The impact of pegylated interferon and ribavirin combination treatment on lipid metabolism and insulin resistance in chronic hepatitis C patients

BACKGROUND/AIMS: Lipid profile and insulin resistance (IR) are associated with hepatitis C virus (HCV) and may predict the chronic hepatitis C (CHC) treatment response. The aim of this study was to determine the association between CHC treatment response and lipid profile and IR change during treatment. METHODS: In total, 203 CHC patients were reviewed retrospectively between January 2005 and December 2011 at Soon Chun Hyang University Hospital. The lipid profile, homeostasis model for assessment (HOMA) of IR (HOMA-IR), and HOMA of beta cells (HOMA-beta) were evaluated before interferon plus ribavirin therapy (BTx), at the end of treatment (DTx), and 24 weeks after the end of treatment (ATx). RESULTS: A sustained virologic response (SVR) was achieved by 81% of all patients (49/60), 60% (n=36) of whom possessed genotype 1, with the remainder being non-genotype-1 (40%, n=24). Apart from age, which was significantly higher in the non-SVR group (SVR, 48.0+/-11.2 years, mean+/-SD; non-SVR, 56.6+/-9.9 years; P2.5), HOMA-IR was significantly changed at DTx in the SVR group. CONCLUSIONS: LDL-C appears to be associated with HCV treatment in SVR patients. Furthermore, eradication of HCV may improve whole-body IR and insulin hypersecretion, as well as high baseline insulin resistance (HOMA-IR >2.5).

Efficacy and cost effectiveness of combined conventional interferon alpha 2A and ribavirin therapy in patients of chronic hepatitis C

To determine end treatment and sustained virological response to conventional interferon's and ribavirin. This descriptive study was conducted from January 2009 to September 2011 at DHQ hospital Dir, KPK, Pakistan. Three hundred and forty-seven patients of chronic hepatitis C aged 18 to 60 years were given conventional Interferons alpha 2a and Ribavirin for six months under Prime Minister Program for control of hepatitis. Out of three hundred and forty seven patients three hundred and thirty nine patients completed the therapy. End treatment response was achieved in 229[67.5%] patients and sustained virological response was seen in 210[61.94%] patients. Combination of conventional interferon and ribavirin has a high sustained virological response with fewer side effects in our study. In resource depleted countries like Pakistan, conventional interferon alpha 2a and ribavirin combination therapy can be used as the first line treatment for non affording chronic hepatitis C patients

IFNα2b augments immune responses of cisplatin+5-fluorouracil treated tongue squamous cell carcinoma patients - A preliminary study.

Background & objectives: Interferon alpha 2b (IFNα2b) has been reported to regulate several immune functions efficiently to enhance the cytotoxic activity of NK and T cells towards various forms of tumours. The objective of the present study was to evaluate the efficacy of IFNα2b in overcoming disease induced and/or treatment associated imunosuppression of tongue squamous cell carcinoma (TSCC) patients undergoing chemotherapy for better clinical outcome. Methods: Seven TSCC patients under cisplatin + 5-fluorouracil chemotherapy in combination with IFNα2b were assessed for various immunohaematological parameters before treatment, after chemotherapy and after IFNα2b therapy. Results: Deterioration of the haematological and immune responses was detected in immunosuppressed TSCC patients after chemotherapy. IFNα2b treatment led to a recovery in these parameters in most of the patients. Greater number of T/NK cells and enhanced secretion of type 1 cytokines were also noted. Haematological complications were reduced after completion of the therapy. Immune- and haematostimulation were also observed in patients with partial response. No positive clinical response was detected in one patient. Interpretation & conclusions: IFNα2b appears to be an effective immunostimulator having clinical impact to combat the immunosuppression in TSCC patients. Successful immunostimulation by IFNα2b may help TSCC patients in clinical improvement. The findings of this preliminary study need to be confirmed on a large number of patients with TSCC.

