From HDAC to Voltage-Gated Ion Channels: What's Next? The Long Road of Antiepileptic Drugs Repositioning in Cancer.

Cancer is a major health burden worldwide. Although the plethora of molecular targets identified in the last decades and the deriving developed treatments, which significantly improved patients' outcome, the occurrence of resistance to therapies remains the major cause of relapse and mortality. Thus, efforts in identifying new markers to be exploited as molecular targets in cancer therapy are needed. This review will first give a glance on the diagnostic and therapeutic significance of histone deacetylase (HDAC) and voltage gated ion channels (VGICs) in cancer. Nevertheless, HDAC and VGICs have also been reported as molecular targets through which antiepileptic drugs (AEDs) seem to exert their anticancer activity. This should be claimed as a great advantage. Indeed, due to the slowness of drug approval procedures, the attempt to turn to off-label use of already approved medicines would be highly preferable. Therefore, an updated and accurate overview of both preclinical and clinical data of commonly prescribed AEDs (mainly valproic acid, lamotrigine, carbamazepine, phenytoin and gabapentin) in breast, prostate, brain and other cancers will follow. Finally, a glance at the emerging attempt to administer AEDs by means of opportunely designed drug delivery systems (DDSs), so to limit toxicity and improve bioavailability, is also given.

Systematic review of the effect of D-mannose with or without other drugs in the treatment of symptoms of urinary tract infections/cystitis (Review).

Several studies, reviews and meta-analyses have documented that D-mannose use lowers the risk of recurrent urinary tract infections (UTI), but its role in the treatment of UTI/cystitis-related symptoms is unclear. In particular, no systematic review has analyzed the role of treatment with D-mannose in acute UTI/cystitis. In this paper, we systematically reviewed the published data on the effect of D-mannose, alone or in association with other compounds, on the typical symptoms of UTI/cystitis. PubMed/Medline and EMBASE databases were searched, from 1990 to January 2022, using combinations of the following keywords: 'urinary tract infections', 'cystalgia', 'recurrent next urinary tract infection', 'cystitis', 'mannose', 'mannoside', 'D-mannose', 'bacteriuria', 'pyuria', 'pyelocystitis' with the appropriate Boolean modifiers (Limits: Human, English, full article). Studies were selected for the systematic review if they were clinical studies and reported original data, the number of patients using D-mannose alone or in association with other treatments, and the number of patients with symptoms of UTI/cystitis at trial entry and after the follow-up period. A total of seven studies were identified. D-mannose was given alone in two studies, and was associated with cranberry extract, Morinda citrifolia fruit extract, pomegranate extract, fructo-oligosaccharides, lactobacilli, and N-acetylcysteine in the others. All studies reported that symptoms decreased after treatment with D-mannose. Despite the limitations of the studies, the consistent results observed among all studies give support to the general findings that D-mannose may be useful in the treatment of UTI/cystitis symptoms.

Bone Safety of Dolutegravir-Containing Regimens in People Living with HIV: Results from a Real-World Cohort.

OBJECTIVE: Few data exist about the effect of dolutegravir (DTG) on bone mineral density (BMD) in real life. The aim of this study was to determine rates of change in BMD over time in people living with HIV (PLWH) treated with DTG. DESIGN: The SCOLTA project is a multicenter observational study enrolling HIV-infected people who start newly commercialized drugs prospectively, with the aim of identifying toxicities and adverse events (AE) in a real-life setting. METHODS: Dual-energy X-ray absorptiometry at the femoral neck (FN) and lumbar spine (LS) was performed at study entry (baseline, BL) and after 96 weeks. Percentage BMD change from BL was evaluated using a general linear model, including factors potentially associated with bone loss. RESULTS: One hundred and sixty PLWH were enrolled (26.3% female, mean age 49.9 ± 11.2 years) from April 2015 to April 2017. Overall, we could calculate BMD change from baseline, for at least one site, in 133 subjects (83.1%). After a median of 102 weeks (IQR: 90-110), mean FN BMD increased, but not significantly, whereas LS BMD showed a significant mean increase of 13.1 (95% confidence interval, CI: 1.7-24.6) mg/cm3 (+1.6%, 95% CI: 0.3%, 2.8%) after a median time of 102 weeks (IQR: 84-110). As regards LS BMD, patients with osteopenia/osteoporosis at study entry experienced a high increase from baseline (20.6, 95% CI: 3.1, 38.1 mg/cm3), as well as experienced subjects (16.9, 95% CI: 4.7, 29.2 mg/cm3) and those on vitamin D supplementation (26.8, 95% CI: 7.7, 45.9 mg/cm3). CONCLUSION: Dolutegravir-containing regimens could reduce the negative impact of antiretroviral therapy on bone, especially in patients with low BMD.

