Cardiomyocyte Damage: Ferroptosis Relation to Ischemia-Reperfusion Injury and Future Treatment Options.

About half a century ago, Eugene Braunwald, a father of modern cardiology, shared a revolutionary belief that "time is muscle", which predetermined never-ending effort to preserve the unaffected myocardium. In connection to that, researchers are constantly trying to better comprehend the ongoing changes of the ischemic myocardium. As the latest studies show, metabolic changes after acute myocardial infarction (AMI) are inconsistent and depend on many constituents, which leads to many limitations and lack of unification. Nevertheless, one of the promising novel mechanistic approaches related to iron metabolism now plays an invaluable role in the ischemic heart research field. The heart, because of its high levels of oxygen consumption, is one of the most susceptible organs to iron-induced damage. In the past few years, a relatively new form of programmed cell death, called ferroptosis, has been gaining much attention in the context of myocardial infarction. This review will try to summarize the main novel metabolic pathways and show the pivotal limitations of the affected myocardium metabolomics.

Novel Applications of NSAIDs: Insight and Future Perspectives in Cardiovascular, Neurodegenerative, Diabetes and Cancer Disease Therapy.

Once it became clear that inflammation takes place in the modulation of different degenerative disease including neurodegenerative, cardiovascular, diabetes and cancer the researchers has started intensive programs evaluating potential role of non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention or therapy of these diseases. This review discusses the novel mechanism of action of NSAIDs and its potential use in the pharmacotherapy of neurodegenerative, cardiovascular, diabetes and cancer diseases. Many different molecular and cellular factors which are not yet fully understood play an important role in the pathogenesis of inflammation, axonal damage, demyelination, atherosclerosis, carcinogenesis thus further NSAID studies for a new potential indications based on precise pharmacotherapy model are warranted since NSAIDs are a heterogeneous group of medicines with relative different pharmacokinetics and pharmacodynamics profiles. Hopefully the new data from studies will fill in the gap between experimental and clinical results and translate our knowledge into successful disease therapy.

Cytochrome P450 2C19 enzyme, Cytochrome P450 2C9 enzyme, and Cytochrome P450 2D6 enzyme allelic variants and its possible effect on drug metabolism: A retrospective study.

ABSTRACT: The objective of the present study was to assess the allelic variations of Cytochrome P450 (CYP) enzymes Cytochrome P450 2C19 (CYP2C19), Cytochrome P450 2C9 (CYP2C9), and Cytochrome P450 2D6 (CYP2D6) as they play a major role in drug metabolism. The interindividual genetic variabilities of these enzymes can account for different responsiveness as well as concentration fluctuations for a particular drug.During the period of 2017 to 2018 a total of 54 patients have received pharmacogenetic testing at the Department of Genetics and Molecular Medicine at Kaunas Clinics. According to the genotype-metabolic phenotypes of CYP2C19, CYP2D6, CYP2C9 enzymes patients were classified according to the guidelines by Clinical Pharmacogenetics Implementation Consortium (CPIC): normal metabolizers (NMs), intermediate metabolizers (IMs), rapid metabolizers (RMs), ultrarapid metabolizers (UMs), and poor metabolizers (PMs).CYP2C19 enzyme allelic distribution: 18 patients (33.33%) with ∗1/∗1 genotype were NMs; 14 patients (25.93%) with ∗1/∗2; ∗2/∗17 genotypes were classified as IMs; 15 patients (27.78%) possessed ∗1/∗17 genotype and were RMs; 4 patients (7.4%) had ∗17/∗17 genotype with increased enzyme activity compared with RMs, were classified as UMs; 3 patients (5.56%) had ∗2/∗2 genotype and were marked as PMs. CYP2D6 enzyme allelic distribution: 26 patients (48.148%) contained ∗1/∗1,∗2/∗2,∗1/∗2,∗1/∗41,∗2/∗41 genotypes with normal enzymatic function so were accounted as NMs; 21 patients (38.89%) with ∗1/∗5, ∗2/∗4, ∗10/∗41, ∗1/∗4, ∗1/∗3, ∗2/∗5, ∗2/∗4, ∗2/∗6 genotypes were accounted as IMs; 2 patients (3.7%) possessed ∗2XN genotype and were accounted as UMs and 5 patients (9.26%) possessed ∗4/∗5,∗4/∗10,∗4/∗9,∗4/∗41 genotypes and had non-functional enzymatic activity so were accounted as PMs; CYP2C9 enzyme allelic distribution: 44 patients (81.48%) with∗1/∗1 genotype were NMs; 10 patients (18.52%) with ∗1/∗2;∗1/∗3 genotypes were IMs.The results of our study indicate that deviations from the normal enzymatic activity is common amongst Lithuanian people and combinatory genotyping of CYP2D6, CYP2C9, and CYP2C19 has to be promoted as an advanced method because of most commonly prescribed medicines like analgesics, antihypertensive, antidepressants are metabolized by multiple pathways involving enzymes in the CYP450 family.

