Digestive and Liver Disease Supplements最新文献

In the adult, the human intestine houses myriads of microorganisms, quantitatively up to 100 trillion and qualitatively over 500 species of bacteria, exceeding the number of host somatic cells by at least one order of magnitude. Actually, it remains a mystery as to how the intestine is able to contain such large quantities of bacteria without evident harm to the host. However, it is well known that a very complex symbiotic relationship between the intestinal microflora and the host insures mutual advantages for both partners.

Despite the recent advances in immunology and microbiology, the possibility of studying human intestinal microflora is limited by great inter-individual variability and difficulties in creating standard conditions to uniform the samples. However, there are clinical conditions which are useful to explain the role of intestinal bacteria in the human gut. Small intestinal bacterial overgrowth (SIBO) is a good example, because this is a microbial alteration of intestinal microflora, in absence of pathogenic bacteria and severe dysregulation of the immune system. On the other hand, the pathogenesis and clinical aspects of SIBO could clarify the complex and bi-directional relationship between the microbiota and the host.

The hydrogen and methane breath test represents a very simple, cheap, non-invasive diagnostic procedure to evaluate intraluminal events occurring in the gastrointestinal tract. Its clinical applications are, first of all, lactose malabsorption and small bowel bacterial overgrowth, but it has also been used to evaluate mouth-to-cecum transit time, sweetener malabsorption and intestinal mucosa integrity. Methodological aspects should be better evaluated and an improvement of its accuracy should be obtained through the adoption of new protocols.

The digestive tract harbours the largest and most complex microbial community of the human body, the intestinal microbiota, including about 800 different bacteria species. The distribution of this microflora is uneven, with highest concentrations in the colon. Bacterial colonization of human gut by environmental microbes, beginning immediately after birth, becomes more complex with increasing age, with a high degree of variability among human individuals. The gastrointestinal tract is the main site where environmental microorganisms and antigens interact with the host, through intensive cross-talks. Gut microbiota is essential for intestinal development, homeostasis and protection against pathogenic challenge; moreover, gut microbes are involved in metabolic reactions, with harvest of energy ingested but not digested by the host; they have also trophic effects on the intestinal epithelium, by favouring the development of intestinal microvilli, and play a fundamental role in the maturation of the host's innate and adaptive immune responses.

The human intestine lodges a large amount of microorganisms, with over 500 species of bacteria whose density increases through the small bowel reaching concentrations from 10⁹ to 10¹⁴ colony-forming unit/ml in the colon. More than 99% of the gut microbiota is composed of bacteria that can be divided into 4 main families: Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria. Numerous factors are involved in the control of gut microbiota stability such as intestinal pH, temperature, microbial interaction, peristalsis, bile acid, drug therapy and immune responses. When these mechanisms fail, imbalance of intestinal microflora can occur, resulting in the onset of both extra-intestinal (infectious and allergic) and intestinal (infectious, inflammatory, autoimmune and neoplastic) diseases.

Interferons (IFNs) regulate a number of key biological functions in innate immune response, including antiviral activity, immunomodulatory tasks as well as cell growth regulation. The diverse effects of the type I IFNs are of differential therapeutic importance: In cancer therapy, an anti-proliferative effect may be beneficial whereas in the therapy of viral infection, the same anti-proliferative effect would lead to dose limiting bone marrow suppression.

IFN-α binds to interferon receptor 1 and 2 and forms a ternary complex that includes both receptor chains instigating signaling. Two types of signals are initiated and reflect on the production of secondary cytokines: IFN-γ mediating the antiviral activity on one hand, and interleukin 6, interleukin 4, interleukin 10 and IFN-inducible suppressive proteins mediating the anti-proliferative response on the other.

All pegylated interferons are not alike in terms of cytokine response. Based on their 3-D conformation, the differential ability of the different IFNs to bind preferentially to subunits of their receptor determines their therapeutic potentials, balancing their antiviral response on one hand and their anti-proliferative potential on the other and echoing on their haematological side effect profile.

Introduction

Egypt has the highest HCV prevalence in the world, mostly genotype 4.

Aim

Assessment of the efficacy, safety and compliance of a novel 20-kDa linear PEG interferon α-2a (Reiferon Retard®) derived from Hansenula polymorpha expression system combined with ribavirin for the treatment of chronic HCV Egyptian patients.

Patients and methods

One hundred chronic HCV patients divided according to the degree of fibrosis on liver biopsy into group A, including F1and F2 patients and group B including F3 and F4. Patients received a fixed weekly dose of 160 μg of the PEG interferon in combination with ribavirin in standard with adjusted dosage and were followed up by PCR after 3, 6, 12 and 18 months. End of treatment response (ETR), sustained virological response (SVR), possible side effects, discontinuation of the drug and concomitant use of cytokines were reported.

Results

At 48 weeks the overall ETR rate was 64% with 73% and 40% for group A and B respectively, and SVR at 72 weeks revealed an overall response rate of 56% viral clearance with 69% and 22% for group A and B respectively. There were notably minimal haematological complications.

Conclusion

The efficacy and high safety profile in absence of significant haematological reactions substantiates the hypothesis that the chemistry of different interferons and their pegylation pattern may reflect on the clinical outcome.

The majority of interferons available for therapeutic use are derived from the prokaryote E. coli. A new recombinant human interferon α2a (IFN-α2a; Reiferon®) has been derived from the yeast Hansenula polymorpha – a eukaryotic expression system. Safety and efficacy for this drug was tested in patients with chronic hepatitis C in Egypt. The unmodified yeast-derived IFN-α2a is the basis for a newly developed PEGylated IFN-α2a (Reiferon Retard®) which will be described in the following.

From their discovery in 1957, the characterization and development of interferons (IFNs) as major biotherapeutic products has been a continuing enterprise for over 50 years. The IFNs have featured in pioneering fundamental research that has uncovered countless facets of their structural and biological properties. A great deal has been learned too about the induction and mechanisms of action of interferons, this knowledge being translated into their development as potent therapeutic agents. While they proved of limited success in the clinic against malignant tumours, great progress has been made in establishing IFN-α as the first choice of treatment for chronic hepatitis C virus (HCV) infections and, surprisingly, IFN-β for relapsing remitting multiple sclerosis. Biological standardization has enabled IFN products to be measured in meaningful units of biological activity, thus ensuring consistency of production and dose administration to patients. Within the last 10 years, development of novel pegylated IFN-α2 products with extended in vivo half-lives has dramatically improved treatment regimes for HCV patients. Undesirable side effects and immunogenicity of therapeutic IFN products remain obstacles to overcome for further improvements in clinical applications. It is confidently expected that research in the IFN field will continue, not only to face these immediate challenges but also to extend the range of IFN products and clinical targets.

The acute phase of hepatitis C virus (HCV) infection represents a key point in the evolution of hepatitis C. The infection either resolves spontaneously, or progresses into chronic disease. However, the asymptomatic nature of acute hepatitis C contributes to difficulties in detection, diagnosis and hence, the assessment of therapy when indicated. Controversies in chronic HCV related to the implications of both selected predictors of treatment outcome and clinical experience with structurally different Peg-IFNs are discussed.