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  • Fagone, Paolo  (66)
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  • 1
    Language: English
    In: International Journal of Molecular Medicine, September 2011, Vol.28(3), pp.437-442
    Description: Preclinical studies have shown that the anti-glucocorticoid drug mifepristone effectively inhibits HIV replication both in vitro and in vivo. However, the drug did not demonstrate anti-HIV activity in a previous phase I/II study when administered at the daily dose of 75-225 mg. The aim of this study was to assess whether mifepristone may exert antiretroviral activity or influence immunological parameters when administered orally at daily doses of 150 or 300 mg in highly active antiretroviral therapy (HAART)-naïve HIV-infected patients. We performed an open label non-randomized phase II study that included 26 patients who underwent 28 days of once daily oral administration of 150 (12 subjects) or 300 mg (14 subjects) of mifepristone. A total of 3 patients dropped out of the study, respectively 1 in the 150 mg dose group and 2 in the 300 mg dose group. The main hemato­chemical alterations reported were hypokalemia and increase in the blood levels of cortisol, especially in those patients that received mifepristone at the dose of 300 mg/day. Although we observed a trend of reduced viral load along the study in both groups, statistical significance was not achieved for either the primary nor the secondary endpoints. In summary, mifepristone treatment was well-tolerated but it failed to significantly influence viro-immunological parameters in HAART-naïve HIV-infected patients.
    Keywords: Surgical Stapler;
    ISSN: 1107-3756
    E-ISSN: 1791244X
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  • 2
    In: International Journal of Cancer, 15 April 2017, Vol.140(8), pp.1713-1726
    Description: The possible use of HIV protease inhibitors (HIV‐PI) as new therapeutic option for the treatment of cancer primarily originated from their success in treating HIV‐related Kaposi's sarcoma (KS). While these findings were initially attributed to immune reconstitution and better control of oncogenic viral infections, the number of reports on solid tumors, KS, lymphoma, fibrosarcoma, multiple myeloma and prostate cancer suggest other mechanisms for the anti‐neoplastic activity of PIs. However, a major drawback for the possible adoption of HIV‐PIs in the therapy of cancer relies on their relatively weak anticancer potency and important side effects. This has propelled several groups to generate derivatives of HIV‐PIs for anticancer use, through modifications such as attachment of different moieties, ligands and transporters, including saquinavir‐loaded folic acid conjugated nanoparticles and nitric oxide (NO) derivatives of HIV‐PIs. In this article, we discuss the current preclinical and clinical evidences for the potential use of HIV‐PIs, and of novel derivatives, such as saquinavir‐NO in the treatment of cancer.
    Keywords: Hiv Protease Inhibitors ; Saquinavir‐No ; Cancer Therapeutics
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 3
    Language: English
    In: European Journal of Pharmacology, 05 September 2018, Vol.834, pp.92-102
    Description: Gasotransmitters are a group of gaseous molecules, with pleiotropic biological functions. These molecules include nitric oxide (NO), hydrogen sulfide (H S), and carbon monoxide (CO). Abnormal production and metabolism of these molecules have been observed in several pathological conditions. The understanding of the role of gasotransmitters in the immune system has grown significantly in the past years, and independent studies have shed light on the effect of exogenous and endogenous gasotransmitters on immune responses. Moreover, encouraging results come from the efficacy of NO-, CO- and H S -donors in preclinical animal models of autoimmune, acute and chronic inflammatory diseases. To date, data on the influence of gasotransmitters in immunity and immunopathology are often scattered and partial, and the scarcity of clinical trials using NO-, CO- and H S -donors, reveals that more effort is warranted. This review focuses on the role of gasotransmitters in the immune system and covers the evidences on the possible use of gasotransmitters for the treatment of inflammatory conditions.
