Corrigendum to "Utilisation Trend of Long-Acting Insulin Analogues including Biosimilars across Europe: Findings and Implications".

[This corrects the article DOI: 10.1155/2021/9996193.].

Challenges and Opportunities With Routinely Collected Data on the Utilization of Cancer Medicines. Perspectives From Health Authority Personnel Across 18 European Countries.

Background: Rising expenditure for new cancer medicines is accelerating concerns that their costs will become unsustainable for universal healthcare access. Moreover, early market access of new oncology medicines lacking appropriate clinical evaluation generates uncertainty over their cost-effectiveness and increases expenditure for unknown health gain. Patient-level data can complement clinical trials and generate better evidence on the effectiveness, safety and outcomes of these new medicines in routine care. This can support policy decisions including funding. Consequently, there is a need for improving datasets for establishing real-world outcomes of newly launched oncology medicines. Aim: To outline the types of available datasets for collecting patient-level data for oncology among different European countries. Additionally, to highlight concerns regarding the use and availability of such data from a health authority perspective as well as possibilities for cross-national collaboration to improve data collection and inform decision-making. Methods: A mixed methods approach was undertaken through a cross-sectional questionnaire followed-up by a focus group discussion. Participants were selected by purposive sampling to represent stakeholders across different European countries and healthcare settings. Descriptive statistics were used to analyze quantifiable questions, whilst content analysis was employed for open-ended questions. Results: 25 respondents across 18 European countries provided their insights on the types of datasets collecting oncology data, including hospital records, cancer, prescription and medicine registers. The most available is expenditure data whilst data concerning effectiveness, safety and outcomes is less available, and there are concerns with data validity. A major constraint to data collection is the lack of comprehensive registries and limited data on effectiveness, safety and outcomes of new medicines. Data ownership limits data accessibility as well as possibilities for linkage, and data collection is time-consuming, necessitating dedicated staff and better systems to facilitate the process. Cross-national collaboration is challenging but the engagement of multiple stakeholders is a key step to reach common goals through research. Conclusion: This study acts as a starting point for future research on patient-level databases for oncology across Europe. Future recommendations will require continued engagement in research, building on current initiatives and involving multiple stakeholders to establish guidelines and commitments for transparency and data sharing.

Regulatory aspects of biological medicines in Bosnia and Herzegovina.

The use of the biological medicines, also called "biologics," has contributed to the progress of the treatment of many chronic diseases, such as cancer, rheumatoid arthritis, Crohn's disease, multiple sclerosis, and psoriasis. However, biologicals are expensive for healthcare systems in several countries. Their availability has been a global issue, which has affected many patients that suffer from various diseases. A biosimilar medicine, also called "biosimilar," is a medicine with similar characteristics in terms of quality, biological activity, safety, and efficacy as the approved original biological medicine, known as "originator biologic." Biosimilars generate competition within the market because they lower the prices of biologics and thus allow for an increase in patient access. However, there are barriers when it comes to the acceptability rate of biosimilars and how interchangeable they are with the originator biologic. In this review, we present a national regulatory framework for biologics along with its limitations, a system of monitoring the safety profile of biologics, the guideline for interchangeability, and a list of approved and available biologics in Bosnia and Herzegovina. Additionally, recommendations were made here in order to provide opportunities for greater acceptance of biosimilars and better access to biologics. These recommendations include, but are not limited to, strengthening the national regulatory framework for biologics, capacity building, increasing awareness among healthcare providers for reporting adverse drug events and active pharmacovigilance, and better definitions of interchangeability. Finally, awareness among healthcare providers regarding biosimilars and biologics should be raised through continuous education and workshops, and by including this important topic in the graduate and postgraduate curriculum programs in the country.

Utilisation Trend of Long-Acting Insulin Analogues including Biosimilars across Europe: Findings and Implications.