Coffee and caffeine intake and male infertility: a systematic review.

BACKGROUND: Semen quality, a predictor of male fertility, has been suggested declining worldwide. Among other life style factors, male coffee/caffeine consumption was hypothesized to influence semen parameters, but also sperm DNA integrity. To summarize available evidence, we performed a systematic review of observational studies on the relation between coffee/caffeine intake and parameters of male fertility including sperm ploidy, sperm DNA integrity, semen quality and time to pregnancy. METHODS: A systematic literature search was performed up to November 2016 (MEDLINE and EMBASE). We included all observational papers that reported the relation between male coffee/caffeine intake and reproductive outcomes: 1. semen parameters, 2. sperm DNA characteristics, 3. fecundability. All pertinent reports were retrieved and the relative reference lists were systematically searched in order to identify any potential additional studies that could be included. RESULTS: We retrieved 28 papers reporting observational information on coffee/caffeine intake and reproductive outcomes. Overall, they included 19,967 men. 1. Semen parameters did not seem affected by caffeine intake, at least caffeine from coffee, tea and cocoa drinks, in most studies. Conversely, other contributions suggested a negative effect of cola-containing beverages and caffeine-containing soft drinks on semen volume, count and concentration. 2. As regards sperm DNA defects, caffeine intake seemed associated with aneuploidy and DNA breaks, but not with other markers of DNA damage. 3. Finally, male coffee drinking was associated to prolonged time to pregnancy in some, but not all, studies. CONCLUSIONS: The literature suggests that caffeine intake, possibly through sperm DNA damage, may negatively affect male reproductive function. Evidence from epidemiological studies on semen parameters and fertility is however inconsistent and inconclusive. Well-designed studies with predefined criteria for semen analysis, subject selection, and life style habits definition, are essential to reach a consistent evidence on the effect of caffeine on semen parameters and male fertility.

HIV Clinical Pathway: A New Approach to Combine Guidelines and Sustainability of Anti-Retroviral Treatment in Italy.

The present article describes the case study of a "real world" HIV practice within the debate concerning the strategic role of Clinical Governance (CG) tools in the management of a National Healthcare System's sustainability. The study aimed at assessing the impact of a Clinical Pathway (CP) implementation, required by the Regional Healthcare Service, in terms of effectiveness (virological and immunological conditions) and efficiency (economic resources absorption), from the budget holder perspective. Data derived from a multi-centre cohort of patients treated in 6 Hospitals that provided care to approximately 42% of the total HIV+ patients, in Lombardy Region, Italy. Two phases were compared: Pre-CP (2009-2010) vs. Post-CP implementation (2011-2012). All HIV infected adults, observed in the participating hospitals during the study periods, were enrolled and stratified into the 3 categories defined by the Regional CP: first-line, switch for toxicity/other, and switch for failure. The study population was composed of 1,284 patients (Pre-CP phase) and 1,135 patients (Post-CP phase). The results showed that the same level of virological and immunological effectiveness was guaranteed to HIV+ patients: 81.2% of Pre-CP phase population and 83.2% of Post-CP phase population had undetectable HIV-RNA (defined as <50 copies/mL) at 12-month follow up. CD4+ cell counts increased by 28 ± 4 cells/mm3 in Pre-CP Phase and 39 ± 5 cells/mm3 in Post-CP Phase. From an economic point of view, the CP implementation led to a substantial advantage: the mean total costs related to the management of the HIV disease (ART, hospital admission and laboratory tests) decreased (-8.60%) in the Post-CP phase (p-value < 0.0001). Results confirmed that the CP provided appropriateness and quality of care, with a cost reduction for the budget holder.

Coffee and caffeine intake and risk of endometriosis: a meta-analysis.

