Marko Folić

Cost-effectiveness of four immunomodulatory therapies for relapsingremitting multiple sclerosis: A Markov model based on data a Balkan country in socioeconomic transition

BACKGROUND/AIM A cost-effectiveness analyses of immunomodulatory treatments for relapsing-remitting multiple sclerosis (RRMS) in developed countries have shown that any benefit from these drugs is achieved at very high cost. The aim of our study was to compare the cost-effectiveness of five treatment strategies in patients diagnosed with RRMS (symptom management alone and in combination with subcutaneous glatiramer acetate, intramuscular interferon beta-1a, subcutaneous interferon beta-1a, or intramuscular interferon [beta-1b) in a Balkan country in socio-economic transition. METHODS The Markov model was developed based on the literature about effectiveness and on local Serbian cost calculations. The duration of a cycle in the model was set to a month. The baseline time horizon was 480 months (40 years). The societal perspective was used for costs and outcomes, and they were discounted for 3% annually. Monte Carlo micro simulation with 1000 virtual patients was done. RESULTS Significant gain with immunomodulatory therapy was achieved only in relapse-free years, while the time spent in health states EDSS 0.0-5.5 was longer with symptomatic therapy only, and gains in life years and QALYs were only marginal. One QALY gained costs more than a billion of Serbian dinars (more than 20 million US dollars), making each of the four immunomodulatory therapies cost-ineffective. CONCLUSION Our study suggests that immunomodulatory therapy of RRMS in a Balkan country in socioeconomic transition is not cost-effective, regardless of the type of the therapy. Moderate gain in relapse-free years does not translate to gain in QALYs, probably due to adverse effects of immunomodulatory therapy.

Risk factors for carbapenem-resistant Pseudomonas aeruginosa infection in a tertiary care hospital in Serbia.

Introduction Pseudomonas aeruginosa is well-known cause of hospital infections with high morbidity and mortality rates [1]. According to the National Nosocomial Infections Surveillance System (NNISS), P. aeruginosa is responsible for approximately 8% of all hospital infections. It was the most frequent cause of ventilator-associated pneumonias (VAP), the fourthrated on the list of causes of hospital urinary infections, and fifth cause of surgical site infections according to frequency of occurence (2). Infections caused by P. aeruginosa are difficult to control and treat due to its high rate of resistance to antibiotics and to the limited number of available antibiotics with efficacy against P. aeruginosa. During the last decade, an increase in resistance to imipenem and meropenem was observed among many strains of Gram-negative bacteria, and especially among isolates of P. aeruginosa [3,4,5]. Numerous studies have also shown that carbapenem-resistant P. aeruginosa (CRPA) is frequently simultaneously resistant to other antipseudomonal antibiotics, making the treatment very difficult [6]. A number of risk factors for the emergence of CRPA-caused hospital infections was identified, including spending time in an intensive care unit and/or prior use of certain antibiotics [7,8,9,10]; however, for the majority of factors, the strength of the association was either low or equivocal. Sound knowledge of the risk factors and quantification of their influence on hospital infections are important for proper prevention and treatment of the CRPA-caused nosocomial infections. The aim of this study was to identify risk factors associated with the CRPA-caused hospital infections.

The contractile effects of endothelins on isolated isthmic segment of human oviduct at the luteal phase of the menstrual cycle.

The purpose of this study was to investigate the effects of endothelins (ET) 1, 2 and 3 on isolated isthmic segments of the human oviduct at the luteal phase of menstrual cycle. Fallopian tubes were taken from 21 patients and the isthmic segments were mounted in an organ bath longitudinally. Tension of the isolated preparations was recorded with an isometric transducer. ET-1 and ET-2 triggered concentration-dependent tonic contractions of the isolated isthmic segment and inhibited rhythmic activity, while ET-3 caused no effect. Furthermore, the selective ET(A) antagonist BQ-123 and the selective ET(B) antagonist BQ-788 inhibited the ET-1 effects on both tone and spontaneous rhythmic contractions. These results suggested that during the luteal phase of the menstrual cycle, both ET(A) and ET(B) receptors participate in contractile effects of endothelins on isthmic segment of fallopian tubes, probably regulating the length of time the oocyte remains in the oviduct ampulla.

Health care–acquired infections in neonatal intensive care units: Risk factors and etiology

A 1-year prospective cohort study of health care-acquired infections was conducted at the neonatal intensive care unit of the University Clinical Centre Kragujevac, Serbia. The incidence rate of neonates with health care-acquired infections was 18.6%, and the incidence rate of the infections themselves was 19.4%. The incidence density of the health care-acquired infections was 9.1 per 1,000 patient days. The independent risk factors for health care-acquired infections were birth weight, length of hospitalization, duration of mechanical ventilation, and Apgar score. More than half of all isolated microorganisms were Klebsiella-Enterobacter (39.3%) and Escherichia coli (25.0%).

