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1.
Pharmaceutics ; 16(6)2024 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-38931954

RESUMEN

The tyrosine kinase Inhibitor (TKI) imatinib is approved for the treatment of the chronic phase of chronic myeloid leukemia (CP-CML). Pharmacokinetic studies have highlighted the importance of inter-patient variability on imatinib plasma trough concentrations (ima[C]min). In the OPTIM-imatinib trial, we demonstrated that therapeutic drug monitoring (TDM) is able to improve the molecular response of CP-CML patients treated with imatinib. Here, we analyzed the constitutional exomes and RNAseq data of these patients. We performed an association analysis between the constitutional genetic variants of the patients and their ima[C]min, measured after 12 weeks of treatment with 400 mg once daily. Using linear regression, we identified 50 SNPs that showed excess heterozygosity depending on the ima[C]min. Ten SNPs were from non-coding sequences, and among the 40 remaining, 30 (from 25 genes) could be split into two categories. The first group of 16 SNPs concerns genes encoding extracellular matrix, cell junction, and membrane proteins. Coincidentally, cell adhesion proteins were also identified by RNA-seq as being overexpressed in patients with high ima[C]min. The other group of 14 SNPs were from genes encoding proteins involved in transcription/translation. Although most of the SNPs are intronic variants (28), we also identified missense (3), synonymous (4), 5'/3' (2), splicing (1), and upstream (4) variants. A haplotype analysis of four genes showed a significant association with high ima[C]min. None of the SNPs were significantly associated with the response. In conclusion, we identified a number of ima[C]min-associated SNPs, most of which correspond to genes encoding proteins that could play a role in the diffusion and transit of imatinib through membranes or epithelial barriers.

2.
Ann Biol Clin (Paris) ; 81(4): 403-409, 2023 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-37864446

RESUMEN

OBJECTIVES: SARS-CoV-2 has impacted the detection of seasonal respiratory viruses. We retrospectively assessed the trend in the detection of 10 viruses in the COVID-19 area in 2 hospitals located in the Paris area. METHODS: All patients positive for a respiratory virus in two hospitals from September 2016 to August 2021 were retrospectively included. The rate of RT-PCR positive for each virus was calculated for the 2020-2021 season and the 2019-2020 season in comparison to a baseline of 3 seasons, i.e. 2016-2017, 2017-2018, and 2018-2019. RESULTS: Overall, 7,835 patients were tested positive from September 2016 to August 2021. The detection of respiratory virus dramatically falls on week-11 of 2020, as the number of RT-PCR performed. Then, 3 trends were identified: a) almost a disappearance for influenza; b) a 10-weeks delay in the seasonal outbreak for RSV; c) a persistence of circulation with variable activity for other viruses. In comparison to a baseline of three seasons (2016-2019), the rate of positive patients was lower during the 2020-2021 season for coronavirus (4.51% vs. 1.26%, P < 0.0001), adenovirus (1.93% vs. 1.34%, P = 0.14), bocavirus (0.58% vs. 0.11%, P = 0.08), and enterovirus (0.28% vs. 0.0%, P = 0.12). In contrast, the rate of hMPV-positive (1.92% vs. 2.83%, P = 0.03) and hPIV-positive (2.17% vs. 2.99%, P = 0.06) patients increased. CONCLUSIONS: The fall in the number of respiratory viruses detected might be related to the lower number of tests performed and the implementation of non pharmaceutical intervention (NPI). Then, all viruses except influenza are detected, probably as a consequence of high adherence to influenza vaccines. Despite, a lower number of tests being performed, the rate of hMPV-positive and hPIV-positive patients increased suggesting an active circulation of these viruses. Altogether, these findings suggest a persistent circulation of common respiratory viruses all over the COVID-19 era.


