Marina Kostić

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.

Pharmacokinetics of linezolid in critically ill patients.

ABSTRACT Introduction: Linezolid is an oxazolidinone antibiotic active against Gram-positive bacteria, and is most commonly used to treat life-threatening infections in critically ill patients. The pharmacokinetics of linezolid are profoundly altered in critically ill patients, partly due to decreased function of vital organs, and partly because life-sustaining drugs and devices may change the extent of its excretion. Areas covered: This article is summarizes key changes in the pharmacokinetics of linezolid in critically ill patients. The changes summarized are clinically relevant and may serve as rationale for dosing recommendations in this particular population. Expert opinion: While absorption and penetration of linezolid to tissues are not significantly changed in critically ill patients, protein binding of linezolid is decreased, volume of distribution increased, and metabolism may be inhibited leading to non-linear kinetics of elimination; these changes are responsible for high inter-individual variability of linezolid plasma concentrations, which requires therapeutic plasma monitoring and choice of continuous venous infusion as the administration method. Acute renal or liver failure decrease clearance of linezolid, but renal replacement therapy is capable of restoring clearance back to normal, obviating the need for dosage adjustment. More population pharmacokinetic studies are necessary which will identify and quantify the influence of various factors on clearance and plasma concentrations of linezolid in critically ill patients.

Alcohol consumption among adolescents in Kraljevo, Serbia

The aim of this study was to investigate the prevalence and predictors of alcohol consumption among adolescents in one town in Central Serbia. A questionnaire was used to obtain data from 191 Serbian students aged 18 years regarding personal experience with alcohol consumption and cigarette smoking, along with sociodemographics data. Alcohol consumption was reported by 97.4% subjects, with 34.9% having the first experience with alcohol at the age of 14 years or less. Binge drinking (the intake of five or more drinks at one sitting) was reported by 37.8% subjects. Significantly higher consumption of beer (p<0.0001) and spirits (p=0.03) was observed in boys. The most common reason for both initiation and continuation of drinking, regardless of gender, were celebrations (p≥0.12). Smokers were more likely than nonsmokers to consume all alcoholic beverages more frequently (p≤0.04) and in larger quantities (p≤0.004). More frequent or more extensive alcohol consumption, or both, was associated in boys with frequent going out and socializing (p≤0.01), close peer relationship (p=0.04), alcohol abuse within the immediate environment (p≤0.04), better financial status of family (p=0.04), and parental criticism (p≤0.02); in girls, it was associated with parental disapproval (p≤0.02), alcohol abuse within the immediate environment (p≤0.04), and general discontentedness (p=0.049). Regardless of gender, positive alcohol outcome expectancies increased alcohol consumption (p≤0.048), and negative expectancies decreased intake (p≤0.047).

Evaluation of brivaracetam: a new drug to treat epilepsy

ABSTRACT Introduction: High prevalence of therapy-resistant epilepsy demands development of anticonvulsants with new mechanisms of action. Brivaracetam is an analogue of levetiracetam which binds to the synaptic vesicle protein 2A (SV2A) and decreases release of excitatory neurotransmitters. Areas covered: Relevant published studies were searched for by predefined strategy in MEDLINE, EBSCO and SCINDEKS electronic databases. Brivaracetam is effective as adjunctive therapy for uncontrolled partial-onset seizures with or without secondary generalization in patients 16 years and older with epilepsy. It reduces baseline-adjusted focal seizure frequency per week from 7.3 to 12.8% over placebo. Adverse events rate in patients with brivaracetam is not higher than in patients with placebo. Expert opinion: Brivaracetam is an important step forward in the treatment of therapy-resistant partial-onset seizures with or without secondary generalization. Its development was systematic and targeted. Due to its efficacy and excellent safety profile, it is likely that brivaracetam will be often prescribed. In future, efficacy and safety of brivaracetam should be tested in monotherapy settings and also in the first-line therapy of partial-onset seizures.