Effects of Methyldopa and Nifedipine on Uteroplacental and Fetal Hemodynamics in Gestational Hypertension

Objective. Investigation of methyldopa and nifedipine effects on maternal and fetal hemodynamics in women with mild gestational hypertension during the third pregnancy trimester. Methods. A prospective cohort study. Methyldopa effects were followed in 28 patients, and nifedipine effects in another 28 patients. There were also 28 healthy controls. Results. Uterine artery blood velocity waveform indices were improved only by nifedipine. Neither of the drugs affected the indices in umbilical and fetal middle cerebral artery. Both drugs normalized maternal blood pressure and pulse. Conclusions. Methyldopa and nifedipine did not show clinically significant influence on umbilical artery and fetal cerebral blood flow.

Distribution and antibiotic susceptibility of pathogens isolated from adults with hospital-acquired and ventilator-associated pneumonia in intensive care unit

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are the most common hospital infections with the highest prevalence in intensive care units (ICU). The aim of this study was to investigate prevalence of bacterial pathogens isolated from ICU patients with HAP/VAP and reveal their susceptibility rates in order to establish a basis for empirical antibiotic therapy. Prospective cohort study was conducted in central ICU of Clinical Centre Kragujevac, Serbia, from January 2009 to December 2015, enrolling 620 patients with documented HAP (38.2%) or VAP (61.8%). Gram-negative agents were isolated in 95.2%. Generally, the most common pathogens were Acinetobacter spp. and Pseudomonas aeruginosa, accounting for over 60% of isolates. The isolates of Acinetobacter spp. in HAP and VAP had low susceptibility to the 3rd generation cephalosporins, aminoglycosides, fluoroquinolones (0-10%). The rate of susceptibility to piperacillin-tazobactam was below 15%, whereas for carbapenems and 4th generation cephalosporins it was about 15-20%. Isolates of P. aeruginosa from HAP and VAP showed low susceptibility to ciprofloxacin and gentamicin (below 10%), followed by amikacin (25%), while the rate of susceptibility to carbapenems and 4th generation cephalosporin was 30-35%. Furthermore, 86% of isolates of P. aeruginosa non-susceptible to carbapenems were also non-susceptible to ciprofloxacin. The highest level of susceptibility from both groups was retained toward piperacilin-tazobactam. In ICU within our settings, with predominance and high resistance rates of Gram-negative pathogens, patients with HAP or VAP should be initially treated with combination of carbapenem or piperacillin-tazobactam with an anti-pseudomonal fluoroquinolone or aminoglycoside. Colistin should be used instead if Acinetobacter spp. is suspected. Vancomycin, teicoplanin or linezolide should be added only in patients with risk factors for MRSA infections.

Risk factors for hospital infections caused by carbapanem-resistant Acinetobacter baumannii

INTRODUCTION Acinetobacter baumannii is one of major causative agents of severe, life-threatening hospital infections (HIs), especially in intensive care units (ICUs). Our aim was to discover the risk factors associated with the emergence of HIs caused by carbapenem-resistant Acinetobacter baumannii (CRAB), as well as those associated with death in patients who suffer from such infections. METHODOLOGY A prospective cohort study was conducted over a five-year period in the medical-surgical ICU of the Clinical Centre in Kragujevac, Serbia. The study group comprised patients who had HIs caused by CRAB, while the control group comprised patients infected with carbapenem-sensitive Acinetobacter baumannii. RESULTS In total, 137 patients developed HIs caused by Acinetobacter baumannii. The mean age of the patients was 59.65 ± 16.08 years, and 99 (72.26%) of them were males. In 95 patients (69.35%), the infection was caused by CRAB. There were six independent risk factors for CRAB infections: use of mechanical ventilation, previous stay in another department, stay in ICU for more than a month, and previous use of carbapenems, aminoglycosides, and metronidazole. Three independent risk factors were found for death in patients with HIs caused by CRAB: use of mechanical ventilation, previous stay in another department, and previous use of carbapenems. CONCLUSIONS The results of this study can be helpful when identifying patients with risk of HIs caused by CRAB and in planning preventive measures. Modification of known risk factors and appropriate institutional policy of antibiotic utilization are important measures that may decrease the incidence and mortality of such infections.