Asunto(s)
COVID-19 , Gripe Humana , Infecciones del Sistema Respiratorio , Virus , Humanos , Lactante , Gripe Humana/epidemiología , Estudios Retrospectivos , COVID-19/diagnóstico , COVID-19/epidemiología , SARS-CoV-2 , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/epidemiología
3.
Pharmaceutics ; 14(8)2022 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-36015302

RESUMEN

The registered dose for imatinib is 400 mg/d, despite high inter-patient variability in imatinib plasmatic exposure. Therapeutic drug monitoring (TDM) is routinely used to maximize a drug's efficacy or tolerance. We decided to conduct a prospective randomized trial (OPTIM-imatinib trial) to assess the value of TDM in patients with chronic phase chronic myelogenous treated with imatinib as first-line therapy (NCT02896842). Eligible patients started imatinib at 400 mg daily, followed by imatinib [C]min assessment. Patients considered underdosed ([C]min < 1000 ng/mL) were randomized in a dose-increase strategy aiming to reach the threshold of 1000 ng/mL (TDM arm) versus standard imatinib management (control arm). Patients with [C]min levels ≥ 1000 ng/mL were treated following current European Leukemia Net recommendations (observational arm). The primary endpoint was the rate of major molecular response (MMR, BCR::ABL1IS ≤ 0.1%) at 12 months. Out of 133 evaluable patients on imatinib 400 mg daily, 86 patients had a [C]min < 1000 ng/mL and were randomized. The TDM strategy resulted in a significant increase in [C]min values with a mean imatinib daily dose of 603 mg daily. Patients included in the TDM arm had a 12-month MMR rate of 67% (95% CI, 51−81) compared to 39% (95% CI, 24−55) for the control arm (p = 0.017). This early advantage persisted over the 3-year study period, in which we considered imatinib cessation as a censoring event. Imatinib TDM was feasible and significantly improved the 12-month MMR rate. This early advantage may be beneficial for patients without easy access to second-line TKIs.

4.
Br J Haematol ; 190(5): 718-722, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32542672

RESUMEN

Complementary tools are warranted to increase the sensitivity of the initial testing for COVID-19. We identified a specific 'sandglass' aspect on the white blood cell scattergram of COVID-19 patients reflecting the presence of circulating plasmacytoid lymphocytes. Patients were dichotomized as COVID-19-positive or -negative based on reverse transcriptase polymerase chain reaction (RT-PCR) and chest computed tomography (CT) scan results. Sensitivity and specificity of the 'sandglass' aspect were 85·9% and 83·5% respectively. The positive predictive value was 94·3%. Our findings provide a non-invasive and simple tool to quickly categorize symptomatic patients as either COVID-19-probable or -improbable especially when RT-PCR and/or chest CT are not rapidly available.


Asunto(s)
Betacoronavirus/metabolismo , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/diagnóstico , Linfocitos/metabolismo , Tamizaje Masivo , Neumonía Viral/sangre , Neumonía Viral/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , COVID-19 , Infecciones por Coronavirus/diagnóstico por imagen , Femenino , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/diagnóstico por imagen , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , SARS-CoV-2 , Tomografía Computarizada por Rayos X
5.
J Clin Invest ; 126(9): 3207-18, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27482885

RESUMEN

Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development.


Asunto(s)
Antineoplásicos/efectos adversos , Dasatinib/efectos adversos , Hipertensión Pulmonar/inducido químicamente , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Adulto , Animales , Antineoplásicos/farmacología , Apoptosis , Células Cultivadas , Dasatinib/farmacología , Selectina E/sangre , Femenino , Predisposición Genética a la Enfermedad , Hemodinámica , Humanos , Hipoxia/metabolismo , Mesilato de Imatinib/farmacología , Molécula 1 de Adhesión Intercelular/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Molécula 1 de Adhesión Celular Vascular/sangre
6.
Nature ; 525(7569): 380-3, 2015 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-26331539