Analyses of AUC(0-12) and C0 Compliances within Therapeutic Ranges in Kidney Recipients Receiving Cyclosporine or Tacrolimus.

The AUC (area under the concentration time curve) is considered the pharmacokinetic exposure parameter best associated with clinical effects. Unfortunately, no prospective studies of clinical outcomes have been conducted in adult transplant recipients to investigate properly the potential benefits of AUC(0-12) monitoring compared to the C0-guided therapy. The aim of the present study was to compare two methods, C0 (through level) and AUC(0-12) (area under the concentration time curve), for assessing cyclosporine and tacrolimus concentrations. The study included 340 kidney recipients. The AUC(0-12) was estimated using a Bayesian estimator and a three-point limited sampling strategy. Therapeutic drug monitoring of tacrolimus performed by using AUC(0-12) and C0 showed that tacrolimus in most cases is overdosed when considering C0, while determination of the AUC(0-12) showed that tacrolimus is effectively dosed for 27.8-40.0% of patients receiving only tacrolimus and for 25.0-31.9% of patients receiving tacrolimus with MMF (mycophenolate mofetil). In the 1-5 years post-transplantation group, 10% higher CsA (cyclosporine) dose was observed, which was proportionate with a 10% higher AUC(0-12) exposure value. This indicates good compatibility of the dosage and the AUC(0-12) method. The Bland-Altman plot demonstrated that C0 and AUC(0-12) might be interchangeable methods, while the ROC (receiver operating characteristic) curve analysis of the C0/AUC(0-12) ratio in the tacrolimus-receiving patient group demonstrated reliable performance to predict IFTA (interstitial fibrosis and tubular atrophy) after kidney transplantation, with an ROC curve of 0.660 (95% confidence interval (CI): 0.576-0.736), p < 0.01. Moreover, AUC(0-12) and C0 of tacrolimus depend on concomitant medication and adjustment of the therapeutic range for AUC(0-12) might influence the results.

Pharmacokinetic evaluation of MFF in combinations with tacrolimus and cyclosporine. Findings of C0 and AUC.