A reduced dose of ribavirin does not influence the virologic response during pegylated interferon alpha-2b and ribavirin combination therapy in patients with genotype 1 chronic hepatitis C

BACKGROUND/AIMS: When combined with pegylated interferon alpha-2b (Peg-IFN alpha-2b) for the treatment of genotype 1 chronic hepatitis C (CHC) in Korea, the current guideline for the initial ribavirin (RBV) dose is based on body weight. However, since the mean body weight is lower for Korean patients than for patients in Western countries, current guidelines might result in Korean patients being overdosed with RBV. METHODS: We retrospectively reviewed the medical records of patients with genotype 1 CHC who were treated with Peg-IFN alpha-2b and RBV combination therapy. We divided the patients into groups A (> or =15 mg/kg/day, n=23) and B (<15 mg/kg/day, n=26), given that the standard dose is 15 mg/kg/day. The clinical course in terms of the virologic response, adverse events, and dose modification rate was compared between the two groups after therapy completion. RESULTS: The early response rates (92.0% vs. 83.3%, P=0.634) and sustained virologic response rates (82.6% vs. 73.1%, P=0.506) did not differ significantly between the two groups. During the treatment period, the RBV dose reduction rate was significantly higher in group A than in group B (60.9% vs. 23.1%, P=0.01). CONCLUSIONS: RBV dose reduction is performed frequently when patients are treated according to the current Korean guidelines. Given that lowering the RBV dose did not appear to decrease the virologic response during therapy, reducing RBV doses below the current Korean guideline may be effective for treatment, especially in low-weight patients.

The effect of combining interferon-α and gefitinib in human colon cancer cell lines / El efecto de combinar el interferón α y el gefitinib en las líneas celulares del cáncer de colon humano

BACKGROUND AND AIMS: Interferon-α (IFN-α) treatment is associated with up-regulation of epidermal growth factor receptor (EGFR) expression and marked growth inhibition of colon cancer cell lines. We aimed to determine the effect of combining IFN-α and gefitinib in the growth of human colon cancer cell lines. METHODS: Two human colon cancer cell lines SW480 and LOVO were treated with IFN-α alone or gefitinib alone or IFN-α plus gefitinib. Proliferation of colon cancer cells was measured by methyl thiazolyl tetrazolium (MTT) assay; the apoptosis rate was analysed by flow cytometry (FCM). The expression of XIAP, XAF1 mRNA was detected by RT-PCR and the expression of XIAP, XAF1 protein was detected by western blotting. RESULTS: Methyl thiazolyl tetrazolium showed that IFN-α, gefitinib and IFN-α plus gefitinib significantly inhibited SW480 and LOVO cells in a dose-dependent manner (p < 0.05). The FCM revealed that IFN α, gefitinib and IFN-α plus gefitinib could markedly upgrade the apoptosis rate (p < 0.05). The expression of XIAP mRNA down-regulated markedly (p < 0.05) while the expression of XAF1 mRNA up-regulated significantly (p < 0.05). The expression of XIAP protein was down-regulated markedly (p < 0.05) while the expression of XAF1 protein was up-regulated significantly (p < 0.05). CONCLUSION: IFN-α promotes the antiproliferaative effect of gefitinib on human colon cancer cell lines and the mechanism may be related to up-regulation expression of EGFR by IFN-α.