RESUMEN

Whether cancer is maintained by a small number of stem cells or is composed of proliferating cells with approximate phenotypic equivalency is a central question in cancer biology. In the stem cell hypothesis, relapse after treatment may occur by failure to eradicate cancer stem cells. Chronic myeloid leukaemia (CML) is quintessential to this hypothesis. CML is a myeloproliferative disorder that results from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR-ABL. During the chronic phase, this sole genetic abnormality (chromosomal translocation Ph(+): t(9;22)(q34;q11)) at the stem cell level causes increased proliferation of myeloid cells without loss of their capacity to differentiate. Without treatment, most patients progress to the blast phase when additional oncogenic mutations result in a fatal acute leukaemia made of proliferating immature cells. Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR-ABL have improved patient survival markedly. However, fewer than 10% of patients reach the stage of complete molecular response (CMR), defined as the point when BCR-ABL transcripts become undetectable in blood cells. Failure to reach CMR results from the inability of TKIs to eradicate quiescent CML leukaemia stem cells (LSCs). Here we show that the residual CML LSC pool can be gradually purged by the glitazones, antidiabetic drugs that are agonists of peroxisome proliferator-activated receptor-γ (PPARγ). We found that activation of PPARγ by the glitazones decreases expression of STAT5 and its downstream targets HIF2α and CITED2, which are key guardians of the quiescence and stemness of CML LSCs. When pioglitazone was given temporarily to three CML patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained CMR, up to 4.7 years after withdrawal of pioglitazone. This suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Células Madre Neoplásicas/efectos de los fármacos , PPAR gamma/agonistas , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Tiazolidinedionas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Benzamidas/farmacología , Benzamidas/uso terapéutico , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , PPAR gamma/metabolismo , Pioglitazona , Piperazinas/farmacología , Piperazinas/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Proteínas Represoras/metabolismo , Factor de Transcripción STAT5/metabolismo , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéutico , Transactivadores/metabolismo
7.
Clin Chim Acta ; 411(3-4): 140-6, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19853594

RESUMEN

BACKGROUND: Imatinib, a competitive inhibitor of BCR-ABL tyrosine kinase, is now the first-line treatment for chronic myelogenous leukemia (CML). Therapeutic drug monitoring targeting trough plasma levels of about 1000ng/mL may help to optimize the therapeutic effect. METHODS: We developed a high-performance liquid chromatography (HPLC) method with UV/Diode Array Detection (DAD) for trough imatinib concentration determination in human plasma. Imatinib trough levels were measured in plasma from 65 CML patients using our method and LC-MS/MS as the reference method. Results with these two methods were compared using Deming regression, chi-square test, and sign test. RESULTS: The calibration curve was prepared in blank human plasma. HPLC-UV/DAD calibration curves were linear from 80 to 4000ng/mL, and the limit of quantification was set at 80ng/mL. The between-day variation was 6.1% with greater than 96% recovery after direct plasma deproteinization and greater than 98% recovery from the column. No significant differences in imatinib plasma levels were found between HPLC-UV/DAD and LC-MS/MS. CONCLUSIONS: This HPLC-UV/DAD method was sufficiently specific and sensitive for imatinib TDM, with no evidence of interference. Our rapid inexpensive HPLC-UV/DAD method that requires only widely available equipment performs well for plasma imatinib assays.


Asunto(s)
Análisis Químico de la Sangre/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Piperazinas/sangre , Pirimidinas/sangre , Rayos Ultravioleta , Benzamidas , Análisis Químico de la Sangre/economía , Análisis Químico de la Sangre/instrumentación , Proteínas Sanguíneas/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Conductividad Eléctrica , Femenino , Humanos , Mesilato de Imatinib , Laboratorios de Hospital , Límite de Detección , Modelos Lineales , Masculino , Persona de Mediana Edad , Piperazinas/aislamiento & purificación , Pirimidinas/aislamiento & purificación , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem , Temperatura , Factores de Tiempo
8.
Fundam Clin Pharmacol ; 23(5): 573-81, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19656212

RESUMEN

Human immunodeficiency virus (HIV) infection is often complicated by the development of acquired immunodeficiency syndrome (AIDS) dementia complex (ADC). Implications of kynurenine pathway (KP) are suggested in ADC and other inflammatories brain diseases. The first and regulatory enzyme of the KP is the indoleamine-2,3-dioxygenase (IDO). IDO activation is known to contribute to the modulation of the immune response during various infectious diseases particularly in AIDS. HIV and viral proteins can activate IDO in immune cells leading to an increase catabolism of tryptophan through the KP; the consequence being the production of immuno-modulative and neuroactive metabolites. This mechanism is likely to favour HIV persistence. The present study analysed concomitantly several parameters involved in IDO regulation and activity associated with HIV-1-infection. We investigated relevant intracellular and extracellular mechanisms involved in the regulation of IDO expression and activity during the HIV infection and replication in human monocyte-derived macrophages (MdM). Using a complementary set of in vitro experiments, we found that HIV-1/Ba-L infection induces IDO expression and increases its activity in MdM. We also showed that IDO activation by HIV-1 is likely to be a direct effect of the infection and seems to be independent of IFN-gamma production.