PURPOSE: The potential association between endometriosis and coffee/caffeine consumption has been analysed in several epidemiological studies. In order to establish whether caffeine influences the risk of endometriosis, we provide to summarize the evidence from published studies on this issue. METHODS: We performed a meta-analysis of epidemiological studies published up to January 2013. We computed summary relative risks (RR) of endometriosis for any, high and low versus no coffee/caffeine consumption. RESULTS: We identified a total eight studies, six case-control and two cohort studies, including a total of 1,407 women with endometriosis. The summary RR for any versus non-consumption were 1.26 [95% confidence interval (CI) 0.95-1.66] for caffeine and 1.13 (95% CI 0.46-2.76) for coffee consumption; the overall estimate was 1.18 (95% CI 0.92-1.49). The summary RR were 1.09 (95% CI 0.84-1.42) and 1.09 (95% CI 0.89-1.33) for high and low caffeine consumption as compared to no consumption, respectively. CONCLUSION: The present meta-analysis provided no evidence for an association between coffee/caffeine consumption and the risk of endometriosis. Coffee/caffeine consumption, as currently used in diet, does not carry a health risk.

Diet in pregnancy and risk of small for gestational age birth: results from a retrospective case-control study in Italy.

This study aims to analyse the association between selected dietary indicators during pregnancy and the risk of small for gestational age (SGA) births in a South European population. This is a case-control study. Cases were 555 women who delivered SGA babies at the Luigi Mangiagalli Clinic of Milan and the Obstetric and Gynecology Clinic of the University of Verona. The controls were women who gave birth at term (≥37 weeks of gestation) to healthy infants with normal weight in the same clinics. Dietary information was collected with a food frequency questionnaire. Women with SGA babies reported a more frequent consumption of meat and olive oil, and a less frequent consumption of fish and eggs. Women with high consumption of olive oil had an increased risk of delivering an SGA baby [odds ratio (OR) 1.6, 95% confidence interval (CI) 1.0-2.5]. The multivariate OR for high meat consumption was 1.4 (95% CI 1.1-1.9); for fish 0.8 (95% CI 0.6-1.0, χ² for trend 4.0, P = 0.045 ) and for egg 0.7 (95% CI 0.5-0.9). After allowing for factors generally known to be associated with SGA, we have shown that eating more fish and eggs, and less meat and possibly olive oil, are associated with a lower risk of delivering an SGA baby.

Effects of soy isoflavones and genistein on glucose metabolism in perimenopausal and postmenopausal non-Asian women: a meta-analysis of randomized controlled trials.

OBJECTIVE: Several randomized controlled trials (RCTs) have examined the role of soy isoflavones on cardiovascular risk factors in perimenopausal and postmenopausal women and have yielded inconsistent results. This meta-analysis aimed to assess the overall effect of soy isoflavones on glucose metabolism: fasting blood glucose, insulin, and insulin resistance. METHODS: We searched for all articles published in English and indexed in Medline from January 1990 to December 2009. We included RCTs for soy isoflavone supplementation in perimenopausal and postmenopausal women not taking hormone therapy, selecting non-Asian women only. The main outcomes were fasting blood glucose changes from baseline. RESULTS: We identified 10 eligible RCTs containing blood glucose data of 794 women. The main result was that soy isoflavones did not affect fasting blood glucose significantly. Under a random-effects model, the average difference in fasting blood glucose values between women assigned to isoflavones and women assigned to placebo was -2.16 mg/dL (95% CI, -5.21 to 0.89 mg/dL; P = 0.17). In genistein studies, the mean difference was -7.15 mg/dL (95% CI, -11.47 to -2.82). However, the effects on insulin and homeostasis model assessment insulin resistance were significant: -1.37 microIU/mL (95% CI, -1.92 to -0.81 microIU/mL) and -0.39 (95% CI, -0.65 to -0.14), respectively. Subgroup analyses did not show a significant effect of isoflavone dose, whereas isoflavone mixtures and genistein had a different effect on fasting blood glucose. CONCLUSIONS: This meta-analysis of RCTs showed that isoflavone use was not associated with a significant glycemia reduction in perimenopausal and postmenopausal non-Asian women. However, the few studies that reported insulin and homeostasis model assessment insulin resistance changes suggested that soy isoflavones and genistein alone had a beneficial effect on glucose metabolism.