ANTECEDENTES Y OBJETIVOS: El tratamiento con interferón α (IFN-α) se halla asociado con la regulación por incremento de la expresión del receptor del factor de crecimiento epidérmico y la acentuada inhibición del crecimiento de las líneas celulares del cáncer colorrectal. El presente trabajo tuvo por objetivo determinar el efecto que se produce al combinar el IFN-α y el gefitinib en el crecimiento de las líneas celulares del cáncer de colon. MÉTODOS: Dos líneas celulares de cáncer del colon en humanos - SW480 y LOVO - fueron tratadas con IFN-α solamente, gefitinib solamente, o IFN-α más gefitinib. La proliferación de las células cancerosas del colon se midió mediante ensayo de metil tiazolil tetrazolio (MTT); la tasa de apoptosis se analizó mediante citometría de flujo (CMF); la expresión de XIAP/XAF1 mRNA fue detectada mediante RT-PCR y la expresión de la proteína XIAP/XAF1 fue detectada mediante inmunoblot (western blot). RESULTADOS: El MTT mostró que el IFN-α, el gefitinib, y el IFN-α más gefitinib inhibían de forma significativa las células SW480 y LOVO en dependencia de la dosis (p < 0.05). La CMF reveló que el IFN-α, el gefitinib, y el IFN-α más gefitinib podían aumentar notablemente la tasa de apoptosis (p < 0.05). La expresión de XIAP mRNA tuvo una marcada regulación por decremento (p < 0.05) mientras que la expresión de XAF1 mRNA tuvo una significativa regulación por incremento (p < 0.05); la expresión de la proteína XIAP fue notablemente regulada por decremento (p < 0.05) mientras que la expresión de la proteína XAF1 fue regulada por incremento de manera significativa (p < 0.05). CONCLUSIÓN: El IFN-α promueve el efecto antiproliferativo del gefitinib sobre las líneas celulares del cáncer colorrectal, y el mecanismo puede hallarse relacionado con la expresión de la regulación por incremento del EGFR mediante el IFN-α.

Efficacy of Dendritic Cells Matured Early with OK-432 (Picibanil(R)), Prostaglandin E2, and Interferon-alpha as a Vaccine for a Hormone Refractory Prostate Cancer Cell Line

Dendritic cells (DCs) are potent antigen-presenting cells. OK432 (Picibanil(R)) was introduced as a potent stimulator of DC maturation in combination with prostaglandin-E2 and interferon-alpha. We compared the efficacy of a DC-prostate cancer vaccine using early-mature DCs stimulated with OK432, PGE2 and INF-alpha (OPA) with that of vaccines using other methods. On days 3 or 7 of DC culture, TNF-alpha (T), TNF-alpha and LPS (TL) or OPA were employed as maturation stimulators. DU145 cells subjected to heat stress were hybridized with mature DCs using polyethyleneglycol. T cells were sensitized by the hybrids, and their proliferative and cytokine secretion activities and cytotoxicity were measured. The yields of early-mature DCs were higher, compared to yields at the conventional maturation time (P<0.05). In the early maturation setting, the mean fusion ratios, calculated from the fraction of dual-positive cells, were 13.3%, 18.6%, and 39.9%, respectively (P=0.051) in the T only, TL, and OPA-treated groups. The function of cytotoxic T cells, which were sensitized with the hybrids containing DCs matured early with OPA, was superior to that using other methods. The antitumor effects of DC-DU145 hybrids generated with DCs subjected to early maturation with the OPA may be superior to that of the hybrids using conventional maturation methods.

Lysozyme plays a dual role against the dimorphic fungus Paracoccidioides brasiliensis / A lisozima desempenha um papel duplo contra o fungo dimórfico Paracoccidioides brasiliensis

In order to determine the role of lysozyme, an antimicrobial peptide belonging to the innate immune system, against the dimorphic fungus Paracoccidioides brasiliensis, co-cultures of the MH-S murine alveolar macrophages cell line with P. brasiliensis conidia were done; assays to evaluate the effect of physiological and inflammatory concentrations of lysozyme directly on the fungus life cycle were also undertaken. We observed that TNF-α-activated macrophages significantly inhibited the conidia to yeast transition (p = 0.0043) and exerted an important fungicidal effect (p = 0.0044), killing 27 percent more fungal propagules in comparison with controls. Nonetheless, after adding a selective inhibitor of lysozyme, the fungicidal effect was reverted. When P. brasiliensis propagules were exposed directly to different concentrations of lysozyme, a dual effect was observed. Physiologic concentrations of the enzyme facilitated the conidia-to-yeast transition process (p < 0.05). On the contrary, inflammatory concentrations impaired the normal temperature-dependant fungal transition (p < 0.0001). When yeast cells were exposed to lysozyme, irrespective of concentration, the multiple-budding ability was badly impaired (p < 0.0001). In addition, ultra-structural changes such as subcellular degradation, fusion of lipid vacuoles, lamellar structures and interruption of the fibrilar layer were observed in lysozyme exposed conidia. These results suggest that lysozyme appears to exert a dual role as part of the anti-P. brasiliensis defense mechanisms.

