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Regulatory T cells (Treg), a subset of CD4 + T cells, are potent regulators of immune reactions, which have been shown to be a promising therapeutic alternative to toxic immunosuppressive drugs. Data support the utility of Treg in managing immunopathologies, including solid organ transplant rejection, graft-versus-host disease, and autoimmune disorders. Notably, reports suggest that interleukin-2 (IL-2) is critical to survival of Treg, which constitutively express high levels of CD25, that is, the IL-2 receptor α-chain, and are exquisitely sensitive to IL-2, even at very low concentrations in contrast to effector T cells, which only upregulate IL-2 receptor α-chain on activation. This has led to the notion of using low doses of exogenous IL-2 therapeutically to modulate the immune system, specifically Treg numbers and function. Here, we summarize developments of clinical experience with low-dose IL-2 (LD-IL-2) as a therapeutic agent. So far, no clinical data are available to support the therapeutic use of LD-IL-2 therapy in the solid organ transplant setting. For the latter, fine-tuning by biotechnological approaches may be needed because of the narrow therapeutic window and off-target effects of LD-IL-2 therapy and so to realize the therapeutic potential of this molecule.
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Rechazo de Injerto , Interleucina-2 , Trasplante de Órganos , Linfocitos T Reguladores , Humanos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Interleucina-2/administración & dosificación , Trasplante de Órganos/efectos adversos , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Animales , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Supervivencia de Injerto/efectos de los fármacos , Resultado del TratamientoRESUMEN
The stock market is an indicator of investor sentiment when it comes to new information or innovative firm-level products. Green bonds are both innovative and unique in terms of their higher information disclosures and understanding the impact of sustainable finance on investor outlook for a company's stock. Using the comparative case of Mainland China and Hong Kong's stock market, we examine whether green bond announcements from 2016 to 2019 can create significant investor reactions. By employing the event study methodology, we confirm that both markets react in a positive way toward green bond announcements. This reinforces the reputational and financial benefits of green bonds. We find that issuers that are non-banks, environmentally friendly firms as well as those issuing non-general bonds, create a more positive reaction, whereas ownership aspects do not matter as much for investors. However, even among those issuers listed in both markets, certain institutional dynamics like strategic framing and source credibility tend to reinforce a firm's institutional legitimacy and are seen as being more prominent for investor reaction. The policy implications of our study show that the stock market reaction among two connected economies, where previously varying institutional contexts have resulted in regional differences, are now equally supportive of sustainable financial markets like the green bond. As seen with the positive stock market sentiment, governments and listed issuers can now better align their policies and internal strategies, allowing the low-carbon transition to be a financially attractive opportunity for all investors.
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Background: The impact of certain tumor parameters on the sensitivity of imaging tools is unknown. The purpose was to study the impact of breast cancer histology, tumor grading, single receptor status, and molecular subtype on the sensitivity of contrast-enhanced breast magnetic resonance imaging (CE-BMRI) vs X-ray mammography (XRM) to detect breast cancer. Materials and Methods: We ran a supplemental analysis of 2 global Phase III studies which recruited patients with histologically proven breast cancers. The sensitivity of CE-BMRI vs XRM to detect cancer lesions with different histologies, tumor grading, single receptor status, and molecular subtype was compared. Six blinded readers for each study evaluated the images. Results were summarized as the "Mean Reader." For each reader, sensitivity was defined as the proportion of detected lesions vs the total number of lesions identified by the standard of reference. Two-sided 95% confidence intervals were calculated for within-group proportions, and for the difference between CE-BMRI and XRM, using a normal approximation to the binomial distribution. Results: In 778 patients, 1273 cancer lesions were detected. A total of 435 patients had 1 lesion, 254 had 2 lesions, and 77 had 3 or more lesions. The sensitivity of CE-BMRI was significantly higher compared with XRM irrespective of the histology. The largest difference was seen for invasive lobular carcinoma (22.3%) and ductal carcinoma in situ (19%). Across all 3 tumor grades, the sensitivity advantage of CE-BMRI over XRM ranged from 15.7% to 18.5%. Contrast-enhanced breast magnetic resonance imaging showed higher sensitivity compared with XRM irrespective of single receptor expressions (15.3%-19.4%). The sensitivities for both imaging methods were numerically higher for the more aggressive ER- (estrogen receptor), PR- (progesterone receptor), and HER2+ (human epidermal growth factor receptor 2) tumors. Irrespective of molecular subtype, sensitivity of CE-BMRI was 14.8% to 18.9% higher compared with XRM. Conclusions: Contrast-enhanced breast magnetic resonance imaging showed significantly higher sensitivity compared with XRM independent of tumor histology, tumor grading, single receptor status, and molecular subtype.Trial Registration: ClinicalTrials.gov: NCT01067976 and NCT01104584.