BACKGROUND: Diabetes mellitus rates and associated costs continue to rise across Europe enhancing health authority focus on its management. The risk of complications is enhanced by poor glycaemic control, with long-acting insulin analogues developed to reduce hypoglycaemia and improve patient convenience. There are concerns though with their considerably higher costs, but moderated by reductions in complications and associated costs. Biosimilars can help further reduce costs. However, to date, price reductions for biosimilar insulin glargine appear limited. In addition, the originator company has switched promotional efforts to more concentrated patented formulations to reduce the impact of biosimilars. There are also concerns with different devices between the manufacturers. As a result, there is a need to assess current utilisation rates for insulins, especially long-acting insulin analogues and biosimilars, and the rationale for patterns seen, among multiple European countries to provide future direction. Methodology. Health authority databases are examined to assess utilisation and expenditure patterns for insulins, including biosimilar insulin glargine. Explanations for patterns seen were provided by senior-level personnel. RESULTS: Typically increasing use of long-acting insulin analogues across Europe including both Western and Central and Eastern European countries reflects perceived patient benefits despite higher prices. However, activities by the originator company to switch patients to more concentrated insulin glargine coupled with lowering prices towards biosimilars have limited biosimilar uptake, with biosimilars not currently launched in a minority of European countries. A number of activities were identified to address this. Enhancing the attractiveness of the biosimilar insulin market is essential to encourage other biosimilar manufacturers to enter the market as more long-acting insulin analogues lose their patents to benefit all key stakeholder groups. CONCLUSIONS: There are concerns with the availability and use of insulin glargine biosimilars among European countries despite lower costs. This can be addressed.

Pomegranate peel extract polyphenols attenuate the SARS-CoV-2 S-glycoprotein binding ability to ACE2 Receptor: In silico and in vitro studies.

The novel coronavirus disease (Covid-19) has become a major health threat globally. The interaction of SARS-CoV-2 spike (S) glycoprotein receptor-binding domain (RBD) with ACE2 receptor on host cells was recognized as the first step of virus infection and therefore as one of the primary targets for novel therapeutics. Pomegranate extracts are rich sources of bioactive polyphenols that were already recognized for their beneficial health effects. In this study, both in silico and in vitro methods were employed for evaluation of pomegranate peel extract (PoPEx), their major polyphenols, as well as their major metabolite urolithin A, to attenuate the contact of S-glycoprotein RBD and ACE2. Our results showed that PoPEx, punicalin, punicalagin and urolithin A exerted significant potential to block the S-glycoprotein-ACE2 contact. These in vitro results strongly confirm the in silico predictions and provide a valuable insight in the potential of pomegranate polyphenols for application in SARS-CoV-2 infection.

Adjuvant Treatment of the Salivary Duct Carcinoma with Her2 Overexpression.

Malignant salivary gland tumors form 11% of all head and neck tumors. Salivary duct carcinoma (SDC) of the parotid gland is an uncommon and highly aggressive tumor accounting for 2% of all salivary gland malignancies. The fourth edition of the WHO Classification of Head and Neck Tumors reported global annual incidence of 0.4-2.6/100,000 people. Standard treatment for SDC is wide surgical resection along with lymph node dissection followed by adjuvant radiation therapy. The role of adjuvant chemotherapy is not known. Here, we present a case of an SDC of the parotid gland in a 55-year-old female. She presented with a painless swelling behind her right ear. Surgery was performed, and total right parotidectomy was done along with selective neck dissection (levels II, III, VA). The pathology report concluded that it was a G3 (poorly differentiated) SDC (micropapillary variant) with lymphovascular and perineural invasion. The clinical stage of the disease was T4aN2bM0. Adjuvant therapy consisted of concurrent radiation (TD 66 Gy) and chemotherapy with weekly paclitaxel (45 mg/m2), carboplatin (AUC 1.5), and trastuzumab (2 mg/kg; THC) for 6 weeks followed by 4 cycles of THC every 3 weeks. Adjuvant trastuzumab was continued for a total of 1 year. She is still without the evidence of the disease 7 years later. The consensus regarding the use of adjuvant chemotherapy does not exist. Based on all the data that have been presented before, the conclusion is that we need new treatment modalities to improve the outome of this aggressive disease.

Availability and accessibility of monoclonal antibodies in Bosnia and Herzegovina: Findings and implications.

Background: Monoclonal antibodies (mAbs) represent the most numerous and significant group of biotherapeutics. While mAbs have undoubtedly improved treatment for many chronic diseases, including inflammatory diseases, they are typically expensive for health care systems and patients. Consequently, access to mAbs has been a problem for many patients especially among Central and Eastern European (CEE) countries. However, biosimilars can potentially help with costs, although there are concerns with their effectiveness and safety. This includes biosimilars for long-acting insulin analogues. Aim: Assess the availability and use of biological medicines, including biosimilars within Bosnia and Herzegovina (B&H). Methods: Assess the availability of mAbs via the current lists of approved and accessed mAbs versus those licenced in Europe and the United States and their utilisation, as well as specifically insulin glargine and its biosimilars, within B&H. Results: The availability of the mAbs in B&H appears satisfactory, which is encouraging. However, current usage is limited to a few mAbs which is a concern for subsequent patient care especially with limited use of biosimilars to address issues of affordability. We also see limited use of biosimilar insulin glargine. Conclusion: The limited use of mAbs including biosimilars needs to be addressed in B&H to improve the future care of patients within finite resources. We will monitor these developments.

