Recent advances in nanosystems and strategies for vaginal delivery of antimicrobials

Vaginal infections such as bacterial vaginosis (BV), chlamydia, gonorrhea, genital herpes, candidiasis, and trichomoniasis affect millions of women each year. They are caused by an overgrowth of microorganisms, generally sexually transmitted, which in turn can be favored by alterations in the vaginal flora. Conventional treatments of these infections consist in systemic or local antimicrobial therapies. However, in the attempt to reduce adverse effects and to contrast microbial resistance and infection recurrences, many efforts have been devoted to the development of vaginal systems for the local delivery of antimicrobials. Several topical dosage forms such as aerosols, lotions, suppositories, tablets, gels, and creams have been proposed, although they are sometimes ineffective due to their poor penetration and rapid removal from the vaginal canal. For these reasons, the development of innovative drug delivery systems, able to remain in situ and release active agents for a prolonged period, is becoming more and more important. Among all, nanosystems such as liposomes, nanoparticles (NPs), and micelles with tunable surface properties, but also thermogelling nanocomposites, could be exploited to improve local drug delivery, biodistribution, retention, and uptake in vulvovaginal tissues. The aim of this review is to provide a survey of the variety of nanoplatforms developed for the vaginal delivery of antimicrobial agents. A concise summary of the most common vaginal infections and of the conventional therapies is also provided

Assessment of in‐situ gelling microemulsion systems upon temperature and dilution condition for corneal delivery of bevacizumab

Bevacizumab (BVZ), a recombinant humanized monoclonal antibody, has recently been proposed as a topical application in the treatment of anterior segment neovascularization; however, as there are some disadvantages in the administration of common eye-drops, ophthalmic topical drug delivery systems are under study to improve the precorneal residence time, reducing the frequency of administration. In this work, oil-in-water and water-in-oil BVZ-loaded microemulsions are developed, able to increase their viscosity, either by the formation of a liquid-crystalline structure upon aqueous dilution, thanks to the presence of Epikuron® 200 and polysorbate 80, or by body-temperature-induced jellification for the presence of Pluronic® F127 aqueous solution as an external phase. In oil-in-water microemulsion, hydrophobic ion pairs of BVZ were also prepared, and their incorporation was determined by release studies. Microemulsions were characterized for rheological behavior, corneal opacity, in vitro corneal permeation, and adhesion properties. The studied microemulsions were able to incorporate BVZ (from 1.25 to 1.6 mg/mL), which maintained dose-dependent activity on retinal pigment epithelial ARPE-19 cell lines. BVZ loaded in microemulsions permeated the excised cornea easier (0.76–1.56% BVZ diffused, 4–20% BVZ accumulated) than BVZ commercial solution (0.4% BVZ diffused, 5% accumulated) and only a mild irritation effect on the excised cornea was observed. The good adhesion properties as well the increased viscosity after application, under conditions that mimic the corneal environment (from 1 × 103 to more than 100 × 103 mPa·s), might prolong precorneal residence time, proving these systems could be excellent topical BVZ release systems

Developing actively targeted nanoparticles to fight cancer: Focus on italian research

Active targeting is a valuable and promising approach with which to enhance the therapeutic efficacy of nanodelivery systems, and the development of tumor-targeted nanoparticles has therefore attracted much research attention. In this field, the research carried out in Italian Pharmaceutical Technology academic groups has been focused on the development of actively targeted nanosystems using a multidisciplinary approach. To highlight these efforts, this review reports a thorough description of the last 10 years of Italian research results on the development of actively targeted nanoparticles to direct drugs towards different receptors that are overexpressed on cancer cells or in the tumor microenvironment. In particular, the review discusses polymeric nanocarriers, liposomes, lipoplexes, niosomes, solid lipid nanoparticles, squalene nanoassemblies and nanobubbles. For each nanocarrier, the main ligands, conjugation strategies and target receptors are described. The literature indicates that polymeric nanoparticles and liposomes stand out as key tools for improving specific drug delivery to the site of action. In addition, solid lipid nanoparticles, squalene nanoparticles and nanobubbles have also been successfully proposed. Taken together, these strategies all offer many platforms for the design of nanocarriers that are suitable for future clinical translation

Global patterns of body size evolution in squamate reptiles are not driven by climate

