than 3000 international units/ml). Lines derived from infectious mononucleosis patients were good interferon producers while those from leukaemic donors were poor producers. The data suggest that the clinical conditions of the donor and the source of transforming virus may influence the quantity of interferon produced by a given cell line.
Assuntos
Linhagem Celular , Interferons/biossíntese , Linfócitos/metabolismo , Transformação Celular Viral , Humanos , Mononucleose Infecciosa/sangue , Leucemia/sangue , Vírus da Parainfluenza 1 HumanaRESUMO
The 50% infectious dose of a preparation of herpes simplex virus was measured in eyes of rabbits by a multiple corneal inoculation method. One hour after inoculation of virus, one eye was treated with drops of human leukocyte interferon, and the other was treated with saline or with a different dose of interferon. Results from groups of three to four rabbits were combined for analysis. Treatment reduced the 50% infectious dose of virus in proportion to the concentration of interferon applied (within the range of 6.5 X 10(4)-1.3 X 10(6) units/ml) and not according to the total number of units instilled. Different treatment schedules were tried. Two applications of interferon each day were as effective as eight applications at intervals of 15 min or 1 hr. One application produced near-maximal antiviral effects for 18-24 hr. Thus, in human herpetic keratitis, a single daily application of the most concentrated available preparation of human interferon might be the most efficient schedule of treatment.
Assuntos
Modelos Animais de Doenças , Interferons/uso terapêutico , Ceratite Dendrítica/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Interferons/administração & dosagem , Coelhos , Fatores de TempoRESUMO
Sera obtained from 612 patients enrolled in 40 different clinical trials with an interferon-alpha-n1 (IFN-alpha-n1) preparation have been tested for neutralizing activity against this IFN in a cytopathic effect inhibition assay. Positive samples were assayed in triplicate. Of 391 patients treated for human papillomavirus infections, 13 developed neutralizing antibodies (3.3%); two suffering from condylomata acuminata and 11 from juvenile laryngeal papillomatosis (JLP). None has positive titers prior to receiving IFN-alpha-n1 and none appeared to lose the benefits of IFN treatment. Serial specimens from four JLP patients demonstrated that titers rose during IFN treatment and declined postherapy. None of the 221 cancer patients from whom serum samples were available had positive titers. The overall incidence of IFN neutralizing sera from these IFN-alpha-n1 recipients was 2.1%.