Com a finalidade de determinar o papel da lisozima, um peptídeo antimicrobiano que pertence ao sistema imune inato, contra o fungo dimórfico Paracoccidioides brasiliensis, foram feitas co-culturas de uma linha de macrófagos alveolares murinos (MH-S) com as conídias do fungo na presença ou não do TNF-α e/ou um inibidor da lisozima; também foram feitos ensaios que avaliaram o efeito das concentrações fisiológicas e inflamatórias de lisozima diretamente sobre o ciclo de vida do fungo. Observamos que os macrófagos ativados com a citoquina tiveram um efeito significativo na inibição da transição conídia/levedura (p = 0,0043) e exerceram um efeito fungicida importante (p = 0,0044), matando mais de 27 por cento das propágulas do fungo em comparação com os macrófagos não ativados. No entanto, após ser o inibidor seletivo da lisozima adicionado, o efeito fungicida foi revertido. Quando os propágulos do fungo foram expostos diretamente a diferentes concentrações da lisozima, um duplo efeito foi observado. Assim, as concentrações fisiológicas da enzima facilitaram o processo de transição conídia-levedura (p < 0,05). Contrariamente, as concentrações inflamatórias prejudicaram a transição fúngica (p < 0,0001). Quando as leveduras foram expostas a qualquer concentração de lisozima, sua capacidade de multi-brotação foi gravemente prejudicada (p < 0,0001). Além disso, mudanças ultra-estruturais, como a sub degradação, a fusão dos vacúolos dos lípidos, estruturas lamelares e interrupção da camada fibrilar foram observadas em conídios expostos à lisozima. Estes resultados sugerem que a lisozima poderia exercer um duplo papel no mecanismo antifúngico contra P. brasiliensis.

impact of IFN beta 1a and IFN beta-1b on the clinical and MRI responses in patients with relapsing-remitting multiple sclerosis