Cost-Effectiveness Comparison of Fidaxomicin and Vancomycin for Treatment of Clostridium difficile Infection: A Markov Model Based on Data from a South West Balkan Country in Socioeconomic Transition ☆

BACKGROUND Recent studies have shown that fidaxomicin, a novel antibiotic, can reduce the rate of complications and mortality in patients with colitis induced by Clostridium difficile. Introduction of fidaxomicin in clinical practice is limited by its high costs. OBJECTIVES The purpose of this study was to estimate the cost effectiveness of using fidaxomicin versus vancomycin in patients with colitis induced by C. difficile who did not respond to oral metronidazole. METHODS We constructed a Markov model that was than simulated by Monte-Carlo simulation using 1000 virtual patients with colitis induced by C. difficile. The perspective in our model was institutional. The time horizon was 3 months. Values of transition probabilities and therapy outcomes were estimated from the available literature, the prices of health services were obtained from the Republic Institute for Health Insurance Tariff Book, and the price of fidaxomicin was derived from data gained from the drug manufacturer. RESULTS The total costs of treating one statistical patient for 3 months with fidaxomicin were higher (48,106.19 ± 118.07 Republic of Serbia dinars [RSD]; 95% confidence interval 47,988.12-48,224.27) than the total costs of treating with vancomycin (25,872.85 ± 41.44 RSD; 95% confidence interval 25,831.41-25,914.29). Our results showed that the treatment of infections induced by C. difficile with fidaxomicin correlated with a lower rate of mortality and with a smaller number of colectomies. The incremental cost-effectiveness ratio of fidaxomicin versus vancomycin for colitis induced by C. difficile per saved life was estimated at 2.97 million RSD and for one avoided colectomy at 10.07 million RSD. CONCLUSIONS Results of our model indicate that fidaxomicin is a cost-effective therapy compared with vancomycin in patients with colitis induced by C. difficile if the outcome is life-year saved. However, if the outcome is the number of avoided colectomies, then fidaxomycin is not a cost-effective option compared with vancomycin.

Aplicyanins – brominated natural marine products with superbasic character

Abstract By using quantum chemical methods (B3LYP/6-311+G(2df,p)//B3LYP/6-31G(d)), we investigated the structures of aplicyanin A, aplicyanin B, aplicyanin C, aplicyanin D, aplicyanin E, and aplicyanin F along with their protonated structures. The calculated gas phase proton affinities of aplicyanin A, aplicyanin C, and aplicyanin E are around –250 kcal mol−1 and therefore more than 10 kcal mol−1 higher as in typical proton sponges such as 1,8-bis(dimethylamino)naphthalene. The compounds aplicyanin B, aplicyanin D, and aplicyanin F show reduced proton affinities of approximately –240 kcal mol−1 because of the acetyl group being conjugated with the imine N=C moiety. Nucleus-independent chemical shift (NICS) calculations on the same level of theory do not show any peculiarities, and a reasonable correlation between the toxicity of aplicyanins and the gas phase proton affinity is not observed.

Analysis of the cost–effectiveness of dronedarone versus amiodarone, propafenone, and sotalol in patients with atrial fibrillation: results for Serbia

BACKGROUND Recent studies have shown that dronedarone is associated with significantly fewer adverse effects and treatment discontinuations, and a trend toward reduced all-cause mortality, compared with amiodarone. Introduction of dronedarone in clinical practice is limited by its higher cost than amiodarone, propafenone, and sotalol. AIM To estimate cost-effectiveness of dronedarone versus amiodarone, propafenone, and sotalol in patients with atrial fibrillation (AF). METHODS We constructed a Markov model, which was then simulated by Monte Carlo simulation using 1,000 virtual patients. Costs and outcomes were estimated from the societal perspective and discounted at 3% annually. A lifetime horizon and three-month cycle length were used. The main outcome measurement was the number of years spent without stroke. Values of transition probabilities and therapy outcomes were estimated from available literature. The prices of health services and drugs were obtained from the Republic Institute for Health Insurance Tariff Book and Drug List A and from the drug developer. RESULTS Cost-effectiveness shows that the dronedarone treatment option has the most advantageous relationship, where, for one year without a stroke, the total cost is €1,779.23. In the case of the amiodarone therapy option, for one year without a stroke €3,845.10 is needed, for propafenone €4,674.20, while for sotalol the sum is €14,973.89. Estimated annual costs for patients with first-detected AF in Serbia were €610. CONCLUSIONS The results of our model indicate that dronedarone is a cost-effective therapy compared with amiodarone, propafenone, and sotalol in patients with AF, if the outcome measurement is the number of years spent without stroke.