We hypothesized that area under the concentration time curve (AUC(0-12)) is more accurate pharmacokinetic predictor vs trough level of mycophenolic acid (C0).Study was performed at the University Hospital of Limoges (France) and included 238 renal recipients aged 22 to 82 years. Risk of nephropathy was evaluated by analyzing data of protocol biopsies according to the Banff 97 classification.Assessment of immunosuppressants' exposures was based on the calculation of the mean of AUC(0-12). The AUC(0-12) was estimated using a Bayesian estimator and a 3-point limited sampling strategy. Cyclosporine and tacrolimus analyses were performed using liquid chromatography-mass spectrometry method. The measurement of total mycophenolic acid was performed using a validated high-performance liquid chromatography method with ultraviolet detection. IBM SPSS 20.0 was used for statistical analysis.The most accurate dosing of mycophenolate mofetil (MMF) was observed in patients receiving MMF with tacrolimus, 70.6% of patients' AUC(0-12) exposures were within the therapeutic range. The highest rates of low dosing were observed in patients receiving MMF with cyclosporine, 30.9% of patients had AUC(0-12) exposures below the therapeutic range. The assessment of AUC(0-12) revealed 38% of chronic nephropathy cases, while C0 enables to identify only 20% of chronic nephropathy cases.Probability test results showed that more likely AUC(0-12) and C0 will be maintained within the therapeutic width if patients receive MMF with tacrolimus vs MMF with cyclosporine: 0.6320 vs 0.6410 for AUC(0-12) determination and 0.8415 vs 0.4827 for C0 determination.Combination of MMF with tacrolimus is dosed more precisely vs dosing of MMF with cyclosporine. 72 (70.6%) patients AUC(0-12) and 79 (77.5%) patients C0 out of 102 patients were within the therapeutic range. The AUC(0-12) monitoring of mycophenolic acid in patients receiving MMF with tacrolimus or in patients receiving MMF with cyclosporine enabled to identify more overdosing and possible risky cases.Study results show that standard MMF dosing without monitoring and with mycophenolic acid level within the therapeutic width is possible and demonstrates less risky cases in patients receiving MMF with tacrolimus, while patients receiving MMF with cyclosporine should be intensively monitored to achieve the highest safety. However, AUC(0-12) monitoring is advised showing better compliance vs C0 monitoring.

Low-Dose Omega-3 Fatty Acid and Vitamin D for Anthropometric, Biochemical Blood Indices and Respiratory Function. Does it work?

Omega-3 fatty acids and vitamin D3 have beneficial effects on different blood, cardiovascular parameters and physical performance. However, the effect of low-dose omega-3 fatty acid supplementation remains unclear. 84 office workers aged 40-60 years, participated in a 16-week open, randomized, placebo-controlled, parallel-group study. The experimental group received 330 mg of omega-3 fatty acid and 0.005 mg (200 IU) of vitamin D3 per day and the control group received placebo. Anthropometric, biochemical blood and respiratory indices were measured at 12 and 16 weeks. Body mass (BM) and body mass index (BMI) significantly reduced in both the experimental (BM from 74.4 ± 13.04 to 73.2 ± 13.02 kg, p < 0.001; BMI from 25.8 ± 4.1 to 25.4 ± 4.3 kg/m2, p < 0.001) and the placebo groups (BM from 69.5 ± 11. to 68.7 ± 11.4 kg, p < 0.05; BMI from 24.1 ± 4.0 to 23.8 ± 4.2 kg/m2, p < 0.05). Omega-3 fatty acid supplementation significantly improved glucose (from 5.12 ± 0.55 to 4.97 ± 0.62 mmol/l; p = 0.05), total cholesterol (from 5.86 ± 1.0 to 5.32 ± 1.55 mmol/l; p = 0.003), and vitamin D levels (from 35.07 ± 21.65 to 68.63 ± 25.94 nmol/l; p = 0.000). Maximal oxygen consumption (from 33.7 ± 2.4 to 36.6 ± 3.2 ml/kg/min, p = 0.035), forced vital capacity (from 3.5 ± 0.6 to 3.9 ± 0.9 l, p = 0.044), forced expiratory volume (from 3.2 ± 0.6 to 3.5 ± 0.7 l, p = 0.014), and peak expiratory flow (from 6.7 ± 1.4 to 7.5 ± 1.6 l/s, p = 0.019) also slightly improved in the omega-3 fatty acid group. Daily supplementation of 330 mg of omega-3 fatty acids had a slight positive impact on total cholesterol and glucose level, while there was no effect on low and high density lipoproteins, and triglycerides levels. Therefore, dose of 330 mg per day seems as insufficient.

Antibiotic prescribing trends in a pediatric population in Lithuania in 2003-2012: Observational study.