Computational study of pomegranate peel extract polyphenols as potential inhibitors of SARS-CoV-2 virus internalization.

The search for effective coronavirus disease (COVID-19) therapy has attracted a great deal of scientific interest due to its unprecedented health care system overload worldwide. We have carried out a study to investigate the in silico effects of the most abundant pomegranate peel extract constituents on the multi-step process of serious acute respiratory syndrome coronavirus 2 (SARS-CoV-2) internalization in the host cells. Binding affinities and interactions of ellagic acid, gallic acid, punicalagin and punicalin were studied on four selected protein targets with a significant and confirmed role in the process of the entry of virus into a host cell. The protein targets used in this study were: SARS-CoV-2 spike glycoprotein, angiotensin-converting enzyme 2, furin and transmembrane serine protease 2. The results showed that the constituents of pomegranate peel extracts, namely punicalagin and punicalin had very promising potential for significant interactions with the selected protein targets and were therefore deemed good candidates for further in vitro and in vivo evaluation.

Prospective Risk Assessment of Medicine Shortages in Europe and Israel: Findings and Implications.

INTRODUCTION: While medicine shortages are complex, their mitigation is more of a challenge. Prospective risk assessment as a means to mitigate possible shortages, has yet to be applied equally across healthcare settings. The aims of this study have been to: 1) gain insight into risk-prevention against possible medicine shortages among healthcare experts; 2) review existing strategies for minimizing patient-health risks through applied risk assessment; and 3) learn from experiences related to application in practice. METHODOLOGY: A semi-structured questionnaire focusing on medicine shortages was distributed electronically to members of the European Cooperation in Science and Technology (COST) Action 15105 (28 member countries) and to hospital pharmacists of the European Association of Hospital Pharmacists (EAHP) (including associated healthcare professionals). Their answers were subjected to both qualitative and quantitative analysis (Microsoft Office Excel 2010 and IBM SPSS Statistics®) with descriptive statistics based on the distribution of responses. Their proportional difference was tested by the chi-square test and Fisher's exact test for independence. Differences in the observed ordinal variables were tested by the Mann-Whitney or Kruskal-Wallis test. The qualitative data were tabulated and recombined with the quantitative data to observe, uncover and interpret meanings and patterns. RESULTS: The participants (61.7%) are aware of the use of risk assessment procedures as a coping strategy for medicine shortages, and named the particular risk assessment procedure they are familiar with failure mode and effect analysis (FMEA) (26.4%), root cause analysis (RCA) (23.5%), the healthcare FMEA (HFMEA) (14.7%), and the hazard analysis and critical control point (HACCP) (14.7%). Only 29.4% report risk assessment as integrated into mitigation strategy protocols. Risk assessment is typically conducted within multidisciplinary teams (35.3%). Whereas 14.7% participants were aware of legislation stipulating risk assessment implementation in shortages, 88.2% claimed not to have reported their findings to their respective official institutions. 85.3% consider risk assessment a useful mitigation strategy. CONCLUSION: The study indicates a lack of systematically organized tools used to prospectively analyze clinical as well as operationalized risk stemming from medicine shortages in healthcare. There is also a lack of legal instruments and sufficient data confirming the necessity and usefulness of risk assessment in mitigating medicine shortages in Europe.

Estimation of passive gastrointestinal absorption and membrane retention using PAMPA test, quantitative structure-permeability and quantitative structure-retention relationship analyses of ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid and 1,3-propanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid derivatives.

