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.

Endotoxemia is associated by dysregulated apoptosis of immune and non-immune cells. We investigated whether simvastatin has anti-apoptotic effects, and induces hepatocytes and lymphocytes survival signaling in endotoxin-induced liver and spleen injuries. Wistar rats were divided into the groups pretreated with simvastatin (20 or 40 mg/kg, orally) prior to a non-lethal dose of lipopolysaccharide (LPS), the LPS group, and the control. The severity of tissue inflammatory injuries was expressed as hepatic damage scores (HDS) and spleen damage scores (SDS), respectively. The apoptotic cell was detected by TUNEL (Terminal deoxynucleotidyl transferase dUTP Nick End Labeling) and immunohistochemical staining (expression of cleaved caspase-3, and anti-apoptotic Bcl-xL, survivin and NF-κB/p65). Simvastatin dose-dependently abolished HDS and SDS induced by LPS (p < 0.01), respectively. Simvastatin 40 mg/kg significantly decreased apoptotic index and caspase-3 cleavage in hepatocytes and lymphocytes (p < 0.01 vs. LPS group, respectively), while Bcl-XL markedly increased accordingly with simvastatin doses. In the simvastatin, groups were determined markedly increased cytoplasmic expression of survivin associated with nuclear positivity of NF-κB, in both hepatocytes and lymphocytes (p < 0.01 vs. LPS group). Cell-protective effects of simvastatin against LPS seemed to be mediated by up-regulation of survivin, which leads to reduced caspase-3 activation and inhibition of hepatocytes and lymphocytes apoptosis.

Rare diseases ('orphan diseases') (RDs) count for 5000-8000 diseases with low prevalence and most commonly of genetic origin. Although most of rare diseases are manifested in early childhood, many are diagnosed in adults, even in elderly. Common characteristics, such as severity, debilitating and life-threatening features, with the lack of a specific drugs, make the treatment of RD a significant public-health problem. Even though randomized controlled trials (RCTs) are the most ideal design for evaluating new drugs, the aim of this review was to present the aggravating circumstances that development of so-called orphan drugs faces in context of RD. We searched the PubMed/Medline for publications on studies and ethics in RDs and applying of 'omics' technologies in analysing tissue samples at biobanks published between 2010 and 2017. In this review, we presented the most significant obstacles in conducting clinical trials in RD as well as main alternative clinical trial designs aiming to decrease the number of patients recruited with increased access to innovative medicines as many as possible. Furthermore, we have presented the possibility of accessing innovative drugs outside of clinical trials as well as ethics violations by the involvement of the subject in clinical trial. Modern technologies in molecular biology will enable the development of 'precision medicine' aimed at identifying the best therapeutic goal, depending on the genetic and epigenetic factors in the affected person. That is why RD biobanks have great significance in the preservation and distribution of tissue samples, in the research of diagnostic biomarkers and the drug development.

Background: It is considered that acute lung injury (ALI) is an uncontrolled inflammation, mainly attributed to the release of inflammatory mediators and extensive apoptosis. Aim: As simvastatin exerts antiinflammatory properties by regulating cellular signaling pathways, we explored its effects on ALI development and apoptotosis of immune and epithelial cells in endotoxic shock. Methods: Male Wistar rats were intraperitoneally injected with 0.25 of the medial lethal dose of endotoxin (lipopolysaccharide, LPS). Simvastatin was given orally (10, 20, 40 mg/kg, per group) as a five-day pre-treatment prior to a single dose of LPS, and 48 afterwards the animals were sacrificed. Lung tissue inflammatory damage was assessed by histopathological examination (haematoxylin-eosin staining), and expressed as a tissue damaged score (TDS). Apoptosis was analysed by TUNEL (DNA fragmentation assay) and expressed as an apoptotic index (AI), and immunohistochemically by detection of cleaved caspase-3, Bcl-XL, inhibitor of apoptosis, survivin as well as expression of nuclear factor (NF)- κB signalling pathway. Results: TDSs showed that simvastatin ameliorated ALI induced by LPS in dose-dependent manner (simvastatin 20 mg/kg and 40 mg/kg vs LPS, 2.0±0.59 and 1.33±0.48 vs 3.35 ±0.42, p<0.01, respectively). LPS induced significant apoptosis (AI 43.8%±11.3), and increased expression of cleaved caspase-3

