Dragana Protic

Clopidogrel cessation triggers aspirin rebound in patients with coronary stent

Premature discontinuation of clopidogrel in patients undergoing percutaneous coronary intervention is a significant risk factor for thrombotic adverse outcomes. However, recent studies indicate that even discontinuation of long‐term use of clopidogrel may be associated with multiple adverse outcomes, that is, rebound phenomenon whose mechanism is not definitely clear. The aim of the study was to examine the effect of clopidogrel withdrawal in those on combined aspirin and clopidogrel therapy.

Effect of Wine Polyphenol Resveratrol on the Contractions Elicited Electrically or by Norepinephrine in the Rat Portal Vein

We investigated the effects of resveratrol on rat portal vein (RPV) contractility without endothelium. Contractions were produced by electrical field stimulation of perivascular nerves (EFS), norepinephrine (NE), adenosine 5′‐triphosphate (ATP), high K+ solution and by calcium chloride (CaCl2) in Ca2+‐free and high K+, Ca2+‐free solution. The EFS‐evoked contractions were more sensitive to resveratrol and to NS1619‐selective openers of big calcium‐sensitive (BKCa) channels, than NE‐evoked contractions. Effects of resveratrol on the ATP‐evoked contractions were weak. Blockers of BKCa channels partly inhibited the effect of resveratrol only in EFS‐contracted preparations. Western blotting showed that RPV expressed KCa1.1 protein. Inhibitors of ATP‐ and voltage‐sensitive K+ channels did not modify the effects of resveratrol. None of the antagonists of K+ channels affected the resveratrol inhibition of NE‐evoked contractions and effect of high concentrations of resveratrol on the EFS‐evoked contractions. Resveratrol more potently inhibited CaCl2 than potassium chloride contractions of RPV. Thus, BKCa channels partly mediate the inhibitory effect of resveratrol on the neurogenic contractions of RPV. The smooth muscle Ca2+ channels and/or Ca2+ mobilizing through cells might be involved in the effects of resveratrol on the contractility of RPV. Our results are important for better understanding the impact of resveratrol on the portal circulation. Copyright

The Different Effects of Resveratrol and Naringenin on Isolated Human Umbilical Vein: The Role of ATP‐Sensitive K+ Channels

The blood flow from the placenta to the fetus depends on human umbilical vein (HUV) vascular tone. ATP‐sensitive K+ (KATP) channels link the metabolic state of the cell to membrane potential, and their activation in the HUV represents protection against hypoxia. The aims of our study were to assess the effects of resveratrol and naringenin on the HUV and to define the roles of KATP channels in their effects. Serotonin or 100 mM K+ were used for precontraction of the HUV without endothelium. The cumulative concentration–response curves were obtained by adding increasing concentrations of resveratrol or naringenin. Glibenclamide was used, in order to test the role of KATP channels in its effect. Resveratrol induced more potent vasodilatation of serotonin‐ and 100 mM K+‐precontracted HUV than naringenin. Glibenclamide induced significant shift to the right of the concentration–response curves of resveratrol and P1075 (a specific opener of KATP channels). Western blotting showed that HUV expressed protein Kir6.1. Thus, resveratrol and naringenin produce dilatation of HUV. It seems that KATP channels are involved in the relaxation of HUV induced by resveratrol, while naringenin seems to interact with other ion channels. The K+ channel‐independent mechanism(s) of these polyphenols could not be excluded. Copyright

Men with Lower HDL Cholesterol Levels have Significant Increment of Soluble CD40 Ligand and High-sensitivity CRP Levels Following the Cessation of Long-term Clopidogrel Therapy

AIM The aim of this study was to examine whether the termination of long-term clopidogrel therapy results in a proinflammatory state and whether lipid parameters influence the inflammatory response after stopping the drug. METHODS A prospective, multicenter study was conducted among 200 patients with implanted coronary stents who received dual antiplatelet therapy for one year, without ischemic or bleeding events. According to the guidelines, clopidogrel was discontinued after one year. In all patients, the high-sensitivity C-reactive protein (hsCRP), soluble CD40 ligand (sCD40L) and lipid [total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)] levels were measured twice: on the day of cessation of clopidogrel and 45 days after the termination of clopidogrel treatment. RESULTS In men (n=151), the sCD40L serum levels were significantly higher 45 days after the discontinuation of clopidogrel (p=0.007), while the hsCRP levels were not significantly different (p=0.407). Furthermore, when analyzed across the HDL-C quartiles, the hsCRP and sCD40L values were found to be associated with the levels of HDL-C after the discontinuation of clopidogrel in men. In addition, the men in the first HDL-C quartile exhibited the most pronounced increase in the sCD40L levels (p=0.001) and had significantly higher hsCRP levels (p=0.001) compared to the subjects in the other quartiles. Other lipid parameters did not show any associations with the sCD40L or hsCRP levels. CONCLUSIONS The discontinuation of clopidogrel is associated with higher increments in the sCD40L level, and a pronounced proinflammatory response is associated with a lower HDL-C concentration.