Multiple Sclerosis [MS] is a common demyelinating and inflammatory disease of the CNS with a presumed autoimmune etiology. IFN beta-1a and IFN beta-1b have a proven treatment effect on RRMS presumably through its regulatory properties on T-cell activation and cytokines production. Here we studied the clinical and MRI effects of these drugs in four groups of clinically and laboratory [Cerebrospinal fluid evaluation revealed elevation of immunoglobulin [IgG] synthesis rate and oligoclonal bands] definite RRMS patients for 18 months. In IFN beta-1a group [n = 25], the patients used IFN beta-la 30 micro g [6MU] intramuscular once a week, the other three groups of IFN beta-1a [n = 25] 22 micro g [6MU], IFN beta-la 44 micro g [n = 25] and IFN beta-1b 8MU [0.25 mg] [n = 25] were injected subcutaneously 3-time a week. In comparison with the pre-treatment values, reduction in the relapse rate was statistically significant in IFN beta-la 44 micro g, IFN beta-la 30 micro g and IFN beta-lb 8MU groups more than IFN beta-la 22 micro g [P < 0.001, 0.008, 0.001 and > 0.5 respectively], and the mean EDSS significantly reduced in the IFN beta-lb [P < 0.001], IFN beta-la intramuscular [P < 0.02] and 44 micro g IFN beta-la [P < 0.001], in contrast to 22 micro g IFN beta-la treated patients [P > 0.5]. Moreover, IFN beta-lb [P < 0.001] and 44ug IFN beta-la [P < 0.003] groups showed highly statistical significant reduction in MRI disease activity load [p < 0.05] in comparison with 22micro g IFN beta-1a [p < 0.5] and IFN beta-la intramuscular groups [p < 0.07]. The study confirmed also the effect of beta-IFNs on the short term physical disability scale [p < 0.01] while they have no significant effect on long term disability scale [p > 0.64]. Additionally, beta-IFNs groups showed no statistically significant severe drugs adverse effects [p > 0.8] while revealed significant effects of recovered side effects [p < 0.01]. The common adverse effects of lFN beta that were significantly found [p < 0.01], are flu-like symptoms, fatigue, chills and fever, injection site pain and local redness, headache, irregular menses and mild depression specially with IFN beta-la intramuscular. No difference in the clinical suspicions of binding antibodies development to beta-IFNs was found. On the whole, all groups showed significant reduction of relapse frequency and MRI load with different values [p < 0.01]. In summary, this study does make available meaningful and helpful clinical and radiological data to the clinician regarding the relative efficacy of each therapy in RRMS. First, the results of our study suggest that IFN beta-lb 8MU and IFN beta-1a 44 micro g may be more optimal choices than IFN beta-la 30 micro g Intramuscular and IFN beta-la 22 micro g at the currently available dose in treatment of RRMS patients. Secondly, the results do not differ from remarks made after 18 months of treatment in larger and more rigorously controlled studies. Thirdly, therapy does construct a difference and early treatment should be encouraged

Interleukin 2 induction of proliferation in resting T lymphocytes requires contact with monocytes

Resting human T cells are known to express significant numbers of intermediate but none or barely detectable low and high a affinity IL-2 receptors (IL-2R). IL-2 alone failed to induce proliferation in these cells, However, in presence of small proportion of autologous monocytes, as low as 22 pM, IL-2 induced high levels of proliferation in resting T cells. Introduction of a semi permeable between the two cell types or addition of an anti-CD 11b mAb inhibited such induction of proliferation by IL-2. Neither recombinant IL-1 por IL-1 containing cell-free extracts from activated monocytes substituted for intact monocytes. Autologous B cells failed to replace monocytes. Using antigen-specific cloned human T cells we have shown a lack of requirement for antigen. The proliferation was inhibited by anti-IL-2R alpha mAb. IL-2 appears to be unique since neither IL-4 nor IL-6, alone or in presence of monocytes, led to induction of proliferation in resting T cells. Combination of IL-2 and monocytes induced proliferation in all T cell subpopulations (CD4, CD8, CD45RA and CD45RO) and antigen-specific clones examined. It also induces mRNA and surface expression of IL-2R alpha, appearance of high affinity IL-2R and induction of proliferation in large proportions of T cells. As in humans, the IL-2 induction of proliferation in murine resting T cell required contact with syngeneic monocytes, suggesting that such a mechanism of cells activation is highly conserved.

Detection of a factor released by L5178Y lymphoblasts that inhibits mouse Macrophage-Activation induced by lipopolysaccharides

