The evolution of the illegal market of falsified medicines and the experience of the Italian OMCL: from control to research.

Abstrac

The Slowly Aggregating Salmon Calcitonin: A Useful Tool for the Study of the Amyloid Oligomers Structure and Activity

Amyloid proteins of different aminoacidic composition share the tendency to misfold and aggregate in a similar way, following common aggregation steps. The process includes the formation of dimers, trimers, and low molecular weight prefibrillar oligomers, characterized by the typical morphology of globules less than 10 nm diameter. The globules spontaneously form linear or annular structures and, eventually, mature fibers. The rate of this process depends on characteristics intrinsic to the different proteins and to environmental conditions (i.e., pH, ionic strength, solvent composition, temperature). In the case of neurodegenerative diseases, it is now generally agreed that the pathogenic aggregates are not the mature fibrils, but the intermediate, soluble oligomers. However, the molecular mechanism by which these oligomers trigger neuronal damage is still unclear. In particular, it is not clear if there is a peculiar structure at the basis of the neurotoxic effect and how this structure interacts with neurons. This review will focus on the results we obtained using salmon Calcitonin, an amyloid protein characterized by a very slow aggregation rate, which allowed us to closely monitor the aggregation process. We used it as a tool to investigate the characteristics of amyloid oligomers formation and their interactions with neuronal cells. Our results indicate that small globules of about 6 nm could be the responsible for the neurotoxic effects. Moreover, our data suggest that the rich content in lipid rafts of neuronal cell plasma membrane may render neurons particularly vulnerable to the amyloid protein toxic effect

Health risks related to illegal and on-line sale of drugs and food supplements: results of a survey on marketed products in Italy from 2011 to 2013

Objectives. The increasing illegal and on-line market of medicines and food supplements is helping the widespread diffusion of harmful counterfeit and forbidden products among consumers of developed countries. The objectives of this survey were the description of the main frauds recognized by public officers and the detection of illegal or counterfeit drugs and food supplements.Methods. Medicines and food supplements found by Police forces on the illegal market or resulting from seizures made by Italian Customs authorities were visually inspected and analysed to evaluate their quality and the presence of other undeclared substances.Results. The visual inspection and the chemical analysis revealed unsuitable packaging (mostly lacking of adequate information for consumers), absence of the declared active substances and presence of undeclared active substances. Products containing doping agents, illegal substances and active ingredients requiring medical supervision were found.Conclusion. The present work confirmed the health risk associated with assumption of medicines purchased on the Internet and from the illegal supply chain and evidenced a new threat to consumer safety related to the presence of pharmaceutical active ingredients in food supplements claiming to contain only “natural ingredients”.

Medicines informal market in Congo, Burundi and Angola: counterfeit and sub-standard antimalarials

BACKGROUND: The presence of counterfeits and sub-standards in African medicines market is a dramatic problem that causes many deaths each year. The increase of the phenomenon of pharmaceutical counterfeiting is due to the rise of the illegal market and to the impossibility to purchase branded high cost medicines. METHODS: In this paper the results of a quality control on antimalarial tablet samples purchased in the informal market in Congo, Burundi and Angola are reported. The quality control consisted in the assay of active substance by means of validated liquid chromatographic methods, uniformity of mass determination, disintegration and dissolution tests. Moreover, a general evaluation on label and packaging characteristics was performed. RESULTS: The results obtained on thirty antimalarial tablet samples containing chloroquine, quinine, mefloquine, sulphadoxine and pyrimethamine showed the presence of different kinds of problems: a general problem concerning the packaging (loose tablets, packaging without Producer name, Producer Country and sometimes without expiry date); low content of active substance (in one sample); different, non-declared, active substance (in one sample); sub-standard technological properties and very low dissolution profiles (in about 50% of samples). This last property could affect the bioavailability and bioequivalence in comparison with branded products and could be related to the use of different excipients in formulation or bad storage conditions. CONCLUSION: This paper evidences that the most common quality problem in the analysed samples appears to be the low dissolution profile. Here it is remarked that the presence of the right active substance in the right quantity is not a sufficient condition for a good quality drug. Dissolution test is not less important in a quality control and often evidences in vitro possible differences in therapeutic efficacy among drugs with the same active content. Dissolution profile can be dramatically affected by the choice of excipients in the oral solid formulation and, in many cases, is out of specifications due to the absence of formulation studies by producers of developing countries