The differential effect of resveratrol on the renal artery of normal and diabetic rats

Results Resveratrol relaxed RA of normal rats more potently than RA of rats with diabetes (EC50 8 and 50 μM, respectively). L-NAME and methylene blue partly antagonized the relaxation of RA of normal animals only. A nonselective blocker of voltage-gated K (KV) channels, 4-aminopyridine (4-AP) partly inhibited the relaxation of RA of normal as well as of diabetic rats. However, margatoxin, a selective antagonist of KV1.x channels, completely antagonized the relaxation of RA of diabetic rats only. Glibenclamide, a highly selective blocker of ATP-sensitive K channels, did not block resveratrolinduced relaxation in both experimental models. Conclusions In conclusion, we have shown that resveratrol induces a strong endothelium-dependent relaxation of RA of normal rats, and that 4-AP-sensitive K channels are involved in this relaxation. In diabetic rats, resveratrol induced NO-independent relaxation and maragtoxinsensitive K channels are involved.

Mutacije FMR1 gena uzrokuju razvojne i degenerativne poremećaje nervnog sistema: Značaj testiranja na nestabilni X hromozom u Srbiji

Scientific advances in biomedicine have enabled translation of preclinical research breakthroughs to clinical trials during the last decades. Resources required for such effort are typically available in developed countries such as the USA. Kennedy Krieger Institute in Baltimore, Maryland is an internationally recognized institution dedicated to improving the lives of individuals with disorders of the brain, spinal cord, and musculoskeletal system (https://www.kennedykrieger.org). Clinical Trials Unit (CTU) at the Institute is one of the top-level institutions in the world that conduct the advances in translational medicine. The Unit helps advance treatment, prevention, and possible cures (https://www.kennedykrieger.org/researchtraining/centers-labs-cores/clinical-trials-unit). This and other similar institutions bring together world-leading experts in clinical research in order to provide state-of-the-art treatment of previously untreatable disorders for participants. One of them is fragile X syndrome (FXS), the hallmark of Fragile X-associated disorders (FXD), which is at the forefront of translational efforts to develop such targeted treatments. Specifically, FXS is the most translated among all neurodevelopmental disorders in human clinical trials. Namely, preclinical breakthroughs have generated much interest by the field to translate them into humans with FXS, and possibly autism spectrum disorder (ASD), a major public and economic health burden on society worldwide. Specifically, a recent search of www.clinicaltrials.gov, the National Institute of Health (NIH) sponsored website, and literature search revealed that 22 double-blind, placebo-controlled clinical trials 1, 2 have been registered in humans with FXS, as required by the Food and Drug Administration (FDA) Act of 2007. Gaps in translating the above successes have been identified. At present, no symptomatic or disease modifying treatments for FXS have received regulatory approval. Then the most respectable medicinal regulatory authorities in the world (e.g. FDA) greatly benefit from efforts of leading clinical and research experts in the USA to address these gaps and advance these clinical trials of humans with FXS that were conducted mostly from 2008 to 2015 . To briefly backtrack, collaborative effort among scientific institutions in developed, and some developing countries, is key to the establishment of local specialty fragile X clinics, and even clinical and research consortiums, which is of a vital importance for the successful translation of such treatment advances. Here, we highlight the importance of the Fragile X Clinical & Research Consortium (FXCRC). The Consortium is a collaborative endeavor initiated in 2006 by the National Fragile X Foundation (NFXF) to advance clinical practice and facilitate coordinated, collaborative multi-site research on FXS, which currently consists of 28 clinics in the USA and Canada. The Consortium has formed several committees designed to address common issues with regard to best practices in evaluation and treatment, strategies for supporting and enhancing clinic work, and research priorities, such as Clinical Trials Committees. Next, Fragile X Clinical and Research Consortium Registry and Database (FORWARD) is the Center for the Disease Control (CDC) funded project now 5-year renewed through 2020 (PI: Brown, 1 U01 DD001189-01) in which the Consortium works closely with the CDC and the NFXF. The project helps establish standards of care, facilitate the conduct of multi-institutional clinical research projects, coordinate and organize research across sites, build a reliable, dynamic patient registry and assist member clinics in data collection and analysis, including effective and relevant outreach and surveillance The Institute is one of the sites for the FORWARD

Nosocomial coagulase-negative staphylococci in Belgrade: between Scylla and Charybdis