Asunto(s)
VIH-1/crecimiento & desarrollo , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Macrófagos/enzimología , Macrófagos/virología , Fármacos Anti-VIH/farmacología , Células Cultivadas , Efecto Citopatogénico Viral , VIH-1/efectos de los fármacos , Humanos , Interferón gamma/biosíntesis , Interferón gamma/farmacología , Macrófagos/efectos de los fármacos , Modelos Biológicos , ARN Mensajero/biosíntesis , Proteínas Recombinantes , Replicación Viral/efectos de los fármacos , Zidovudina/farmacología
9.
Blood ; 112(12): 4598-608, 2008 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-18787223

RESUMEN

Plasmacytoid dendritic cells (pDCs) are antigen-presenting cells that develop into type-I interferon (IFN-I)-producing cells in response to pathogens. Their role in human immunodeficiency virus (HIV) pathogenesis needs to be understood. We analyzed their dynamics in relation to innate and adaptive immunity very early during the acute phase of simian immunodeficiency virus (SIV) infection in 18 macaques. pDC counts decreased in blood and increased in peripheral lymph nodes, consistent with early recruitment in secondary lymphoid tissues. These changes correlated with the kinetic and intensity of viremia and were associated with a peak of plasma IFN-I. IFN-I and viremia were positively correlated with functional activity of the immune suppression associated enzyme indoleamine-2,3-dioxygenase (IDO) and FoxP3(+)CD8(+) T cells, which both negatively correlated with SIV-specific T-cell proliferation and CD4(+) T-cell activation. These data suggest that pDCs and IFN-I play a key role in shaping innate and adaptive immunity toward suppressive pathways during the acute phase of SIV/HIV primary infection.


Asunto(s)
Movimiento Celular/inmunología , Células Dendríticas/inmunología , Tolerancia Inmunológica/inmunología , Interferón Tipo I/sangre , Ganglios Linfáticos/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Reacción de Fase Aguda/inmunología , Animales , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Células Dendríticas/metabolismo , Células Dendríticas/patología , Células Dendríticas/fisiología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Interleucina-18/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Macaca fascicularis , Síndrome de Inmunodeficiencia Adquirida del Simio/sangre , Síndrome de Inmunodeficiencia Adquirida del Simio/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Virus de la Inmunodeficiencia de los Simios/inmunología , Viremia/inmunología , Viremia/metabolismo
10.
Immunology ; 124(2): 223-33, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18217951

RESUMEN

Dendritic cells (DCs) are known to be essential for the induction and regulation of immune responses. Non-human primates are essential in biomedical research and contribute to our understanding of the involvement of DCs in human infectious diseases. However, no direct single-platform method for quantifying DC precursors has yet been optimized in macaques to give accurate absolute blood counts of these rare-event cell populations in the blood. We adapted a rapid whole-blood assay for the absolute quantification of DCs in cynomolgus macaques by four-colour flow cytometry, using a single-platform assay compatible with human blood. Cynomolgus macaque plasmacytoid DCs (pDCs) and CD1c(+) myeloid DCs (CD1c(+) mDCs) were quantified in the blood of 34 healthy macaques and the results obtained were compared with those for blood samples from 11 healthy humans. In addition, circulating absolute numbers of pDCs were quantified in cynomolgus macaques chronically infected with SIVmac. During infection, pDC counts decreased whereas circulating CD1c(+) mDC counts increased. Information regarding absolute pDC and mDC counts in non-human primates may improve our understanding of the role of these cells in SIV/HIV infection and in other infectious diseases.


