The first-generation phosphodiesterase 5 inhibitors and their pharmacokinetic issue.

BACKGROUND: Erectile dysfunction (ED) is a relatively frequent disease that negatively impacts the overall quality of life, well-being, and relationships. Although the use of phosphodiesterase 5 inhibitors (PDE5is) has revolutionized the treatment of ED, a high percentage of ED patients discontinue PDE5i treatment. OBJECTIVES: (i) To analyze the reasons for patient dissatisfaction leading to PDE5i discontinuation; (ii) analyze the pharmacokinetics of new formulations focusing on the time needed to reach an effective plasma concentration of PDE5is (Tonset ) following drug intake; and (iii) summarize the physicochemical properties of sildenafil to understand which excipients may increase the absorption rate. MATERIAL AND METHODS: An online PubMed literature search was conducted to identify English language publications from inception to January 2019. RESULTS: The main reasons for patient dissatisfaction when using PDE5is on demand are the relatively long Tonset after taking vardenafil and sildenafil, including formulations such as film-coated tablets, fine granules, orally disintegrating tablets (ODTs), and oral thin films (ODFs). The relatively long Tonset , further worsened when accompanied by eating, highlights the following: (i) the need for planning intercourse, determining partner-related issues; (ii) issues when having sex before the maximum effect of the drug; and (iii) lower drug-related placebo effects. Some data suggest that sildenafil is a 'difficult' molecule, but Tonset can be improved following absorption by buccal mucosa using appropriate excipients. CONCLUSIONS: We conclude that several ODT and ODF formulations can improve the 'discretion' issue because they are taken without water, but they have similar pharmacokinetics to corresponding film-coated tablet formulations. One ODF formulation of sildenafil was characterized by a shorter Tonset and could potentially increase patient satisfaction following treatment. However, more clinical studies are needed to confirm the findings. Surfactants and ascorbic acid appear to be crucial excipients for achieving a high absorption rate, but more studies are needed.

L-GILZ binds p53 and MDM2 and suppresses tumor growth through p53 activation in human cancer cells.

The transcription factor p53 regulates the expression of genes crucial for biological processes such as cell proliferation, metabolism, cell repair, senescence and apoptosis. Activation of p53 also suppresses neoplastic transformations, thereby inhibiting the growth of mutated and/or damaged cells. p53-binding proteins, such as mouse double minute 2 homolog (MDM2), inhibit p53 activation and thus regulate p53-mediated stress responses. Here, we found that long glucocorticoid-induced leucine zipper (L-GILZ), a recently identified isoform of GILZ, activates p53 and that the overexpression of L-GILZ in p53(+/+) HCT116 human colorectal carcinoma cells suppresses the growth of xenografts in mice. In the presence of both p53 and MDM2, L-GILZ binds preferentially to MDM2 and interferes with p53/MDM2 complex formation, making p53 available for downstream gene activation. Consistent with this finding, L-GILZ induced p21 and p53 upregulated modulator of apoptosis (PUMA) expression only in p53(+/+) cells, while L-GILZ silencing reversed the anti-proliferative activity of dexamethasone as well as expression of p53, p21 and PUMA. Furthermore, L-GILZ stabilizes p53 proteins by decreasing p53 ubiquitination and increasing MDM2 ubiquitination. These findings reveal L-GILZ as a regulator of p53 and a candidate for new therapeutic anti-cancer strategies for tumors associated with p53 deregulation.

Expansion of CD4+CD25-GITR+ regulatory T-cell subset in the peripheral blood of patients with primary Sjögren's syndrome: correlation with disease activity.

OBJECTIVES: CD4+CD25high regulatory T cells (TREG) represent a suppressive T cell subset deeply involved in the modulation of immune responses and eventually in the prevention of autoimmunity. Growing evidence demonstrated that patients with autoimmune and inflammatory chronic diseases display an impairment of TREG cells or activated effector T cells unresponsive to TREG. Glucocorticoid-induced TNFR-related protein (GITR) is a widely accepted marker of murine TREG cells, but little is known in humans. Aim of the present study was to investigate the characteristics of different subsets of TREG cells in Sjögren's syndrome and the potential role of GITR as marker of human TREG cells. METHODS: Fifteen patients with primary Sjogren's syndrome (SS) and 10 sex- and age-matched normal controls (NC) were enrolled. CD4+ T cells were magnetic sorted from peripheral blood by negative selection. Cell phenotype was analyzed through flow-cytometry using primary and secondary antibodies. Disease activity was assessed using the EULAR Sjögren's syndrome disease activity index (ESSDAI). RESULTS: Although the proportion of circulating CD25highGITRhigh subset was similar in SS patients and NC, an expansion of the CD25-GITRhigh cell population was observed in the peripheral blood of SS patients. Interestingly, this expansion was more relevant in patients with inactive rather than active disease. CONCLUSIONS: The number of CD4+CD25-GITRhigh cells is increased in SS as compared to NC. Moreover, the fact that the expansion of this cell subset is prevalently observed in patients with inactive disease suggests that these cells may play a role in counteracting inflammatory response.