INTRODUCTION Coagulase-negative staphylococci (CoNS) are increasingly resistant nosocomial pathogens. We aimed to analyze the prevalence of CoNS isolates in clinical settings, the evolution of antimicrobial resistance of CoNS, and antibiotic consumption in a hospital. METHODOLOGY This retrospective cohort study was carried out at a tertiary healthcare facility over 17 months. Identification of isolated cultures and antibiotic susceptibility testing were performed using the Vitek2 system. Of 1,217 isolates, 209 were obtained from 193 patients who had symptoms of nosocomial infections. Data were analyzed by descriptive statistics. Antibiotic consumption in the hospital is expressed in defined daily doses/100 patient days. RESULTS Sixty-one percent of patients were admitted to the internal medicine ward, while others were admitted to the surgical ward. Forty-four percent of Gram-positive isolates were from wound swabs, and 26% were from blood. The predominant Gram-positive bacteria were CoNS. Antibiotic resistance of CoNS was highest against beta-lactam antibiotics, macrolides, and tetracyclines. Tigecycline, linezolid, and vancomycin produced the highest activities against CoNS in in vitro conditions, and consumption of linezolid and tigecycline increased in the same period. CONCLUSION There are just a few remaining therapeutic options for the treatment of CoNS according to our results; vancomycin, linezolid, and tigecycline might be considered as first-choice antibiotics, but such a hypothesis should be supported with a pharmacoeconomic analysis. Unfortunately, novel antimicrobial agents are still unavailable and/or too expensive in developing countries. However, inappropriate use of those antibiotics may lead to the rapid development of resistant strains in the near future.

PREDICT score and CYP2C19 polymorphism independently predict lack of efficacy of clopidogrel in cardiology patients

Sne zana Mugo sa,* Nata sa Djordjevi c, Zoran Bukumiri c, Nina Djukanovi c, Jelena Cuki c, Ivan Radosavljevi c, Dejan Baski c, Dragana Proti c, Marija Zdravkovi c** and Zoran Todorovi c** *Faculty of Pharmacy, University of Montenegro, Podgorica, Montenegro, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, , Faculty of Medicine, University of Belgrade, High Medical School “Milutin Milankovi c”, Belgrade, Public Health Institute, Kragujevac, and **Medical Center “Be zanijska kosa”, Belgrade, Serbia

Knowledge about blood-borne pathogens and the prevalence of needle stick injuries among medical students in Serbia

Abstract Introduction Medical students are mainly exposed to needle stick and sharp object injuries in the course of their clinical activities during studying. They are at high risk due to their undeveloped skills, restricted clinical experience, lack of knowledge and risk perception. The objectives of this study were to determine the prevalence of needle stick injuries of the fourth and final year medical students, and to estimate their knowledge about blood-borne pathogens disease transmission and standard precautions. Methods This cross-sectional study was conducted at the Faculty of Medicine, in February 2014. The students were invited to self-administer a questionnaire of 26 closed questions prepared for this study. Results The questionnaire was filled in and returned by 637 students. The prevalence of needle sticks and sharp object injuries was 29.5%. Needle stick injuries were the most common type of accidents, more frequent among the fourth compared to the sixth year students (p=0.002). The majority of accidents occurred in patient rooms (53%) and the emergency department (15%). 54% of participants reported an accident to the responsible person. Students without accidents had a significantly better perception of risk (3.79 vs. 3.35; p<0.05). Out of the total participating students, only 16.6% (106/637) received all three doses of Hepatitis B vaccination, while 16.2% were partially vaccinated. Conclusions There is a need for additional theoretical and practical education of our students on blood exposure via accidents, raising the awareness of the necessity of hepatitis B vaccination, and introducing the unique/comprehensive procedure for accident reporting for students and healthcare workers in the entire country.

Factors affecting the development of adverse drug reactions to β-blockers in hospitalized cardiac patient population.

The aim of the present study was to undertake a study on the prevalence of cytochrome P450 2D6 (CYP2D6) poor metabolizer alleles (*3, *4, *5, and *6) on a Montenegrin population and its impact on developing adverse drug reactions (ADRs) of β-blockers in a hospitalized cardiac patient population. A prospective study was conducted in the Cardiology Center of the Clinical Center of Montenegro and included 138 patients who had received any β-blocker in their therapy. ADRs were collected using a specially designed questionnaire, based on the symptom list and any signs that could point to eventual ADRs. Data from patients’ medical charts, laboratory tests, and other available parameters were observed and combined with the data from the questionnaire. ADRs to β-blockers were observed in 15 (10.9%) patients. There was a statistically significant difference in the frequency of ADRs in relation to genetically determined enzymatic activity (P<0.001), with ADRs’ occurrence significantly correlating with slower CYP2D6 metabolism. Our study showed that the adverse reactions to β-blockers could be predicted by the length of hospitalization, CYP2D6 poor metabolizer phenotype, and the concomitant use of other CYP2D6-metabolizing drugs. Therefore, in hospitalized patients with polypharmacy CYP2D6 genotyping might be useful in detecting those at risk of ADRs.