The safety of tattoo inks: Possible options for a common regulatory framework

Tattoo prevalence has been increasing in the last 25 years, but specific regulations on tattoo inks are still missing. In the European Union, no supranational regulation is available and only few national provisions cover them. In the United States, tattoo inks are classified as cosmetics but are not approved for injection into the dermis. Health risks for consumers may derive from microbiological contamination and the presence of toxic substances or nanomaterials. However, current regulations and non-binding recommendations, where present, only address the microbiological and chemical risks, completely overlooking nanotoxicity. The aim of this paper is to promote awareness of the risks associated with tattoo inks and the nanomaterials contained therein. In particular, the need for a harmonised regulation or, at least, a set of minimal requirements is highlighted to improve the safety of tattoo inks and market surveillance by regulatory authorities

Design and development of topical liposomal formulations in a regulatory perspective

The skin is the absorption site for drug substances intended to treat loco-regional diseases, although its barrier properties limit the permeation of drug molecules. The growing knowledge of the skin structure and its physiology have supported the design of innovative nanosystems (e.g. liposomal systems) to improve the absorption of poorly skin-permeable drugs. However, despite the dozens of clinical trials started, few topically applied liposomal systems have been authorized both in the EU and the USA. Indeed, the intrinsic complexity of the topically applied liposomal systems, the higher production costs, the lack of standardized methods and the more stringent guidelines for assessing their benefit/risk balance can be seen as causes of such inefficient translation. The present work aimed to provide an overview of the physicochemical and biopharmaceutical characterization methods that can be applied to topical liposomal systems intended to be marketed as medicinal products, and the current regulatory provisions. The discussion highlights how such methodologies can be relevant for defining the critical quality attributes of the final product, and they can be usefully applied based on the phase of the life cycle of a liposomal product: to guide the formulation studies in the early stages of development, to rationally design preclinical and clinical trials, to support the pharmaceutical quality control system and to sustain post-marketing variations. The provided information can help define harmonized quality standards able to overcome the case-by-case approach currently applied by regulatory agencies in assessing the benefit/risk of the topically applied liposomal systems. Graphical abstract: [Figure not available: see fulltext.

Fixed Versus Free Combinations of Antihypertensive Drugs: Analyses Of Real-World Data Of Persistence With Therapy In Italy

Purpose: To analyse the pattern of use and cost of antihypertensive drugs in new users in an Italian population, and explore the patient/treatment factors associated with the risk of therapy discontinuation. Patients and methods: In this retrospective study, information was collected from a population-based electronic primary-care database. Persistence with medication use 1 year from therapy initiation was evaluated for each user using the gap method. Each new user was classified according to his/her pattern of use as: \u201ccontinuer\u201d, \u201cdiscontinuer\u201d \u201cswitching\u201d or \u201cadd-on\u201d. A Cox regression model was used to analyse the factors influencing therapy discontinuation. Primary-care costs comprised specialists\u2019 visits, diagnostic procedures and pharmacologic therapies. Results: Among 14,999 subjects included in persistence analyses, 55.1% of cases initially started on monotherapy were classified as discontinuers vs 36.5% of cases taking combination therapy (42.3% vs 32.7%, respectively, for free and fixed combinations, P < 0.01). Old age, high cardiovascular risk and being in receipt of fixed-combination therapy were associated with greater persistence. Overall, the primary-care cost/person/year of hypertension management was 3c\u20ac95.3 (IQR, 144.9). The monotherapy cost was \u20ac88 per patient (IQR, 132.9), and that for combination therapy was \u20ac151\ub1148.3. The median cost/patient with a fixed combination was lower than that for a free combination (\u20ac98.4 (IQR, 155.3) and \u20ac154.9 (IQR, 182.6), respectively). Conclusion: The initial type of therapy prescribed influences persistence. Prescribing fixed combinations might be a good choice as initial therapy

Study of fractal objects by means of low angle light scattering

Low angle elastic light scattering techniques have been successfully applied to the study of solid particle size distributions. In this work we evaluate the possibility of extending this method to the study of fractal objects, like aggregating colloids. We present computer simulations on a peculiar iterative inversion scheme to recover the cluster gyration radiuses distribution. The computer simulations are made assuming realistic estimates of the noise associated to the measurements and the results of the data inversion procedure will be compared with the input data. The rate of convergence with the number of iterations will also be discussed. \ua9 1987 SPIE

Combined effects of nutrients and climate change interaction on Piburger See (Austria)–Results from paleo- and neolimnology