    Keywords: Gasotransmitter ; Nitric Oxide ; Hydrogen Sulfide ; Carbon Monoxide ; Immune System ; Eae ; Neuroinflammation ; Multiple Sclerosis ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0014-2999
    E-ISSN: 1879-0712
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  • 4
    Language: English
    In: Parkinson's Disease, Sept-Oct, 2012
    Description: 17[alpha]-Ethynyl-androst-5-ene-3[beta],7[beta],17[beta]-triol (HE3286) is a synthetic androstenetriol in Phase II clinical development for the treatment of inflammatory diseases. HE3286 was evaluated for blood-brain barrier (BBB) permeability in mice, and efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson's disease (PD). We found that HE3286 freely penetrated the BBB. HE3286 treatment significantly improved motor function compared to vehicle in the rotarod test (mean 58.2 sec versus 90.9 sec, P〈 0.0001), and reduced inflammatory mediator gene expression in the brain (inducible nitric oxide synthase, 20%, P = 0.002; tumor necrosis factor a, 40%, P = 0.038, and interleukin-1[beta], 33%, P = 0.02) measured by reversetranscriptase polymerase chain reaction. Brain tissue histopathology and immunohistochemistry showed that HE3286 treatment increased the numbers of tyrosine hydroxylase-positive cells by 17% compared to vehicle (P = 0.003), and decreased the numbers of damaged neurons by 38% relative to vehicle (P = 0.029). L-3,4-dihydroxyphenylalanine (L-DOPA) efficacy was not enhanced by concurrent administration of HE3286. HE3286 administration prior to MPTP did not enhance efficacy. Our data suggest a potential role for HE3286 in PD treatment, and provides incentive for further investigation.
    ISSN: 2042-0080
    Source: Cengage Learning, Inc.
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  • 5
    Language: English
    In: Parkinson's Disease, Sept-Oct, 2012
    Description: 17[alpha]-Ethynyl-androst-5-ene-3[beta],7[beta],17[beta]-triol (HE3286) is a synthetic androstenetriol in Phase II clinical development for the treatment of inflammatory diseases. HE3286 was evaluated for blood-brain barrier (BBB) permeability in mice, and efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson's disease (PD). We found that HE3286 freely penetrated the BBB. HE3286 treatment significantly improved motor function compared to vehicle in the rotarod test (mean 58.2 sec versus 90.9 sec, P〈 0.0001), and reduced inflammatory mediator gene expression in the brain (inducible nitric oxide synthase, 20%, P = 0.002; tumor necrosis factor a, 40%, P = 0.038, and interleukin-1[beta], 33%, P = 0.02) measured by reversetranscriptase polymerase chain reaction. Brain tissue histopathology and immunohistochemistry showed that HE3286 treatment increased the numbers of tyrosine hydroxylase-positive cells by 17% compared to vehicle (P = 0.003), and decreased the numbers of damaged neurons by 38% relative to vehicle (P = 0.029). L-3,4-dihydroxyphenylalanine (L-DOPA) efficacy was not enhanced by concurrent administration of HE3286. HE3286 administration prior to MPTP did not enhance efficacy. Our data suggest a potential role for HE3286 in PD treatment, and provides incentive for further investigation.
    ISSN: 2042-0080
    Source: Cengage Learning, Inc.
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  • 6
    Language: English
    In: Drug Discovery Today, 2011, Vol.16(15), pp.715-721
    Description: Patients undergoing long-term highly active antiretroviral therapy treatment are probably at a higher risk of various HIV-related complications. Hyperactivation of The mammalian target of rapamycin (mTOR) has been found to contribute to dysregulated apoptosis and autophagy which determine CD4 -T-cell loss, impaired function of innate immunity and development of neurocognitive disorders. Dysregulated mTOR activation has also been shown to play a key part in the development of nephropathy and in the pathogenesis of HIV-associated malignancies. These studies strongly support a multifunctional key role for mTOR in the pathogenesis of HIV-related disorders and suggest that specific mTOR inhibitors could represent a novel approach for the prevention and treatment of these pathologies.
    Keywords: Engineering ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 1359-6446
    E-ISSN: 1878-5832
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  • 7
    Language: English
    In: European Journal of Pharmacology, 2011, Vol.658(2), pp.257-262
    Description: 5-Androstene-3β,7β,17β-triol (AET) is a naturally occurring anti-inflammatory adrenal steroid that limits acute and chronic inflammation. HE3286 (17α-ethynyl-5-androstene-3β,7β,17β-triol) is a synthetic derivative of AET with improved pharmaceutical properties and efficacy in some animal models of autoimmunity. Here, daily oral doses of HE3286 led to a suppression of spontaneous autoimmune diabetes in the non-obese diabetic mouse model of type 1 diabetes mellitus when administered either shortly before or after the first incidence of disease onset. Efficacy was associated with reduced insulitis and a suppression of the pathogenic T helper cell type 1 and type 17 phenotypes in peripheral lymphoid organs. These results demonstrate that daily oral treatment with HE3286 administrated relatively late in the destructive autoimmune process led to a suppression of type 1 diabetes mellitus onset and of the pathological inflammatory status, supporting its clinical evaluation in type 1 diabetes mellitus subjects.