Aim: Variation in body size across animal species underlies most ecological and evolutionary processes shaping local- and large-scale patterns of biodiversity. For well over a century, climatic factors have been regarded as primary sources of natural selection on animal body size, and hypotheses such as Bergmann's rule (the increase of body size with decreasing temperature) have dominated discussions. However, evidence for consistent climatic effects, especially among ectotherms, remains equivocal. Here, we test a range of key hypotheses on climate-driven size evolution in squamate reptiles across several spatial and phylogenetic scales. Location: Global. Time period: Extant. Major taxa studied: Squamates (lizards and snakes). Methods: We quantified the role of temperature, precipitation, seasonality and net primary productivity as drivers of body mass across ca. 95% of extant squamate species (9,733 spp.). We ran spatial autoregressive models of phylogenetically corrected median mass per equal-area grid cell. We ran models globally, across separate continents and for major squamate clades independently. We also performed species-level analyses using phylogenetic generalized least square models and linear regressions of independent contrasts of sister species. Results: Our analyses failed to identify consistent spatial patterns in body size as a function of our climatic predictors. Nearly all continent- and family-level models differed from one another, and species-level models had low explanatory power. Main conclusions: The global distribution of body mass among living squamates varies independently from the variation in multiple components of climate. Our study, the largest in spatial and taxonomic scale conducted to date, reveals that there is little support for a universal, consistent mechanism of climate-driven size evolution within squamates

Age-stratified interview campaigns suggest ongoing decline of a threatened tortoise species in the West African Sahel

Face-to-face interviews with local populations are often used to determine the distribution and population trends of elusive threatened species. Although interviewee responses may suffer from some bias, historical trends in the status of a species can be investigated from age-structured questionnaires. In this paper, we tested this idea by analysing separately answers given by older (> 60 years age) and younger respondents (25-44 years old) on the status of the African spurred tortoise, (Centrochelys sulcata), a charismatic large reptile listed as Vulnerable in the IUCN Red List. We interviewed 619 persons (hunters/farmers/cattle farmers) of different ages in three of the species’ habitat countries (Burkina Faso, Niger and Nigeria). Interviewees were asked whether in their experience the tortoise was common, rare or absent. By using Generalized Linear Models we showed that the probability to answer “common” increased with age in Nigeria and Burkina Faso, whereas the probability of responding “absent” declined with age in Nigeria and Niger. There were no significant effects of age for the answer 'rare' in any country and no differences were found between villages in any of the studied countries. From our data we conclude that spurred tortoises have been extirpated in 16.7% of study sites. We argue that if statistical differences emerge between answers given by respondents of various age classes on the population status of a target species, it is possible to conclude that the species’ situation may have significantly changed during the last 30-40 years

The global biogeography of lizard functional groups

Aim: Understanding the mechanisms determining species richness is a primary goal of biogeography. Richness patterns of sub-groups within a taxon are usually assumed to be driven by similar processes. However, if richness of distinct ecological strategies respond differently to the same processes, inferences made for an entire taxon may be misleading. We deconstruct the global lizard assemblage into functional groups and examine the congruence among richness patterns between them. We further examine the species richness – functional richness relationship to elucidate the way functional diversity contributes to the overall species richness patterns. Location: Global. Methods: Using comprehensive biological trait databases we classified the global lizard assemblage into ecological strategies based on body size, diet, activity times and microhabitat preferences, using Archetypal Analysis. We then examined spatial gradients in the richness of each strategy at the one-degree grid cell, biomes and realm scales. Results: We found that lizards can best be characterized by seven 'ecological strategies': scansorial, terrestrial, nocturnal, herbivorous, fossorial, large and semiaquatic. There are large differences among the global richness patterns of these strategies. While the major richness hotspot for lizards in general is in Australia, several strategies exhibit highest richness in the Amazon Basin. Importantly, the global maximum in lizard species richness is achieved at intermediate values of functional diversity and increasing functional diversity further result in a shallow decline of species richness. Main conclusions: The deconstruction of the global lizard assemblage along multiple ecological axes offers a new way to conceive lizard diversity patterns. It suggests that local lizard richness mostly increases when species belonging to particular ecological strategies become hyper-diverse there, and not because more ecological types are present in the most species rich localities. Thus maximum richness and maximum ecological diversity do not overlap. These results shed light on the global richness pattern of lizards, and highlight previously unidentified spatial patterns in understudied functional groups

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)