Vitamin D as Modulator of Drug Concentrations: A Study on Two Italian Cohorts of People Living with HIV Administered with Efavirenz

To date, vitamin D seems to have a significant role in affecting the prevention and immunomodulation in COVID-19 disease. Nevertheless, it is important to highlight that this pro-hormone has other several activities, such as affecting drug concentrations, since it regulates the expression of cytochrome P450 (CYP) genes. Efavirenz (EFV) pharmacokinetics is influenced by CYPs, but no data are available in the literature concerning the association among vitamin D levels, seasonality (which affects vitamin D concentrations) and EFV plasma levels. For this reason, the aim of this study was to evaluate the effect of 25-hydroxy vitamin D (25(OH)D3) levels on EFV plasma concentrations in different seasons. We quantified 25(OH)D3 by using chemiluminescence immunoassay, whereas EFV plasma concentrations were quantified with the HPLC–PDA method. A total of 316 patients were enrolled in Turin and Rome. Overall, 25(OH)D3levels resulted in being inversely correlated with EFV concentrations. Some patients with EFV levels higher than 4000 ng/mL showed a deficient 25(OH)D3 concentration in Turin and Rome cohorts and together. EFV concentrations were different in patients without vitamin D supplementation, whereas, for vitamin D-administered individuals, no difference in EFV exposure was present. Concerning seasonality, EFV concentrations were associated with 25(OH)D3 deficiency only in winter and in spring, whereas a significant influence was highlighted for 25(OH)D3 stratification for deficient, insufficient and sufficient values in winter, spring and summer. A strong and inverse association between 25(OH)D3and EFV plasma concentrations was suggested. These data suggest that vitamin D is able to affect drug exposure in different seasons; thus, the achievement of the clinical outcome could be improved by also considering this pro-hormone

Non-hormonal treatment of vulvo-vaginal atrophy-related symptoms in post-menopausal women

In post-menopausal period vulvo-vaginal atrophy (VVA)-related symptoms may seriously affect women's quality of life. Hormonal replacement therapy effectively relieves these symptoms but it is not always safe or accepted, and a non-hormonal treatment is often needed instead. Over a period of 12 weeks, we tested the effect of a twice-a-week vulvo-vaginal application of a hyaluronic acid, AC collagen, isoflavones and vitamins-based cream (Perilei Pausa(®)) on 35 women in post-menopausal period, reporting VVA-related symptoms. After 12 weeks of treatment with Perilei Pausa(®) a significant improvement in vaginal dryness, vulvo-vaginal itching, dyspareunia (P < 0.001), dysuria (P = 0.02), nocturia (P = 0.009) and pollakiuria (P = 0.005) was reported by the women. Colposcopical score assessing the intensity of atrophic colpitis, cervico-vaginal paleness and petechiae was also reduced (P = 0.037, P = 0.016 and P = 0.032, respectively). No significant difference in terms of maturation value of cervico-vaginal epithelium was observed. In conclusion, Perilei Pausa(®) may represent an effective and safe alternative treatment of symptomatic VVA in post-menopausal women

Early expansion of myeloid-derived suppressor cells inhibits SARS-CoV-2 specific T-cell response and may predict fatal COVID-19 outcome

The immunological mechanisms underlying the clinical presentation of SARS-CoV-2 infection and those influencing the disease outcome remain to be defined. Myeloid-derived suppressor cells (MDSC) have been described to be highly increased during COVID-19, however, their role remains elusive. We performed an in depth analysis of MDSC in 128 SARS-CoV-2 infected patients. Polymorphonuclear (PMN)-MDSC expanded during COVID-19, in particular in patients who required intensive care treatments, and correlated with IL-1β, IL-6, IL-8, and TNF-α plasma levels. PMN-MDSC inhibited T-cells IFN-γ production upon SARS-CoV-2 peptides stimulation, through TGF-β- and iNOS-mediated mechanisms, possibly contrasting virus elimination. Accordingly, a multivariate regression analysis found a strong association between PMN-MDSC percentage and fatal outcome of the disease. The PMN-MDSC frequency was higher in non-survivors than survivors at the admission time, followed by a decreasing trend. Interestingly, this trend was associated with IL-6 increase in non-survivors but not in survivors. In conclusion, this study indicates PMN-MDSC as a novel factor in the pathogenesis of SARS-CoV2 infection, and open up to new therapeutic options

Marked increase in etravirine and saquinavir plasma concentrations during atovaquone/proguanil prophylaxis

The case of a 32-year-old Caucasian female with multi-drug resistant HIV-1 subtype B infection treated with a salvage regimen including maraviroc, raltegravir, etravirine and unboosted saquinavir who started atovaquone/proguanil prophylaxis, is reported. The potential interactions between atovaquone/proguanil and these anti-retroviral drugs are investigated. Pharmacokinetic analyses documented a marked increase in etravirine and saquinavir plasma concentrations (+55% and +274%, respectively), but not in raltegravir and maraviroc plasma concentrations. The evidence that atovaquone/proguanil significantly interacts with etravirine and saquinavir, but not with raltegravir and maraviroc, suggests that the mechanism of interaction is related to cytochrome P450

Cross-subtype Immunity against Avian Influenza in Persons Recently Vaccinated for Influenza

Seasonal influenza vaccination may induce heterosubtypic immunity against avian influenza virus (H5N1)

Análisis de proyectos de tecnología Blockchain en el sector gubernamental en Argentina y el mundo : caso registro de patentes del Instituto Nacional de Propiedad Industrial de Argentina

Fil: Tempestilli, Federico José. Universidad de San Andrés. Escuela de Negocios; Argentina.Prince, Alejandr

Surgical management of acute subdural hematoma: a comparison between decompressive craniectomy and craniotomy on patients treated from 2010 to the present in a single center.