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OBJECTIVES: To evaluate multiphase low kV computed tomography (CT) imaging of the abdomen with reduced contrast media (CM) dose using different injection protocols. METHODS: Two injection protocols were evaluated for use with low kV (80 kV) multiphase abdominal imaging in comparison to the standard procedure acquired at 120 kV (500 mgI/kg; 5 mL/s). This evaluation was conducted in a highly standardized animal study (5 Goettingen minipigs). The low kV protocols consisted of (a) a single-flow (SF) injection with 40% reduced CM dose and injection rate (300 mgI/kg; 3 mL/s) and (b) a DualFlow (DF) injection protocol consisting of 60%/40% contrast to saline ratio administered at 5 mL/s. Dynamic CT was first performed within representative liver regions to determine optimal contrast phases, followed by evaluation of the three protocols in multiphase abdominal CT imaging. The evaluation criteria included contrast enhancement (CE) of abdominal organs and vasculature. RESULTS: The 80 kV DF injection protocol showed similar CE of the abdominal parenchymatous organs and vessels to the 120 kV reference and the 80 kV SF protocol. Hepatic parenchyma showed comparable CT values for all contrast phases. In particular, in the portal venous parenchymal phase, the 80 kV DF protocol demonstrated higher hepatic parenchymal enhancement; however, results were statistically non-significant. Similarly, CE of the kidney, pancreas, and abdominal arterial/venous vessels showed no significant differences between injection protocols. CONCLUSIONS: Adapted SF and DF injection protocols with reduced IDR/iodine load offer the potential to calibrate optimal CM doses to the tube voltage in abdominal multiphase low kV CT imaging. The data suggest that the DF approach allows the use of predefined injection protocols and adaption of the contrast to saline ratio to an individualized kV setting and yields the potential for patient-individualized CM adaption.
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Medios de Contraste , Yodo , Abdomen , Animales , Humanos , Porcinos , Porcinos Enanos , Tomografía Computarizada por Rayos X/métodosRESUMEN
BACKGROUND: Detection of breast cancer in women with high breast densities is a clinical challenge. PURPOSE: To study the influence of different degrees of breast density on the sensitivity of contrast-enhanced breast magnetic resonance imaging (CE-BMRI) versus X-ray mammography (XRM). MATERIAL AND METHODS: We performed an additional analysis of two large Phase III clinical trials (G1; G2) which included women with histologically proven breast cancers, called "index cancers." Additional cancers were detected during image reading. We compared the sensitivity of CE-BMRI and XRM in women with different breast densities (ACR AâD; Version 5). For each study, six blinded readers evaluated the images. Results are given as the "Median Reader." RESULTS: A total of 774 patients were included, 169 had additional cancers. While sensitivity of CE-BMRI for detecting all index cancers was independent of breast density (ACR AâD) (G1: 83%â83%; G2: 91%â91%) the sensitivity of XRM declined (ACR AâD) (G1: 79%â62%; G2: 82%â64%). Thus, the sensitivity difference between both imaging modalities in ACR A breasts of 3% (G1) and 9% (G2) increased to 21% (G1) and 26% (G2) in ACR D breasts. Sensitivity of CE-BMRI for detecting at least one additional cancer increased with increasing breast density (ACR AâD) (G1: 50%â73%, G2: 57%â81%). XRM's sensitivity decreased (G1: 34%â20%) or remained stable (G2: 24%â25%). CONCLUSION: CE-BMRI showed significantly higher sensitivity compared to XRM.