Background. Several factors inhibit cellular immune response by deactivating macrophages, but very few, such as those described here, prevent macrophage activation. Methods. Ascites liquid from 12-day-old BALB/c mice bearing 5178Y lymphoma tumors was collected, and cell-free ascites liquid (CFAL) was separated from lymphoblasts. The supernatant (SI) was obtained from the homogenized and centrifuged lymphoblasts Then, macrophage cultures contaning 0.2 X 10 a the sixth cells from lymphoma-bearing or hearthly mice were added to 10 µL of CFAL or S1, plus 5 µg of lipopolysaccharides (LPS)/mL, 40 U interferon-ç or a blend of both. Macrophages were incubated with CFAL or S1 prior to or after adding the activators to investigate whether any of the previously mentioned lymphoma fraction inhibited macrophage activation or whether they deactivated them. The effect of CFAL or S1 was estimated as the diminution of the amount of nitric ixide released by the experimental macrophage cultures with respect to controls (activated macrophages treated with none of the lymphoma fractions). Results. LPS, IFN-ç, and the LPS/ç blend activated macrophages from both lymphomabearing and healthy mice. None of the lymphoma fractions deactivated macrophages. CFAL, but not S1, inhibited the macrophage activation, i.e., the percentage of inhibition of nitric oxide releasing 76.7 percent in macrophages from healthy and lymphomabearing mice, respectively. In addition, CFAL was unable to inhibit macrophage-activation effect of IFN-ç or the LPS/IFN-ç blend. Conclusions. Mouse L5178Y Lymphoma releases a factor that in vitro inhibits the macrophage activation induced by LPS, but not by IFN-ç controls

Expressão de receptor para o fator de crescimento insulina-símile tipo I (IGF-IR) na fase crônica da leucemia mielóide crônica (LMC) / Expression of the receptor to the insulin-like growth factor type I (IGF-IR) in chronic phase of the chronic myelogenous leukemia (CML)

Com o objetivo de verificar se o fator de crescimento insulina símile tipo I (IGF-I) e seu receptor (IGF-IR) estão implicados na instalação da leucemia mielóide crônica (LMC) foram estudados 35 pacientes portadores de LMC na fase crônica antes ou durante o tratamento com interferon `ALFA' ou hidroxiurea e 16 indivíduos sadios como grupo controle. A análise do IGF-IR realizada através da citometria de fluxo e expressão de seu RNAm pelo ensaio molecular de RT-PCR nas células sanguíneas dos pacientes com LMC não tratada não mostrou diferenças estatísticas em relação ao grupo controle. Pacientes tratados com hidroxiurea apresentaram expressão diminuída do receptor em granulócitos, monócitos e linfócitos (P`MENOR'0,01) quando comparados aos demais grupos analisados...

Interferon selectively inhibits the synthesis of Mayaro virus glycoproteins

We have previously observed that interferon(recIFNa2b) blocks the process of mophogenesis of Mayaro virus in TC7 cells (monkey kidney). In this work we show that IFNa inhibits preferentially virus glycoproteins and their precursors, and this effects is probably correlated to the alterations in the morphogenesis process previously observed

Intracellular Leishmania amazonensis killing induced by the guanine nucleoside 8-bromoguanosine

Neste trabalho, nos investigamos o efeito da 8-Bromoguanosina, um composto imunoestimulador, na citotoxicidade de macrofagos infectados com Leishmania amazonensis em um sistema in vitro. Os resultados mostraram que macrofagos tratados com 8-Bromoguanosina pre- ou pos-infeccao foram capazes de reduzir a carga parasitaria, monitorada pelo numero de amastigotas por macrofago e a percentagem de celulas infectadas (i.e. indice fagocitico). Sendo a 8-Bromoguanosina inocua para promastigotas, concluimos que o composto induz ativacao celular. Os macrofagos produziriam interferon alfa e beta e teriam seus mecanismos leishmanicidas estimulados. Esses resultados sugerem que compostos como a 8-Bromoguanosina (ribonucleosideos de guanina) podem auxiliar no tratamento contra patogenos intracelulares

Efeito da temperatura na síntese de proteínas em células de adenocarcinoma de pulmäo (A549) pré-tratadas com interferon / Effect of temperature on proteins synthesis in human lung adenocarcinoma cells (A549) pre-treated with interferon

No presente trabalho foi investigado o efeito da temperatura elevada na síntese de proteínas em células de adenocarcinoma de pulmao (A549) previamente tratadas com Interferon recombinante humano alpha-2b. Os resultados mostram que em nossas condiçoes experimentais, o pré-tratamento das células com esta droga inibe a expressao dos genes de choque térmico.