BACKGROUND: Acute subdural hematoma represents an important cause of disability and mortality. Its surgical treatment takes advantage of two surgical procedures: craniotomy and decompressive craniectomy, nevertheless the effectiveness of one procedure rather than the other is still debated. This study was conducted to identify which of the surgical procedures could provide better neurological outcome after traumatic acute subdural hematoma; as a secondary endpoint, the study tries to settle pre-operative prognostic factors useful to identify the most appropriate surgical technique for every specific patient and kind of trauma. METHODS: A retrospective analysis was performed on patients who underwent craniotomy or decompressive craniectomy between January 2010 and July 2017 at the Department of Neurosurgery of Umberto I Hospital in Rome. Ninty-four patients were selected and reviewing clinical records, pre-operative and post-operative's data were collected (e.g. GCS, mechanism of trauma, CT findings, mortality rate, neurological outcome at discharge, mRS at 12 months). Data were analyzed using X2 test and the F test. The multivariate analysis was performed using a stepwise logistic regression. The analysis was carried out using SPSS software and a p value ≤ 0.05 was considered significant. RESULTS: On 94 patients 46.8% underwent decompressive craniectomy and 53.2% underwent craniotomy. The mortality rate was (53.2%); it was shown to be related to a GCS 60 years old (p = 0.0001). Decompressive craniectomy was performed most frequently for high energy trauma (p =0.006); the mean GCS at admission was 7.91 for decompressive craniectomy and 9.64 for craniotomy (p = 0.05). Patients who underwent decompressive craniectomy and survived surgery showed a better neurological outcome compared to those who underwent craniotomy (p = 0.009). The evaluation of mRS after 12 months didn't show a statistically significant difference between the two groups. CONCLUSIONS: In case of high energy trauma and GCS ≤8 different neurosurgeons decided to perform most frequently decompressive craniectomy rather than craniotomy. Furthermore, even if not related to survival rate, decompressive craniectomy showed a better neurological outcome especially in patients with GCS ≤8 at admission. In conclusion, even if prospective studies are required, these results depict the current attitude about the choice between craniotomy and decompressive craniectomy

Analysis of single-nucleotide polymorphisms (SNPs) in human CYP3A4 and CYP3A5 genes: potential implications for the metabolism of HIV drugs

Background: Drug metabolism via the cytochrome P450 (CYP450) system has emerged as an important determinant in the occurrence of several drug interactions (adverse drug reactions, reduced pharmacological effect, drug toxicities). In particular, CYP3A4 and CYP3A5 (interacting with more than 60% of licensed drugs) exhibit the most individual variations of gene expression, mostly caused by single nucleotide polymorphisms (SNPs) within the regulatory region of the CYP3A4 and CYP3A5 genes which might affect the level of enzyme production. In this study, we sought to improve the performance of sensitive screening for CYP3A polymorphism detection in twenty HIV-1 infected patients undergoing lopinavir/ritonavir (LPV/r) monotherapy. Methods: The study was performed by an effective, easy and inexpensive home-made Polymerase Chain Reaction Direct Sequencing approach for analyzing CYP3A4 and CYP3A5 genes which can detect both reported and unreported genetic variants potentially associated with altered or decreased functions of CYP3A4 and CYP3A5 proteins. Proportions and tests of association were used. Results: Among the genetic variants considered, CYP3A4*1B (expression of altered function) was only found in 3 patients (15%) and CYP3A5*3 (expression of splicing defect) in 3 other patients (15%). CYP3A5*3 did not appear to be associated with decreased efficacy of LPV/r in any patient, since none of the patients carrying this variant showed virological rebound during LPV/r treatment or low levels of TDM. In contrast, low-level virological rebound was observed in one patient and a low TDM level was found in another; both were carrying CYP3A4*1B. Conclusions: Our method exhibited an overall efficiency of 100% (DNA amplification and sequencing in our group of patients). This may contribute to producing innovative results for better understanding the inter-genotypic variability in gene coding for CYP3A, and investigating SNPs as biological markers of individual response to drugs requiring metabolism via the cytochrome P450 system

CD3ζ down-modulation may explain Vγ9Vδ2 T lymphocyte anergy in HIV-infected patients

The aim of the present study was to explain the observed anergy of Vγ9Vδ2 T cells from human immunodeficiency virus (HIV)-positive patients. CD3ζ expression and interferon (IFN)-γ production by Vγ9Vδ2 T cells from HIV-positive and HIV-negative subjects were analyzed. We demonstrated that Vγ9Vδ2 T cells from HIV-infected patients expressed a lower level of CD3ζ than did Vγ9Vδ2 T cells from healthy donors. A direct correlation was found between CD3ζ expression and IFN-γ production capability by Vγ9Vδ2 T cells. However, activation of protein kinase C by phorbol myristate acetate is able to restore CD3ζ expression and IFN-γ production. Our findings may contribute to clarification of the molecular mechanisms of Vγ9Vδ2 T cell anergy found in HIV-positive patients. © 2008 by the Infectious Diseases Society of America. All rights reserved