The purpose of this study was to determine the trends in consumption of antibiotics and evaluate the antibiotic prescription rates in the pediatric population in Lithuania during 2003 to 2012.A cross-sectional study. Data of systemic antibiotic use in pediatric population for outpatient treatment was derived from National Health Insurance Fund database. Consumption was expressed as WHO ATC defined daily dose (DDD)/1000 children/day and as a number of prescriptions written in the general population per year. Statistical analysis was performed using the SPSS/W 20.0 software (Statistical Product and Service Solutions for Windows).Total utilization of antibiotics (expressed in DDD units) during study period increased by 8.40% (from 5.67 to 6.19 DDD/1000 children/day) and by 5.96% expressed in prescription rate (from 585.84 to 622.97 prescriptions/1000 children/year). The most popular antibiotic group was macrolides which showed the highest increase of utilization 5.9 times (from 0.27 DDD/1000 children/day in 2003 to 1.66 DDD/1000 children/day in 2012).The most common indications for antibiotic prescribing for children in 2012 were acute bronchitis (25.6%), acute tonsillitis (21.7%) and acute pharyngitis (14.6%). Amoxicillin had the highest probability to be chosen to treat acute tonsillitis (prob. [probability] = .2875) and acute pharyngitis (prob. = .5553). Clarithromycin had the highest probability to be chosen to treat acute bronchitis (prob. = .4222).Most of the diseases treated with antibiotics were viral infections. The most commonly prescribed antibiotics were broad-spectrum. The consumption of antibiotics was evenly increasing during 2003 to 2012 period, but the distribution of separate antibiotic group remained the same.

A case report and literature review: previously excluded tuberculosis masked by amiodarone induced lung injury.

BACKGROUND: Amiodarone is an antiarrhythmic drug which is used to treat and prevent several dysrhythmias. This includes ventricular tachycardia and fibrillation, wide complex tachycardia, as well as atrial fibrillation (AF) and paroxysmal supraventricular tachycardia. Amiodarone may prove to be the agent of choice where the patient is hemodynamically unstable and unsuitable for direct current (DC) cardioversion. Although, it is not recommended for long-term use. The physician might encounter issues when differentiating amiodarone-induced lung toxicity with suspicion of interstitial lung disease, cancer or vasculitis. Adverse drug reactions are difficult to confirm and it leads to serious problems of pharmacotherapy. CASE PRESENTATION: A 78-year-old Caucasian male pensioner complaining of fever, dyspnea, malaise, non-productive cough, fatigue, weight loss, diagnosed with acute respiratory failure with a 16-year long history of amiodarone use and histologically confirmed temporal arteritis with long-term glucocorticosteroid (GCC) therapy. Patient was treated for temporal arteritis with GCC for ~ 1 year, then fever and dyspnea occurred, and the patient was hospitalized for treatment of bilateral pneumonia. Chest X-ray and chest high resolution computed tomography (HRCT) indicated several possible diagnoses: drug-induced interstitial lung disease, autoimmune interstitial lung disease, previously excluded pulmonary TB. Amiodarone was discontinued. Antibiotic therapy for bilateral pneumonia was started. Fiberoptic bronchoscopy with bronchial washings and brushings was performed. Acid fast bacilli (AFB) were found on Ziehl-Nielsen microscopy and tuberculosis (TB) was confirmed (later confirmed to be Mycobacterium tuberculosis in culture), initial treatment for TB was started. After a few months of treating for TB, patient was diagnosed with pneumonia and sepsis, empiric antibiotic therapy was prescribed. After reevaluation and M. Tuberculosis identification, the patient was referred to the Tuberculosis hospital for further treatment. After 6 months of TB treatment, pneumonia occurred which was complicated by sepsis. Despite the treatment, multiple organ dysfunction syndrome evolved and patient died. Probable cause of death: pneumonia and sepsis. CONCLUSIONS: The current clinical case emphasizes issues that a physician may encounter in the differential diagnostics of amiodarone-induced lung toxicity with other lung diseases.

Impact of the World Health Organization Pain Treatment Guidelines and the European Medicines Agency Safety Recommendations on Nonsteroidal Anti-Inflammatory Drug Use in Lithuania: An Observational Study.