Synthesis, crystal and solution structures and antimicrobial screening of palladium(II) complexes with 2-(phenylselanylmethyl)oxolane and 2-(phenylselanylmethyl)oxane as ligands

Two novel Pd(II) complexes with 2-(phenylselanylmethyl)oxolane and 2-(phenylselanylmethyl)oxane as ligands were synthesized. The crystal and molecular structure of the complexes has been determined by single crystal X-ray diffraction. It turned out for both complexes that the two ligands are coordinated to Pd via Se atoms in a trans-fashion and the other two trans-positions are occupied by Cl ions. Detailed 1D- and 2D-NMR analyses revealed the existence of equilibrating trans-diastereomeric species differing in the configuration at four chiral centers (selenium and carbon) in the solution of the complexes. A computational study was also undertaken to assess the relative stabilities of the mentioned stereoisomeric species. The antimicrobial properties of the complexes were investigated against a series of human pathogenic bacterial and fungal strains. The complexes were shown to possess promising broad spectrum moderate antimicrobial activity that is more pronounced against fungal organisms. The noted activity could be completely attributed to the Pd(II) center, whereas the ligands probably mediate the transportation of a Pd(II) species across cell membranes.

Profile of evolocumab and its cost-effectiveness in patients with high cardiovascular risk: literature review

ABSTRACT Introduction: Evolocumab is fully human monoclonal antibody which binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), and prevents its blocking effect on recycling of liver low-density lipoprotein (LDL) receptors. Areas covered: The aim of this review is to assess efficacy, safety, and cost-effectiveness of evolocumab in adult patients with high cardiovascular risk. Major research databases MEDLINE, EBSCO, and CENTRAL were systematically searched for relevant study reports. Expert commentary: Even when given in full doses, statins augmented with ezetimibe and cholesterol-binding resins could not reduce cholesterol baseline level for more than 66%, while evolocumab reduces cholesterol level for 75% or even more. Up to now, evolocumab showed good safety profile, and patents tolerate it very well. The abovementioned advantages of evolocumab made it almost ideal drug for hypercholesterolemia, and probably in the future the best drug for secondary prevention of major cardiovascular events. Evolocumab is borderline cost-effective for the treatment of patients with high cardiovascular risk in European countries, while in the U.S.A. it is under debate where the underlying assumption (risk of cardiovascular disease events) determine the true value.

Cost-Effectiveness of Introducing Point-of-Care Test for Detection of Level of Glycogen Phosphorylase in Early Diagnostic Algorithm of Acute Coronary Syndrome

BACKGROUND The detection of specific biomarkers in the early phase of acute coronary syndrome (ACS) is important for the early diagnosis and appropriate management of patients with ACS. OBJECTIVES To estimate the cost-effectiveness of introducing a diagnostic point-of-care (POC) test for determining the levels of glycogen phosphorylase BB isoform (GPBB) in a standard diagnostic algorithm for the early diagnosis of ACS within the health system of the Republic of Serbia. METHODS The probabilistic decision-tree model was constructed for patients with nontraumatic chest pain comparing the use of standard diagnostic procedure, physical examination, and electrocardiogram monitoring with the use of a diagnostic test for the detection of the levels of specific biomarkers. The perspective of the health care services purchaser (the Republic Institute for Health Insurance, Serbia) was used in the model, and only direct costs were taken into account. The time horizon was set at one treatment episode of ACS, and the discount rate was not included because of the short length of the time horizon. RESULTS Using the GPBB POC test in comparison with not using it in the early diagnosis of ACS results in a significant reduction in the cost per treatment episode (10,034.48 ± 7,283.80 Serbian dinar [RSD]), increase in the number of survivors per 1000 treatment episodes (16 ± 18), decrease in the number of hospitalizations per 1000 treatment episodes (104 ± 44), and decrease in the number of performed coronarographies per 1000 treatment episodes (22 ± 19). The costs per hospitalization avoided (incremental cost-effectiveness ratio) were -145,887.57 ± 5,271.54 RSD, and the costs per coronarography avoided were -137,295.68 ± 4,681.05 RSD. CONCLUSIONS In the circumstances of limited health resources, reducing hospitalizations and decreasing unnecessary treatments and invasive diagnostic procedures by a GPBB POC test could be an effective way to improve the economic status of other Balkan countries with limited health care budgets.