Introduction: Drug-induced liver injury (DILI) is a rare but potentially life threatening adverse drug reactions. DILI may mimic pathophysiology or histopathologic features of an acute or chronic liver disease, and they may be indistinguishable from those of other causes of liver injuries. Liver can be affected directly, in a dose-dependent manner, or idiosyncratically, independently of the dose, and therefore unpredictably developed. Methods: In this special article we provided results given in the articles published in PubMed in the period 2006-2016. The search was made based on the most frequent reported drugs inducing liver injuries, diagnostic assessment, monitoring and outcomes of DILI. Results: The true incidence of DILI still remains unknown but the incidence of up to 14 cases per 100,000 inhabitants/year has been most frequently reported. Antimicrobial agents, analgesics, hipolipemics and antiepileptics are the most common drugs causing DILI. Conclusion: Although several biomarkers have been found through analytical tests, none of them have been able to display enough specificity and sensitivity in DILI diagnosis. Therefore, diagnostic assessment of DILI is still based on clinical examination, pharmacological treatment history, current RUCAM criteria, and liver function laboratory test.

BACKGROUND/AIM Recurrent aphthous stomatitis (RAS) is defined as multifactor immunologic inflammatory lesions in the oral cavity, characterized by painful, recurrent single/multiple, shallow, round or ovoid ulcerations of mucosal tissues. To date, a considerable number of RAS treatment protocols have been suggested, but since the etiology of RAS is idiopathic, these treatment options have symptomatic rather than curative or preventive effect. Recently, it has been suggested that laser therapy could be successfully used as an efficient treatment approach in therapy of RAS. Therefore, the aim of this review was to estimate the effects of laser therapy in treatment of RAS analyzing results of clinical studies published in peer reviewed journals. METHODS The studies published until 31 December 2013 were obtained from the Medline/PubMed, Science Direct and Cochrane Library of the Cochrane Collaboration (CENTRAL) online databases, using following search terms and key words: "laser" AND "recurrent aphthous stomatitis", "laser" AND "aphthous", and "laser" AND "aphthae". In total 4 original research articles met the all required inclusion/exclusion criteria, and were used for this review. The main outcome measures assessed were: a reduction of pain associated with RAS and a reduction in episode duration (faster RAS healing). RESULTS The assessed literature demonstrates the benefits of laser therapy mainly due to immediate analgesia and ability to speed up a RAS healing process. CONCLUSION Even thoughthe assessed literature suggests beneficial outcomes of laser therapy in treatment of RAS, these results should be interpreted with caution. The issues related to the study designs and different sets of laser irradiation parameters of a limited number of available studies with the same treatment outcomes prevent us from making definite conclusions.

INTRODUCTION Hyperkalemia secondary to beta-adrenergic receptor blockade occurs in 1-5% of patients and is likely to develop with non-cardio-selective beta-blockers. CASE REPORT We have described hyperkalemia in a patient with angina pectoris receiving propranolol, clinically manifested as weakness, tightness behind the sternum and numbness in the limbs. Laboratory tests showed hyperkalemia (6.6 mmol/L), peaked T wave and a corrected QT interval of 510 ms. After discontinuation of propranolol, decline in potassium level, normalisation of electrocardiographic changes and clinical improvement were achieved. Causal relationship of drug related hyperkalemia has been confirmed as probable/likely according to Naranjo Adverse Drug Reaction Probability Score of 7 and the World Health Organization Uppsala Monitoring Centre Probability Scale. CONCLUSION Hyperkalemia can be unpredictable and life-threatening complication of propranolol or a non-selective adrenergic beta blocker treatment, and requires timely identification of cause and implementation of therapeutic measures.

We report the case of an 83-year-old female patient who developed diclofenac-associated liver injury nine days after therapy had started. Diclofenac was used to treat back pain associated with an acute exacerbation of a chronic lumbovertebral symptoms reversed. We discuss the adverse reaction profile of diclofenac, particularly diclofenac-induced liver injury. We also discuss the epidemiology, clinical presentation and mechanisms of NSAID-induced liver injury, as well as risk factors and preventive measures.