Asunto(s)
Antígenos CD1/sangre , Células Dendríticas/inmunología , Células Progenitoras Mieloides/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios , Adulto , Animales , Recuento de Células , Enfermedad Crónica , Citometría de Flujo , Humanos , Inmunofenotipificación , Ganglios Linfáticos/inmunología , Macaca fascicularis , Masculino
11.
Fundam Clin Pharmacol ; 21(1): 29-34, 2007 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17227442

RESUMEN

Type I interferons (IFNs) are widely used to treat viral diseases. Depressive symptoms and suicide attempts are common neuropsychiatric side-effects during treatment with type I IFNs. Activation of indoleamine-2,3-dioxygenase (IDO), the first and rate-limiting enzyme of the kynurenine pathway by IFNs, leads to an increase in tryptophan (Trp) catabolism. Low levels of Trp lead to decrease of serotonin synthesis, which is likely to be related to the depressive symptoms. Ovine type I interferon-tau (IFN-tau) has a more potent antiretroviral effect and is less toxic than human type I IFN-alpha. Effects of IFN-tau and IFN-alpha on IDO expression and activity in primary cultures of human macrophages were compared in parallel to those of IFN-gamma, considered as one of the most potent IDO inducer. We found that both IFN-alpha and IFN-tau were poor inducers of IDO compared with IFN-gamma. However, IDO activation was slightly and significantly lower with ovine IFN-tau than human IFN-alpha, suggesting that ovine IFN-tau might have a lower impact on serotoninergic pathway compared with human IFN-alpha.


Asunto(s)
Antivirales/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Interferón Tipo I/farmacología , Interferón-alfa/farmacología , Macrófagos/efectos de los fármacos , Proteínas Gestacionales/farmacología , Animales , Células Cultivadas , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Macrófagos/enzimología , ARN Mensajero/metabolismo , Ovinos
13.
J Interferon Cytokine Res ; 25(8): 444-52, 2005 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16108727

RESUMEN

Interferon-tau (IFN-tau) is a type I IFN responsible for maternal recognition of the fetus in ruminants. In addition to its physiologic role, IFN-tau also inhibits HIV replication in human lymphocytes and macrophages and displays immunomodulatory effects but lacks the toxicity associated with other type I IFNs. Human IFN-alpha promotes a Th1 response, whereas IFN-tau has anti-inflammatory properties, inducing the production of Th2 cytokines in murine models of experimental autoimmune encephalitis (EAE) or fetal loss. We compared the effects of ovine IFN-tau (OvIFN-tau) and human IFN-alpha (HuIFN-alpha) on cytokine mRNA and protein production in human peripheral blood mononuclear cells (PBMCs) activated with a recall antigen, such as purified protein derivative (PPD) of tuberculin or with a proinflammatory stimulus, such as lipopolysaccharide (LPS). In both cases, IFN-alpha increased IFN-gamma production, whereas IFN-tau did not and thereby promoted Th2 cytokine production. This original property renders IFN-tau a potential candidate for therapeutic applications in immune disorders, such as multiple sclerosis (MS), but its therapeutic use in the treatment of HIV infection should be considered with caution.


Asunto(s)
Interferón Tipo I/farmacología , Interferón gamma/biosíntesis , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Proteínas Gestacionales/farmacología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Citocinas/genética , Humanos , Interferón Tipo I/inmunología , Interferón-alfa/farmacología , Interferón gamma/inmunología , Lipopolisacáridos/farmacología , Linfocitos/citología , Linfocitos/inmunología , Proteínas Gestacionales/inmunología , ARN Mensajero/genética , ARN Mensajero/metabolismo
14.
Int Immunol ; 17(8): 1047-57, 2005 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15976033