Background and objective: Irrational use of nonsteroidal anti-inflammatory drugs (NSAIDs) is the main cause of adverse effects-associated hospitalizations among all medication groups leading to extremely increased costs for health care. Pharmacoepidemiological studies can partly reveal such issues and encourage further decisions. Therefore, the aim of our study was to evaluate the utilization of non-opioid analgesics (ATC classification N02B and M01A) in Lithuania, and to compare it with that of other Baltic and Scandinavian countries in terms of compliance to the WHO pain treatment guidelines and the EMA safety recommendations on NSAID use. Materials and methods: The dispensing data were obtained from the sales analysis software provider in the Baltic countries (SoftDent, Ltd., Kaunas, Lithuania); State Medicine Control Agencies of Lithuania, Latvia, and Estonia; Norwegian Prescription Database; Swedish Database for Medicines; and Danish Prescription Database. Data included the utilization of both prescription and over-the-counter drugs. Utilization was expressed in defined daily doses (DDD)/1000 inhabitants/day. Results: During the 11-year period, the utilization of drugs belonging to the N02B and M01A groups increased by 22.8%, from 58.37 in 2005 to 71.68 DDD/1000 inhabitants/day in 2016 in Lithuania. Contrary to the WHO guidelines on pain management, all Baltic countries were more likely to use NSAIDs than other analgesics and antipyretics: in 2015, the drugs of the M01A group were used 6.04, 5.79, and 6.11 times more than those of N02B in Lithuania, Estonia, and Latvia, respectively, whereas the Scandinavian countries preferred the N02B to the M01A group: in Denmark and Sweden, the utilization of other analgesics and antipyretics was 2.33 and 1.24, respectively, times higher than that of NSAIDs. In Norway, the use of both groups was similar. In the Scandinavian countries, paracetamol was the analgesic of first choice, whereas, in Lithuania, it took only the third place. The most popular drug in Lithuania was diclofenac, and its utilization accounted for 30.04% of all non-opioid analgesics in 2016. Although the European Medicines Agency (EMA) restricted the use of certain NSAIDs, i.e., cyclooxygenase-2 (COX-2) inhibitors, nimesulide, and diclofenac, their use consistently increased by 15.91, 2.83, and 1.41 times, respectively, showing incompliance with the international guidelines. Conclusions: Neither the EMA safety policy on NSAID use nor the WHO pain treatment guidelines had a sufficient impact on the rational use of NSAIDs in Lithuania. The use of NSAIDs restricted by the EMA (diclofenac, COX-2 inhibitors, nimesulide, and piroxicam) remains high or even increases, while the utilization of safer alternatives (paracetamol and naproxen) remains relatively low as compared with the Scandinavian countries. Incompliance with international guidelines may result in increased morbidity, mortality and higher costs for health care.

Primary antibiotic resistance of Helicobacter pylori strains among adults and children in a tertiary referral centre in Lithuania.

The study evaluated primary antibiotic resistance of Helicobacter pylori within the period 2013-2015 and trends of antibiotic consumption over the last decade in Lithuania; 242 adults and 55 children were included in the study. E-tests were performed for amoxicillin, metronidazole, clarithromycin, ciprofloxacin, rifampicin and tetracycline. The presence of H. pylori and clarithromycin resistance was additionally tested by PCR. Helicobacter pylori culture was positive in 67 of 242 (28%) adult and in 12 of 55 (21.8%) children samples. Resistance rates among adults by E-tests were as follows: metronidazole - 32.8% (95% confidence interval (CI): 22.7-44.7%), ciprofloxacin - 7.5% (95% CI: 3.2-16.3%), rifampicin - 7.5% (95% CI: 3.2-16.3%), amoxicillin - 0%, whereas resistance rates in children were as follows: metronidazole - 25% (95% CI: 8.9-53.2%), rifampicin - 8.3% (CI: 1.5-35.4%), amoxicillin and ciprofloxacin - 0%. Accumulated clarithromycin resistance rates by E-tests and PCR were 8.2% (95% CI: 4.1-16.0%) in adults and 17.7% (95% CI: 6.2-41.0%) in children. Total use of macrolides and lincosamides in Lithuania increased from 1.26 to 1.86 defined daily dose (DDD)/1000 inhabitants/day among adults, while it has doubled from 1.10 to 2.22 DDD/1000/children/day in children within 2003-2015. There are no significant changes in the susceptibility of H. pylori to the most widely used antibiotics in adults over the last years in Lithuania; however, clarithromycin resistance among children exceeds 15% and mandates further larger-scale studies in paediatric population.