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Calcitonin Forms Oligomeric Pore-Like Structures in Lipid Membranes

Calcitonin is a polypeptidic hormone involved in calcium metabolism in the bone. It belongs to the amyloid protein family, which is characterized by the common propensity to aggregate acquiring a β-sheet conformation and include proteins associated with important neurodegenerative diseases. Here we show for the first time, to our knowledge, by transmission electron microscopy (TEM) that salmon-calcitonin (sCT) forms annular oligomers similar to those observed for β-amyloid and α-sinuclein (Alzheimer's and Parkinson's diseases). We also investigated the interaction between sCT and model membranes, such as liposomes, with particular attention to the effect induced by lipid “rafts” made of cholesterol and G(M1). We observed, by TEM immunogold labeling of sCT, that protein binding is favored by the presence of rafts. In addition, we found by TEM that sCT oligomers inserted in the membrane have the characteristic pore-like morphology of the amyloid proteins. Circular dichroism experiments revealed an increase in β-content in sCT secondary structure when the protein was reconstituted in rafts mimicking liposomes. Finally, we showed, by spectrofluorimetry experiments, that the presence of sCT allowed Ca(2+) entry in rafts mimicking liposomes loaded with the Ca(2+)-specific fluorophore Fluo-4. This demonstrates that sCT oligomers have ion-channel activity. Our results are in good agreement with recent electrophysiological studies reporting that sCT forms Ca(2+)-permeable ion channels in planar model membranes. It has been proposed that, beyond the well-known interaction of the monomer with the specific receptor, the formation of Ca(2+) channels due to sCT oligomers could represent an extra source of Ca(2+) entry in osteoblasts. Structural and functional data reported here support this hypothesis

Counterfeit drugs detection by measurement of tablets and secondary packaging colour

The growth of pharmaceutical counterfeiting is a major public health problem. This growth is resulting in a proportional increase in the number of samples that medicines control laboratories have to test. Thus the need for simple and affordable preliminary screening methods to be used by inspectors to decide in the field whether to collect a sample for further laboratory analysis or not. This paper intends to evaluate the possibility to employ for preliminary examinations of suspicious samples an optical spectrophotometer (colorimeter) used in the graphic industry, capable of measuring the reflectance visible spectrum of solid materials. The colorimeter was tested on original and counterfeited Viagra, Cialis and Levitra by measuring the colour of tablets' surface and of a specific spot of the packages. Various batches of the original drugs were employed both to investigate precision and robustness of the technique and to build spectral libraries. These libraries were used to compare suspicious samples to the corresponding original by means of a wavelength distance pattern recognition method. The method was eventually tested on suspicious samples sized by police authorities in order to evaluate its effectiveness. The device resulted precise and robust toward ambient conditions changes, although some limits emerged: the libraries of original samples need a frequent update and a lower precision is to be expected for tablets which surface is extremely convex. (C) 2010 Elsevier B.V. All rights reserved

An Apparent Diffusion Coefficient-based machine learning model can improve Prostate Cancer detection in the grey area of the PI-RADS 3 category: a single-centre experience

The Prostate Imaging and Reporting Data System (PI-RADS) has a key role in the management of prostate cancer (PCa). However, the clinical interpretation of PI-RADS 3 score lesions may be challenging and misleading, thus postponing PCa diagnosis to biopsy outcome. Multiparametric magnetic resonance imaging (mpMRI) radiomic analysis may represent a stand-alone non invasive tool for PCa diagnosis. Hence, this study aims at developing a mpMRI-based radiomic PCa diagnostic model in a cohort of PI-RADS 3 lesions. We enrolled 133 patients with 155 PI-RADS 3 lesions, 84 of which had PCa confirmation by fusion biopsy. Local radiomic features were generated from apparent diffusion coefficient maps, and the four most informative were selected using LASSO, the Wilcoxon rank-sum test (p &lt; 0.001), and support vector machines (SVMs). The selected features where augmented and used to train an SVM classifier, externally validated on a holdout subset. Linear and second-order polynomial kernels were exploited, and their predictive performance compared through receiver operating characteristics (ROC)-related metrics. On the test set, the highest performance, equally for both kernels, was specificity = 76%, sensitivity = 78%, positive predictive value = 80%, and negative predictive value = 74%. Our findings substantially improve radiologist interpretation of PI-RADS 3 lesions and let us advance towards an image-driven PCa diagnosis