RESUMEN

IFN-tau is a non-cytotoxic type I IFN responsible for maternal recognition of the foetus in ruminants. IFN-tau has been found to inhibit HIV replication more strongly than human IFN-alpha, particularly in human monocyte-derived macrophages, without associated toxicity. Ovine IFN-tau uses the same anti-viral cellular pathways as human IFN-alpha in human macrophages, principally inhibiting the early steps of the biological cycle of HIV, preventing the integration of HIV DNA into the host-cell genome. In this study, we investigated the immunomodulatory properties of IFN-tau in human macrophages. We found that IFN-tau increased the production of IL-10 and IL-6, but not of IL-1beta or tumour necrosis factor alpha, in unstimulated, LPS-stimulated and HIV-1/Ba-L-infected macrophages. We also found that treatment with IL-6 inhibited HIV replication. Moreover, the neutralization of IL-6 activity in the cell culture supernatants of IFN-tau-treated macrophages led to a decrease in the anti-retroviral effects of IFN-tau, suggesting that IL-6 was involved in the anti-viral activity induced by IFN-tau. By focusing on the very early steps of the biological cycle of HIV, we showed that IL-6 co-operated with IFN-tau to decrease intracellular HIV RNA levels 2 h after infection.


Asunto(s)
VIH-1/efectos de los fármacos , VIH-1/inmunología , Interferón Tipo I/farmacología , Interleucina-6/biosíntesis , Proteínas Gestacionales/farmacología , Animales , VIH-1/fisiología , Humanos , Factores Inmunológicos/farmacología , Técnicas In Vitro , Interleucina-1/biosíntesis , Interleucina-10/biosíntesis , Interleucina-10/farmacología , Interleucina-6/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/virología , Proteínas Recombinantes/farmacología , Ovinos , Factor de Necrosis Tumoral alfa/biosíntesis , Replicación Viral/efectos de los fármacos
15.
Psychopharmacology (Berl) ; 178(1): 27-34, 2005 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15289993

RESUMEN

RATIONALE: Oral glucose has been shown to decrease tobacco craving in many but not all previous studies. Glucose ingestion may facilitates entry of tryptophan (TRP), the unique source of brain serotonin, into the brain, glucose's action seems to be opposite of rapid TRP depletion. Therefore, the aim was to assess the effect of high doses of oral glucose on tobacco craving, withdrawal symptoms, plasma TRP and blood serotonin concentrations in temporarily abstinent smokers. METHODS: Aspartame 0.6 g/200 ml (A, placebo), glucose 32.5 g/200 ml (G32.5) and 75 g/200 ml water (G75) were administered to 12 healthy smokers after an overnight abstinence in a crossover, double blind study. Tobacco craving (short version of the Tobacco Craving Questionnaire, TCQ), withdrawal symptoms, choice reaction time, affect, blood glucose, plasma insulin, nicotine, cotinine, free and total TRP, and blood serotonin concentrations were assessed during a period of 5 h after administration. RESULTS: Blood glucose and plasma insulin increased after G32.5, G75 and remained unchanged after A. TCQ score increased with A and remained almost unchanged with both doses of glucose (conditionxtime interaction: P=0.023). Total withdrawal score increased differently according to sex and condition (P<0.05). Motor reaction time increased with A and decreased with glucose (P=0.016). The overall decrease in plasma TRP was 0.31+/-17, 0.49+/-0.19 and 1.44+/-0.24 mg/l with A, G32.5 and G75, respectively (P<0.001). Baseline blood serotonin was lower in women (n=5) than in men; it showed a condition by time (P=0.007) and a condition by time by sex interaction (P=0.023). CONCLUSIONS: Glucose attenuates tobacco craving and withdrawal symptoms in temporarily abstinent smokers. This is accompanied by a decrease in plasma TRP and a sex dependent increase in blood serotonin. Further studies assessing the direct effect of glucose on brain serotonin are needed to ascertain whether a glucose induced reduction in craving is associated with an increase in brain serotonin.


Asunto(s)
Glucosa/farmacología , Serotonina/sangre , Síndrome de Abstinencia a Sustancias/sangre , Tabaquismo/sangre , Triptófano/sangre , Administración Oral , Adulto , Afecto/efectos de los fármacos , Conducta Adictiva/tratamiento farmacológico , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Glucosa/administración & dosificación , Humanos , Masculino , Tiempo de Reacción/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/fisiopatología , Tabaquismo/fisiopatología
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