Piburger See is a soft-water mountain lake located in the Central Eastern Alps (47°11’42’’N, 10°53’18’’E, Tyrol, Austria). The increase in recreational activities, tourism, and the application of fertilizer on nearby fields, resulted in enhanced primary production and rising hypolimnetic oxygen depletion in the lake during the 1950s and 1960s (Pechlaner, 1968). Lake restoration started in 1970 by exporting anoxic and nutrient-rich hypolimnetic waters with an Olszewski tube, and by reducing external nutrient loading by altering fertilizer application and by diverting sewage from a public bath. Lake oxygenation rapidly improved after 1970 (Pechlaner, 1979), while the response of total phosphorus (TP) and phytoplankton biomass to lake restoration was delayed by two decades (Fig. 1). Since the early 2000s, phytoplankton biovolume has increased again, suggesting a reversing trend in lake trophic status (Tolotti et al., 2012). Simultaneously, small changes in TP were recorded (Fig. 1). Although Piburger See was part of the OECD study on eutrophication and is currently included in the Austrian LTER network, the 45 year-long data-base includes several data gaps (e.g. for phytoplankton). To compensate for gaps in moniroring data, a paleolimnological study has been carried out on a radiometrically dated sediment core in order to reconstruct the lakes’ trophic state since the late-19th century and to define the reference conditions for the lake (Thies et al., 2012). Limnological data recorded during the last four decades provided the validation of the inferred TP concentration (Fig. 2). Changes in phytoplankton biomass and species composition were analyzed in relation to nutrients and water temperature. Epilimnetic temperatures of Piburger See, reconstructed by long-term air temperature records, showed a pronounced increase during the mid-1940s and also since the late-20th century. Both periods also show increasing algal growth and changes in diatom species composition (i.e. increase in centric diatoms and recent blooms in Asterionella formosa). The combination of paleo- and neolimnology allowed the analysis of the role of climate and nutrients in driving phytoplankton changes in Piburger See. In particular, the study on sediments showed that long-term phytoplankton changes were mainly attributed to increasing lake temperature, while nutrients acted as modulating factor. On the other side, short-term changes in the phytoplankton of Piburger See since the 2000s were explained by varying nutrient concentrations and ratios (i.e. nitrogen and silica), while rising water temperature and enhanced thermal stability regulated the inter-annual lake variability. Our results underline that the combined impact of nutrients and climate on phytoplankton development can sustain short-time phytoplankton pulses, and thus mimic short-term increases in the trophic level of less productive lakes

Ferrocene-loaded nanocarrier as probe for cochlear biodistribution study

Purpose: The fate of drug nanocarriers (NCs) in the inner ear remains elusive. The aim of the work is to develop ferrocene (FER)-loaded NCs to elucidate the cochlear biodistribution of such NCs. Methods: FER-NCs were prepared by surfactant free solvent-diffusion technique using a mixture of PLGA/PCL-PEG (ratios 1/1, 1/2) dissolved in acetone. FER-NCs were washed and freeze-dried. TEM analyses were carried out to study the FER-NC morphology. Lactose, mannitol, sucrose were tested at different cryoprotectant/nanocarrier ratios (0/1, 1/1, 3/1, 5/1) to stabilize FER-NCs during freeze-drying. The stability of the FER-NCs was checked by measuring particle size and zeta potential (ZP) immediately after water dispersion and after 12 days. FER-NCs were placed in the round window (RW) niche of the middle ear in guinea pigs. After 48 hours, the animals were sacrificed, the cochlea isolated and prepared for TEM. Results: The Ferrocene-loaded NCs had a mean diameter of 201.2\ub157.7, PDI of 0.328\ub10.074 and ZP of -20.2\ub14.8mV. PLGA/PCLPEG NCs of 1/2 allowed higher EE% (85.50\ub111.15) than ones made with 1/1 ratio (42.93\ub13.65). The FER-NCs appeared spherical with smooth surface. All cryoprotectants increased RES-NCs stability during the freeze-drying process. However, lactose, especially when used in 3/1 ratio, was more effective than other ones after dispersion and during 12-day stability studies. FER-NCs crossed the RW membrane and were found adjacent or in the cells lining the scala tympani of the cochlea. Hearing was normal after RW placement of NCs. Conclusion: FER-NCs were successfully prepared by emulsion-diffusion technique and the 1/2 PLGA/PLC-PEG ratio was selected in term of best encapsulation efficiency. Moreover, lactose (3/1 cryoprotectant/NCs ratio) guaranteed FER-NCs stability during freeze-drying process and maintained FER-NCs stable in suspension for at least 12 days. When placed into the RW niche, FER-NCs enter the cochlea and do not appear to cause hearing loss

Orodispersible dosage forms : biopharmaceutical improvements and regulatory requirements

Orodispersible dosage forms have a growing presence in the pharmaceutical market because their administration can improve the bioavailability of some drugs and their prescription can ameliorate patient adherence and/or compliance. Here, we review the main features of orodispersible tablets, including oral lyophilisates, and orodispersible films along with their main production technologies. We summarize the bioavailability data and critically discussed their potential to improve patient adherence and/or compliance. We revisit this information in light of both the European Union (EU) and US regulatory frameworks, focusing on the differences in the definitions of such dosage forms and the requirements for marketing authorization. The technological and biopharmaceutical improvements of orodispersible dosage forms are reviewed in the light of regulatory requirements

Interactions of temperature and nutrient changes: effects on phytoplankton in the Piburger See (Tyrol, Austria)

1. Contemporary limnological and palaeolimnological data from Piburger See (Eastern Alps, Austria) allowed the reconstruction of its trophic state since the late 19th century and the assessment of changes in phytoplankton biomass and species composition in relation to selected environmental parameters. 2. A radiometrically dated sediment core from Piburger See was analysed for geochemical parameters, spheroidal carbonaceous particles (SCPs), bacterial and algal pigments, and diatoms. The low SCP sediment inventory assigns Piburger See to the ‘cleaner’ sites in Europe with respect to fossil-fuel related air pollution. The sedimentary pigment and diatom record reveals moderate eutrophication during the 20th century, followed by a slow re-oligotrophication since the mid-1980s because of lake restoration starting in 1970. 3. Epilimnetic temperature for Piburger See was reconstructed using air temperature records. A pronounced temperature increase has been recorded during the mid-1940s and since the late-20th century, both promoting algal growth and changes in species composition (e.g. increase in centric diatoms and recent bloom of Asterionella formosa). 4. Climate scenarios project additional substantial warming for this mountain lake by the end of the 21st century which will be most pronounced during the growing season. The predicted change in lake water temperature and thermal dynamics represents a key driver for the trophic and ecological status of Piburger See in the futur