    Keywords: Diabetes ; Il-17 ; Androstene ; Nod ; Steroid ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0014-2999
    E-ISSN: 1879-0712
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  • 8
    Language: English
    In: Cancer Research, 2017-09-01, Vol.77(17), pp.4562-4566
    Description: Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease...
    Keywords: Medicin Och Hälsovetenskap ; Klinisk Medicin ; Cancer Och Onkologi ; Medical And Health Sciences ; Clinical Medicine ; Cancer And Oncology ; Cancer-Immunotherapy ; Metastatic Melanoma ; Cell Therapy ; T-Cells ; Reactivity ; Responses ; Oncology
    ISSN: 0008-5472
    E-ISSN: 15387445
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  • 9
    Language: English
    In: Inflammation Research, 2012, Vol.61(10), pp.1131-1139
    Description: Objective: To evaluate the heat shock protein (HSP) variation during the differentiation and polarization of human macrophages. Methods: Gene expression analysis was investigated by real-time PCR from mRNA of human monocytes obtained from the buffy coats of healthy volunteers, polarized to classically activated macrophages (or M1), whose prototypical activating stimuli are interferon-gamma and lipopolysaccharide, and alternatively activated macrophages (or M2) obtained by interleukin-4 exposure. The modulation of HSPs at the transcriptomic levels was investigated using oligonucleotide microarray in the process of primary human monocyte-to-macrophage maturation and subsequent polarization into M1 or M2 cells. Results: We found that 11 HSPs transcripts were modulated throughout monocyte-to-macrophage differentiation. Furthermore a considerable effect on HSP expression was detected in conjunction with the M1 polarizing condition. This affected 21 transcripts in M1 cells, with 6 of them significantly upregulated in comparison to unpolarized macrophages, whereas 15 were downregulated. Slight changes in HSPs expression were observed in M2 cells when compared to unpolarized macrophages. Under these circumstances only five transcripts were significantly modulated. Interestingly, HSPBAP1 was the only HSP significantly downregulated in both M1 and M2 conditions parallel to a significant up-regulation of its target HSPB1. Conclusion: Our study revealed that monocytes undergoing maturation differentially regulate the expression of several members of HSPs and that distinct patterns of HSP expression characterize the M1 and M2 effector stages of macrophage life.
    Keywords: Heat shock proteins ; Monocytes/macrophages ; Differentiation
    ISSN: 1023-3830
    E-ISSN: 1420-908X
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  • 10
    Language: English
    In: Acta Histochemica, October 2015, Vol.117(8), pp.824-828
    Description: Recent immunohistochemical analyses have showed that cyclin D1 is expressed in soft tissue Ewing's sarcoma/peripheral neuroectodermal tumor (PNET) of childhood and adolescents, while it is undetectable in both embryonal and alveolar rhabdomyosarcoma. In the present paper, microarray analysis provided evidence of a significant upregulation of cyclin D1 in Ewing's sarcoma as compared to normal tissues. In addition, we confirmed our previous findings of a significant over-expression of cyclin D1 in Ewing sarcoma as compared to rhabdomyosarcoma. Bioinformatic analysis also allowed to identify some other genes, strongly correlated to cyclin D1, which, although not previously studied in pediatric tumors, could represent novel markers for the diagnosis and prognosis of Ewing's sarcoma/PNET. The data herein provided support not only the use of cyclin D1 as a diagnostic marker of Ewing sarcoma/PNET but also the possibility of using drugs targeting cyclin D1 as potential therapeutic strategies.
    Keywords: Cyclin D1 ; Ewing'S Sarcoma/Peripheral Primitive Neuroectodermal Tumor ; Rhabdomyosarcoma ; Microarray ; Bioinformatic Analysis ; Biology ; Chemistry
    ISSN: 0065-1281
    E-ISSN: 1618-0372
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