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Densidad de la Mama , Neoplasias de la Mama/diagnóstico por imagen , Imagen por Resonancia Magnética , Mamografía , Anciano , Medios de Contraste , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Inactivated Orf virus (iORFV) has been used as a preventative as well as a therapeutic immunomodulator in veterinary medicine in different species. iORFV elicits strong effects on cytokine secretion in mice and human immune cells leading to an auto-regulated loop of initial up-regulation of inflammatory and Th1-related cytokines followed by Th2-related cytokines that attenuate immunopathology. The therapeutic potential of iORFV has been recognized in several models for difficult-to-treat disease areas such as chronic viral diseases, liver fibrosis or various forms of cancer. METHODS: Guinea pigs were infected with Human Herpesvirus (HSV)-2 strain MS and treated with iORFV, Acyclovir (ACV) or placebo, respectively. Clinical score of herpes lesions and viral shedding was assessed over a period of 40 days. In addition, viral DNA in dorsal root ganglia was quantified at the end of the study. RESULTS: Disease symptoms were minimal or absent in iORFV-treated guinea pigs but tended to be severe in animals treated with either ACV or placebo. The cumulated disease score was significantly reduced in iORFV-treated but not in ACV- or placebo-treated guinea pigs. In addition, treatment with iORFV, but not ACV or placebo, led to significant reduction of viral DNA load in dorsal root ganglia. CONCLUSION: iORFV effectively suppressed recurrences in guinea pigs experimentally infected with HSV. iORFV did not only reduce recurrent disease episodes but was, compared with ACV, more effective in reducing latency as measured by viral DNA detected in dorsal root ganglia of infected animals.
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Antivirales/inmunología , Modelos Animales de Enfermedad , Herpes Genital/prevención & control , Herpesvirus Humano 2/efectos de los fármacos , Virus del Orf/inmunología , Prevención Secundaria/métodos , Vacunas Virales/inmunología , Animales , Antivirales/administración & dosificación , ADN Viral/análisis , Femenino , Ganglios/virología , Cobayas , Herpes Genital/virología , Herpesvirus Humano 2/fisiología , Humanos , Inmunomodulación , Vacunas de Productos Inactivados/administración & dosificación , Vacunas de Productos Inactivados/inmunología , Vacunas Virales/administración & dosificación , Esparcimiento de Virus/efectos de los fármacosRESUMEN
AIC649 has been shown to directly address the antigen presenting cell arm of the host immune defense leading to a regulated cytokine release and activation of T cell responses. In the present study we analyzed the antiviral efficacy of AIC649 as well as its potential to induce functional cure in animal models for chronic hepatitis B. Hepatitis B virus transgenic mice and chronically woodchuck hepatitis virus (WHV) infected woodchucks were treated with AIC649, respectively. In the mouse system AIC649 decreased the hepatitis B virus titer as effective as the "gold standard", Tenofovir. Interestingly, AIC649-treated chronically WHV infected woodchucks displayed a bi-phasic pattern of response: The marker for functional cure--hepatitis surface antigen--first increased but subsequently decreased even after cessation of treatment to significantly reduced levels. We hypothesize that the observed bi-phasic response pattern to AIC649 treatment reflects a physiologically "concerted", reconstituted immune response against WHV and therefore may indicate a potential for inducing functional cure in HBV-infected patients.
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Antivirales/uso terapéutico , Antígenos de Superficie de la Hepatitis B/metabolismo , Virus de la Hepatitis B de la Marmota/inmunología , Hepatitis B Crónica/inmunología , Marmota/inmunología , Animales , Terapia Biológica , Biomarcadores/metabolismo , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/tratamiento farmacológico , Inmunidad Celular/inmunología , Interferón-alfa/inmunología , Interferón gamma/inmunología , Células Asesinas Naturales/inmunología , Activación de Linfocitos/inmunología , Marmota/virología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Parapoxvirus/inmunología , Linfocitos T/inmunología , Tenofovir/uso terapéutico , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Vacunas de Productos Inactivados/inmunología , Replicación Viral/efectos de los fármacosRESUMEN
Inactivated orf virus (iORFV), strain D1701, is a potent immune modulator in various animal species. We recently demonstrated that iORFV induces strong antiviral activity in animal models of acute and chronic viral infections. In addition, we found D1701-mediated antifibrotic effects in different rat models of liver fibrosis. In the present study, we compare iORFV derived from two different strains of ORFV, D1701 and NZ2, respectively, with respect to their antifibrotic potential as well as their potential to induce an antiviral response controlling infections with the hepatotropic pathogens hepatitis C virus (HCV) and hepatitis B virus (HBV). Both strains of ORFV showed anti-viral activity against HCV in vitro and against HBV in a transgenic mouse model without signs of necro-inflammation in vivo. Our experiments suggest that the absence of liver damage is potentially mediated by iORFV-induced downregulation of antigen cross-presentation in liver sinus endothelial cells. Furthermore, both strains showed significant anti-fibrotic activity in rat models of liver fibrosis. iORFV strain NZ2 appeared more potent compared to strain D1701 with respect to both its antiviral and antifibrotic activity on the basis of dosages estimated by titration of active virus. These results show a potential therapeutic approach against two important human liver pathogens HBV and HCV that independently addresses concomitant liver fibrosis. Further studies are required to characterize the details of the mechanisms involved in this novel therapeutic principle.