Passive gastrointestinal absorption and membrane retention of twelve esters of (S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid (EDCP) and (S,S)-1,3-propanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid (PDCP), as well as of these two non-esterified acids were estimated using PAMPA test. Artificial PAMPA membrane used in this study for the simulation of gastrointestinal barrier was solution of egg lecithin in dodecane (1 % w/v). All tested compounds belong to class III (high membrane retention and low permeation), whereas EDCP, dipentyl ester of PDCP (DPE-PDCP) and diisopentyl ester of PDCP (DIPE-PDCP) belong to class I (negligible membrane retention and low permeation). Finally, quantitative structure - permeability and structure - retention relationships models were created in order to find quantitative relationships between physico-chemical properties of tested compounds and PAMPA membrane permeability/membrane retention parameters. Statistically the most reliable models were analysed and used for the design of new compounds for which favourable membrane permeability and retention can be expected.

Adverse drug reaction reporting and development of pharmacovigilance systems in Bosnia and Herzegovina, Croatia, Serbia, and Montenegro: a retrospective pharmacoepidemiological study.

AIM: To compare individual case safety reports (ICSR) rates and characteristics between Croatia, Serbia, Montenegro, and Bosnia and Herzegovina (B&H). METHODS: This retrospective pharmacoepidemiological study used the data from ICSR received by the Agency for Medicines and Medical Devices in B&H in 2011-2016. The number, characteristics, and sources of reports, suspected drugs, and patient characteristics were analyzed. The results were compared with the publicly available data from Croatia, Serbia, and Montenegro. RESULTS: The number of reported adverse drug reactions per one million of inhabitants was lowest in B&H and highest in Croatia. There were significant differences in reporter characteristics, sources of reports, and the percentage of missing data in ICSR, while the Anatomical Therapeutic Chemical product classes, patient's sex, and adverse drug reaction System Organ Classes were similar. CONCLUSION: Despite the historical and geographical vicinity of B&H and its neighboring countries, there were significant differences in indicators of pharmacovigilance development.

Prediction of in vivo Bioavailibility by in vitro Characterization of Ethylenediamine Dipropanoic Acid Derivatives with Cytotoxic Activity.

O,O'-diethyl-(S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoate (DE-EDCP) is novel substance with cytotoxic activity in human leukemic cells. The aim of this study has been to predict in vivo bioavailability of the DE-EDCP and its potential metabolite (S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid (EDCP) by in vitro characterization which includes determination of lipophilicity and passive membrane permeability. There has also been evaluated inter-laboratory reproducibility of the bio-analytical method which was previously developed and validated for non-clinical study of the DE-EDCP and EDCP. Distribution coefficient n-octanol/water was 1.68 and 0.03, and apparent permeability coefficient was 4 × 10-4 cm/s and 20 × 10-4 cm/s, for the DE-EDCP and EDCP, respectively. Observed results have shown that the DE-EDCP is more lipophilic with better membrane retention, but the EDCP has better pass through the membrane. Also, there has been demonstrated a reproducibility and robustness of the proposed bio-analytical method.

Dissolution Profile of Nimesulide from Pharmaceutical Preparations for Oral Use.

Nimesulide belongs to the group of semi-selective COX-2 inhibitors, widely used in solid oral formulations. In the present work the influence of surfactants among other drug excipients, as well as particle size of the active substance and the effects of medium pH on the dissolution rate of nimesulide from solid pharmaceutical forms. For that purpose, four different preparations containing 100 mg nimesulide per tablet and available in the market of Bosnia and Herzegovina (labeled here as A, B, C and D) were studied. The test for the assessment of dissolution profiles of the formulations was performed in surfactant-free dissolution medium pH 7.5. The dissolution profiles were compared by calculating difference (f1), and similarity (f2) factors. The increasing dissolution medium pH value from 7.5 to 7.75 resulted in a significant increase of nimesulide dissolution rate from the examined formulations. Also, the results showed that particle size affects to a great extent the dissolution rate and the best results were achieved with micronized nimesulide. The presence of the surfactants among the other excipients expressed a negligible effect on the dissolution profile.

The role of biomarkers in the development of novel cancer therapies.

The etiology of diverse patient responses to a given pharmaceutical treatment has eluded science for decades. Only during the last 10-15 years has our understanding of the interplay between genetics and pharmaceuticals advanced to the point that personalized medicine may optimize therapies for each individual patient. The primary goals of personalized medicine are identifying individuals at risk of developing disease to better prevent disease in the healthy population, accurately monitoring each patient's response to therapy and predicting recurrence in order to pre-empt it. This review gives an explanation of biomarkers and addresses their role in the diagnosis and surveillance of various cancers. It also addresses the challenges of developing novel therapies utilizing newly discovered biomarkers.