Consulting clinical pharmacologist about treatment of inpatients in a tertiary hospital in Serbia

Dear Editor, Clinical pharmacology specialists give many services in various healthcare systems all over the world, but the most complex and responsible one is advising other specialties about treatment of difficult, and often critical, patients in tertiary care hospitals [1–3]. Usually, other clinical specialties call a clinical pharmacologist for a help only when they cannot see any further option to treat a patient who is either deteriorating or not improving as expected [3]. Since clinical pharmacology services are still developing in many regions, it is of interest to present experiences with effects of consulting clinical pharmacologist on treatment outcomes from places where such services have considerable history. Clinical pharmacology department in a tertiary care Clinical Center, Kragujevac, Serbia, was founded back in 1995 and have five fully employed specialists of clinical pharmacology, who on average give about 4000 consultations to other specialists annually. The department is funded by the National Health Insurance Fund, in the same manner as other specialty services, and it is integrated in postgraduate training of future clinical pharmacologists. During the 15-month period from January 2015 to March 2016, the clinical pharmacologists (CPs) were consulted 5137 times for 4692 patients (39 % females and 71 % males), whose average age was 61.67 ± 17.26 years. For 4176 patients, the CPs were consulted only once and for 516 patients, twice or more times. Daily workload per clinical pharmacologist on duty was between five and ten patients, and on average, 30 min was spent per consultation. Primary diagnoses of the patients are shown in the Table 1. After clinical examination of the patients for whom they were consulted and getting introduced with a patient’s history and files, the CPsmade certain interventions, which are shown in Table 2. The acceptance rate of the interventions by other clinical specialists who asked for consultation was 90.3 %. The outcome of the interventions suggested by the CPs and accepted by clinical specialists was improved in the patient’s status in 70.6 %, continuation of the same status in 0.9 %, and deterioration in 28.5 %. The vast majority of consultations was about the choice and/or dosing of antimicrobial drugs, and the most frequent infection sites in the patients were blood (55.4 %), respiratory tract (10.8 %), and skin and soft tissues (10.1 %). A few recent publications presented their experiences with consultations of clinical pharmacologists asked for by the other clinical specialists. In 1-year study from Udine, Italy, the focus was on consultations based on therapeutic monitoring of linezolid [4], and the CPs * Slobodan M. Janković slobnera@gmail.com

Investigational cannabinoids in seizure disorders, what have we learned thus far?

ABSTRACT Introduction:The anticonvulsant activity of cannabinoids attracted much attention in the last decade. Cannabinoids that are currently investigated with the intention of making them drugs for the treatment of epilepsy are cannabidiol, cannabidivarin, Δ9-tetrahydrocannabivarin, and Δ9-tetrahydrocannabinolic acid. Areas covered:In this review, the authors look at the results of preclinical and clinical studies with investigational cannabinoids. Relevant literature was searched for in MEDLINE, SCOPUS, EBSCO, GOOGLE SCHOLAR, and SCINDEX databases. Expert opinion: Preclinical studies confirmed anticonvulsant activity of cannabidiol and cannabidivarin in a variety of epilepsy models. While the results of clinical trials with cannabidivarin are still awaited, cannabidiol showed clear therapeutic benefit and good safety in patients with therapy-resistant seizures associated with Dravet syndrome and in patients with Lennox–Gastaut syndrome who have drop seizures. However, the full therapeutic potential of cannabinoids in treatment-resistant epilepsy needs to be investigated in the near future.

Atherogenic Impact of Homocysteine: Can HMG-CoA Reductase Inhibitors Additionally Influence Hyperhomocysteinaemia?

Abstract The strong association among the risk of coronary artery diseases (CAD), high levels of LDL-C and low levels of HDLC is well established. Hyperhomocysteinaemia (HHcy) is an independent risk factor for cardiovascular disease (CVD) and causes endothelial dysfunction, a hallmark of atherosclerosis. In this study, we ascertained the influence of statins on the atherogenic index, as an indicator and a significant adjunct for predicting atherosclerosis in hyperhomocysteinaemic male Wistar albino rats. For 4 weeks, the animals were fed with one of the following diets (Mucedola SRL., Milan, Italy): standard rodent chow; a diet enriched in methionine with no deficiency in B vitamins or a diet enriched in methio-nine and deficient in B vitamins. The animals were simultaneously exposed to a pharmacology treatment with atorvastatin at dose of 3 mg/kg/day i.p. or simvastatin, at dose of 5 mg/kg/day i.p. We measured weight gain, food intake, and FER and determined the concentrations of biochemical parameters of dyslipidaemia (TC, TGs, LDL-C, VLDL-C, and HDL-C), AI, and CRR. A histopathological examination was conducted on portions of the right and left liver lobes from each animal. A connection between Hhcy and dyslipidaemia was indicated by the findings of biochemical and histological analyses, suggesting that Hhcy was a pro-atherogenic state. An improvement in the lipid profile along with a decrease in the atherogenic index by statins suggests that atorvastatin and simvastatin could be useful antiatherogenic agents, with protective activities during hyperhomocysteinaemia.