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Hepacivirus/patogenicidad , Virus de la Hepatitis B/patogenicidad , Cirrosis Hepática/virología , Virus del Orf/fisiología , Animales , Humanos , Cirrosis Hepática/prevención & control , Masculino , Ratones , Ratas , PorcinosRESUMEN
AIM: Inactivated Orf virus (ORFV, Parapoxvirus ovis) demonstrates strong antiviral activity in animal models including a human hepatitis B virus (HBV)-transgenic mouse. In addition, expression of interferon (IFN)-γ and interleukin-10 (IL-10) was induced after administration of inactivated ORFV in these mice. IFN-γ and IL-10 are known to elicit antifibrotic activity. We therefore aimed to study antifibrotic activity of inactivated ORFV in models of liver fibrosis. METHODS: We characterized ORFV-induced hepatic cytokine expression in rats. We then studied ORFV in two models of liver fibrosis in rats, pig serum-induced liver fibrosis and carbon tetrachloride (CCL4 )-induced liver fibrosis. RESULTS: ORFV induced hepatic expression of IFN-γ and IL-10 in rats. ORFV mediated antifibrotic activity when administrated concomitantly with the fibrosis-inducing agents in both models of liver fibrosis. Importantly, when CCL4 -induced liver fibrosis was already established, ORFV application still showed significant antifibrotic activity. In addition, we were able to demonstrate a direct antifibrotic effect of ORFV on stellate cells. CONCLUSION: These results establish a potential novel antifibrotic therapeutic approach that not only prevents but also resolves established liver fibrosis. Further studies are required to unravel the details of the mechanisms involved.
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AIMS: The purpose of this work was to support the prediction of a potentially effective dose for the CETP-inhibitor, BAY 60-5521, in humans. METHODS: A combination of allometric scaling of the pharmacokinetics of the CETP-inhibitor BAY 60-5521 with pharmacodynamic studies in CETP-transgenic mice and in human plasma with physiologically-based pharmacokinetic (PBPK) modelling was used to support the selection of the first-in-man dose. RESULTS: The PBPK approach predicts a greater extent of distribution for BAY 60-5521 in humans compared with the allometric scaling method as reflected by a larger predicted volume of distribution and longer elimination half-life. The combined approach led to an estimate of a potentially effective dose for BAY 60-5521 of 51 mg in humans. CONCLUSION: The approach described in this paper supported the prediction of a potentially effective dose for the CETP-inhibitor BAY 60-5521 in humans. Confirmation of the dose estimate was obtained in a first-in-man study.
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Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Hidroxiquinolinas/administración & dosificación , Modelos Biológicos , Animales , Biometría , Perros , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hidroxiquinolinas/farmacocinética , Hidroxiquinolinas/farmacología , Masculino , Ratones , Ratones Transgénicos , Ratas , Ratas WistarRESUMEN
AIMS: To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP). METHODS: The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20-45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60-5521 (n= 28) or were treated with a placebo (n= 10). RESULTS: In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60-5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h. CONCLUSIONS: BAY 60-5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated.
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Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , HDL-Colesterol/sangre , Dislipidemias/metabolismo , Hidroxiquinolinas/farmacología , Hidroxiquinolinas/farmacocinética , Administración Oral , Adulto , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Dislipidemias/tratamiento farmacológico , Electrocardiografía/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hidroxiquinolinas/efectos adversos , Masculino , Persona de Mediana Edad , Método Simple Ciego , Adulto JovenRESUMEN
Early during Gram-negative sepsis, excessive release of pro-inflammatory cytokines can cause septic shock that is often followed by a state of immune paralysis characterized by the failure to mount adaptive immunity towards secondary microbial infections. Especially, the early mechanisms responsible for such immune hypo-responsiveness are unclear. Here, we show that TLR4 is the key immune sensing receptor to initiate paralysis of T-cell immunity after bacterial sepsis. Downstream of TLR4, signalling through TRIF but not MyD88 impaired the development of specific T-cell immunity against secondary infections. We identified type I interferon (IFN) released from splenic macrophages as the critical factor causing T-cell immune paralysis. Early during sepsis, type I IFN acted selectively on dendritic cells (DCs) by impairing antigen presentation and secretion of pro-inflammatory cytokines. Our results reveal a novel immune regulatory role for type I IFN in the initiation of septic immune paralysis, which is distinct from its well-known immune stimulatory effects. Moreover, we identify potential molecular targets for therapeutic intervention to overcome impairment of T-cell immunity after sepsis.
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Inmunidad Adaptativa , Interferón Tipo I/metabolismo , Macrófagos/metabolismo , Sepsis/inmunología , Bazo/metabolismo , Animales , Células Dendríticas/metabolismo , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Factor 88 de Diferenciación Mieloide/metabolismo , Sepsis/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismoRESUMEN
Orf virus (ORFV, Parapoxvirus ovis) possesses strong immunomodulating activity including the induction of interferon gamma (IFN-γ) and interleukin-12 (IL-12) expression. Antiviral effects have been described which appeared to be facilitated by an ORFV-induced Type 1 helper T-cell (Th1-type) immune response. In this study, we investigated the potential antitumoral activity of inactivated ORFV in transplantable tumor models. We show that parenteral administration of inactivated ORFV mediates antitumor effects in various models including the murine syngenic B16 F10 melanoma and MDA-MB-231 human breast cancer xenograft. Inhibition of natural killer (NK) and NKT cell activity through administration of an anti-mouse NK-1.1 antibody led to a reduction of ORFV-mediated antitumoral effects. However, residual antitumoral activity was observed. This observation was confirmed in MDA-MB-231 tumor-bearing NOD/LtSz-scid/j mice which not only lack functional T and B lymphocytes but, in addition, have virtually no cells positive for the NK 1.1 cell surface marker. Thus, administration of inactivated ORFV induced inhibitory effects on the growth of transplantable tumors even under conditions of severe immunosuppression.
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Antineoplásicos/farmacología , Virus del Orf/metabolismo , Animales , Linfocitos B/inmunología , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Femenino , Humanos , Sistema Inmunológico , Inmunoterapia/métodos , Interleucina-12/metabolismo , Melanoma Experimental , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Trasplante de Neoplasias , Virus del Orf/genética , Linfocitos T/inmunología , Factores de TiempoRESUMEN
Inactivated orf virus (ORFV, parapoxvirus ovis) induces antiviral activity in animal models of acute and chronic viral infections and exerts strong effects on human immune cells. ORFV activates antigen presenting cells (APC) via CD14 and, probably, Toll-like receptor signalling, and triggers the release of IFN-γ that has been identified as the key mediator of the antiviral activity. After delineating virus proteins as being the most likely active constituent, we aimed to characterize the ORFV proteins responsible for the therapeutic effect. By using a vaccinia virus/ORFV expression library we identified several multi-gene DNA fragments with strong immunomodulatory activity. Together these fragments contain 27 ORFs. The encoded proteins are related to virion structure and transcription but are otherwise unrelated. Two proteins were separately expressed and purified, and demonstrated immunostimulatory activity. Gene expression profiles induced by ORFV and the identified fragments were investigated by microarray analysis. Interestingly, all active fragments induced a similar gene-expression pattern, differing only in quantitative aspects. Obviously, several proteins of ORFV activate similar cellular pathways, modulating APC to generate a strong T-helper 1-dominated immune response. This was balanced by additional induction of immune dampening mechanisms, suggesting regulatory differences compared to single cytokine therapies. We conclude that ORFV may have the potential to enrich the armamentarium of antiviral therapies.
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Ectima Contagioso/inmunología , Virus del Orf/inmunología , Proteínas Virales/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Bovinos , Línea Celular , Ectima Contagioso/virología , Femenino , Humanos , Ratones , Virus del Orf/genética , Proteínas Virales/genéticaRESUMEN
Based on our former development candidate BAY 38-1315, optimization efforts led to the discovery of a novel chemical class of orally active cholesteryl ester transfer protein (CETP) inhibitors. The chromanol derivative 19b is a highly potent CETP inhibitor with favorable pharmacokinetic properties suitable for clinical studies. Chemical process optimization furnished a robust synthesis for a kilogram-scale process.
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Benzopiranos/química , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Cromanos/química , Compuestos de Espiro/química , Administración Oral , Animales , Benzopiranos/síntesis química , Benzopiranos/farmacocinética , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , HDL-Colesterol/metabolismo , Cromanos/síntesis química , Cromanos/farmacocinética , Perros , Humanos , Ratones , Ratones Transgénicos , Ratas , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Relación Estructura-ActividadRESUMEN
Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the transfer of cholesteryl esters from the atheroprotective high density lipoprotein (HDL) to the proatherogenic low density lipoprotein cholesterol (LDL) and very low density lipoprotein cholesterol (VLDL) leading to lower levels of HDL but raising the levels of proatherogenic LDL and VLDL. Inhibition of CETP is considered a potential approach to treat dyslipidemia. However, discussions regarding the role of CETP-mediated lipid transfer in the development of atherosclerosis and CETP inhibition as a potential strategy for prevention of atherosclerosis have been controversial. Although many animal studies support the hypothesis that inhibition of CETP activity may be beneficial, negative phase III studies on clinical endpoints with the CETP inhibitor torcetrapib challenged the future perspectives of CETP inhibitors as potential therapeutic agents. The review provides an update on current understanding of the molecular mechanisms involved in CETP activity and its inhibition.
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Anticolesterolemiantes/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Anticolesterolemiantes/química , Proteínas de Transferencia de Ésteres de Colesterol/genética , Ensayos Clínicos como Asunto , Diseño de Fármacos , HumanosRESUMEN
In the course of our efforts to identify orally active cholesteryl ester transfer protein (CETP) inhibitors, we have continued to explore tetrahydrochinoline derivatives. Based on BAY 19-4789 structural modifications led to the discovery of novel cycloalkyl substituted compounds. Thus, example 11b is a highly potent CETP inhibitor both in vitro and in vivo in transgenic mice with favourable pharmacokinetic properties for clinical development.
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Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Hipolipemiantes/química , Quinolinas/química , Animales , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Perros , Humanos , Hipolipemiantes/síntesis química , Hipolipemiantes/farmacocinética , Ratones , Ratones Transgénicos , Quinolinas/síntesis química , Quinolinas/farmacocinética , Quinolinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Tetrahidronaftalenos/químicaRESUMEN
BACKGROUND: Increasing the efficacy of chemotherapeutics by reducing chemoresistance may be a useful strategy in cancer therapy. Constitutive activation of nuclear factor-kappa B (NF-kappaB) is a hallmark of various cancers, including melanoma, which is almost universally resistant to chemotherapy. NF-kappaB is regulated by inhibitory kappaB (IkappaB) proteins, which are in turn phosphorylated by the IkappaB kinase (IKK) complex. METHODS: The effect on NF-kappaB activity of a novel small-molecule inhibitor of the beta subunit of IKK (KINK-1; kinase inhibitor of nuclear factor-kappaB-1) was assessed by measuring phosphorylation of the alpha subunit of IkappaB by immunoblotting, DNA binding by electrophoretic mobility shift assays, and nuclear translocation of NF-kappaB using immunofluorescence. Regulation of NF-kappaB-dependent gene expression was determined by microarray analysis, real-time and semiquantitative reverse transcription polymerase chain reaction (RT-PCR), and Western blot analyses. The effects of KINK-1 (alone and in combination with cytostatic agents) on melanoma cells were characterized by assessing proliferation, soft agar colony formation, and markers of apoptosis. The antitumoral efficacy of KINK-1 in combination with the cytostatic agents doxorubicin or camptothecin (all injected intraperitoneally) was tested in vivo by measuring lung weight and counting metastases in C57BL6 mice (groups of six) bearing metastases of melanoma cells. All statistical tests were two-sided. Results KINK-1 strongly suppressed both constitutive and induced NF-kappaB activity in melanoma cells. It reduced the expression of NF-kappaB-dependent gene products that regulate proliferation, cytokine production, and antiapoptotic responses but exhibited little antiproliferative or proapoptotic activity at the cellular level. However, KINK-1 markedly increased the activities of some cytostatic agents in vitro and abrogated doxorubicin-induced NF-kappaB activation. Combined treatment of C57BL6 mice that had been injected with melanoma cells with KINK-1 and doxorubicin or camptothecin reduced metastases and pulmonary tumor mass compared with either treatment alone (mean lung weight 19 days after injection of melanoma cells of mice treated with 3 mg/kg KINK-1 alone, 1 mg/kg doxorubicin alone, and 1 mg/kg doxorubicin plus 3 mg/kg KINK-1 = 260 mg, 95% confidence interval (CI) = 216 to 305 mg; 268 mg, 95% CI = 224 to 313 mg; and 181 mg, 95% CI = 171 to 192 mg, respectively, P < .001 from t tests comparing mean lung weight of double-treated mice to that in mice treated with either compound alone). CONCLUSION: Inhibition of constitutive and induced IKKbeta-activity through treatment with KINK-1 might increase tumor susceptibility to chemotherapy.
Asunto(s)
Antineoplásicos/farmacología , Quinasa I-kappa B/antagonistas & inhibidores , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , FN-kappa B/antagonistas & inhibidores , Oxazinas/farmacología , Piridinas/farmacología , Animales , Antineoplásicos/efectos adversos , Apoptosis/efectos de los fármacos , Western Blotting , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Ensayo de Cambio de Movilidad Electroforética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Melanoma/enzimología , Melanoma/secundario , Ratones , Mitosis/efectos de los fármacos , Oxazinas/efectos adversos , Piridinas/efectos adversos , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Inactivated parapoxvirus ovis (Orf virus; PPVO) recently displayed strong immunostimulating and modulating capacities in several animal models for acute and chronic virus infections through the induction of gamma interferon (IFN-gamma) as a key mediator of antiviral activity. The data presented in this work demonstrate that inactivated PPVO has strong effects on cytokine secretion by human immune cells, including the upregulation of inflammatory and Th1-related cytokines (IFN-gamma, tumor necrosis factor alpha [TNF-alpha], interleukin 6 [IL-6], IL-8, IL-12, and IL-18) as well as anti-inflammatory and Th2-related cytokines (IL-4, IL-10, and IL-1 receptor antagonist [IL-1ra]). Studies on the mechanism of action revealed virus particles to be the effective components of the preparation. The virus particles activate monocytes or other antigen-presenting cells (APC), e.g., plasmacytoid dendritic cells, through signaling over CD14 and a Toll-like receptor and the intracellular presence of certain PPVO-specific components. The activation of monocytes or APC is followed by the release of early proinflammatory cytokines (TNF-alpha, IL-6, and IL-8) as well as the Th1-related cytokines IL-12 and IL-18. Both IL-18 and IL-12 are involved in PPVO-mediated IFN-gamma release by T cells and/or NK cells. The proinflammatory response is accompanied by the induction of anti-inflammatory and Th2-related cytokines (IL-4, IL-10, and IL-1ra), which exert a limiting efffect on the inflammatory response induced by PPVO. We conclude that the induction of a natural immune response with physiologically significant amounts of different cytokines and with antiviral potential might provide advantages over existing antiviral immunotherapies.
Asunto(s)
Citocinas/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Virus del Orf/inmunología , Células TH1/inmunología , Células TH1/metabolismo , Células Cultivadas , Proteínas del Sistema Complemento/inmunología , Concanavalina A/inmunología , Citocinas/inmunología , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Interleucina-18/metabolismo , Receptores de Lipopolisacáridos/inmunología , Receptores de Lipopolisacáridos/metabolismo , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Virus del Orf/fisiología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Virus Vaccinia/inmunología , Virus Vaccinia/fisiología , Virión/inmunología , Virión/fisiologíaRESUMEN
It is known that some viruses are able to induce vigorous immune reactions. This study shows that inactivated parapoxvirus ovis (Orf virus), strain D1701 (PPVO), induces an autoregulatory cytokine response that involves the upregulation of IL-12, IL-18, IFN-gamma and other T helper 1-type cytokines and their subsequent downregulation, which is accompanied by induction of IL-4. An increase in IL-10 expression was also found in the livers of PPVO-treated mice. PPVO protects mice from lethal herpes simplex virus type 1 infection and guinea pigs from recurrent genital herpes disease. With dosages as low as 500 000 virus particles, PPVO is more potent than the current standard 3TC therapy in hepatitis B virus transgenic mice. No signs of inflammation or any other side effects were observed. PPVO induces IL-12, TNF-alpha and, together with a suboptimal concentration of Concanavalin A, IFN-gamma in human peripheral blood leukocytes as well. The principle of an autoregulatory cytokine induction by an inactivated virus might have advantages over existing immune therapies and it is concluded that inactivated PPVO should be investigated further for its potential use in antiviral therapy.