Methimazole-induced liver injury overshadowed by methylprednisolone pulse therapy: Case report.

RATIONALE: Treatment choices are limited, when deciding how to manage thyrotoxicosis and moderate to severe Graves ophthalmopathy (GO) with suspected optic nerve damage in patients with elevated liver transaminase levels. The situation become even more complicated, if methimazole induced hepatotoxicity is suspected and intravenous methylprednisolone is co-administrated. PATIENT CONCERNS: A 74-year-old woman presented with spontaneous retro-bulbar pain, eyelid swelling and inconstant diplopia. DIAGNOSES: Thyrotoxicosis and severe GO with suspected optic nerve damage and drug induced liver injury (DILI). INTERVENTIONS: Intravenous methylprednisolone pulse therapy was administered to treat GO and methimazole was continued for thyrotoxicosis. Dose of methimazole was reduced after exclusion of concurrent infection and active liver disease. OUTCOMES: The GO symptoms (eyelid swelling, sight loss, proptosis, retro-bulbar pain, diplopia) markedly decreased after the treatment course. Liver transaminases spontaneously returned to normal ranges and remained normal during the next 12 months until the Graves' disease until the treatment was completed. LESSONS: 1. The interaction of methimazole and methylprednisolone may result in DILI. 2. In a patient without concomitant liver diseases MP can be continued if the methimazole dose is reduced if no other treatment options are available.

Influence of cyclosporine and everolimus on the main mycophenolate mofetil pharmacokinetic parameters: Cross-sectional study.

The objective of the present study was to assess the effect of cyclosporine (CsA) on the pharmacokinetic parameters of mycophenolic acid (MPA), an active mycophenolate mofetil (MMF) metabolite, and to compare with the effect of everolimus (EVR).Anonymized medical records of 404 kidney recipients were reviewed. The main MPA pharmacokinetic parameters (AUC(0-12) and Cmax) were evaluated.The patients treated with a higher mean dose of CsA displayed higher MPA AUC(0-12) exposure in the low-dose MMF group (1000 mg/day) (40.50 ±â€Š10.97 vs 28.08 ±â€Š11.03 h mg/L; rs = 0.497, P < 0.05), medium-dose MMF group (2000 mg/day) (43.00 ±â€Š6.27 vs 28.85 ±â€Š11.08 h mg/L; rs = 0.437, P < 0.01), and high-dose MMF group (3000 mg/day) (56.75 ±â€Š16.78 vs 36.20 ±â€Š3.70 h mg/L; rs = 0.608, P < 0.05).A positive correlation was also observed between the mean CsA dose and the MPA Cmax in the low-dose MMF group (Cmax 22.83 ±â€Š10.82 vs 12.08 ±â€Š5.59 mg/L; rs = 0.507, P < 0.05) and in the medium-dose MMF group (22.77 ±â€Š8.86 vs 13.00 ±â€Š6.82 mg/L; rs = 0.414, P < 0.01).The comparative analysis between 2 treatment arms (MMF + CsA and MMF + EVR) showed that MPA AUC(0-12) exposure was by 43% higher in the patients treated with a medium dose of MMF and EVR than in the patients treated with a medium dose of MMF and CsA.The data of the present study suggest a possible CsA versus EVR influence on MMF pharmacokinetics. Study results show that CsA has an impact on the main MPA pharmacokinetic parameters (AUC(0-12) and Cmax) in a CsA dose-related manner, while EVR mildly influence or does not affect MPA pharmacokinetic parameters. Low-dose CsA (lower than 180 mg/day) reduces MPA AUC(0-12) exposure under the therapeutic window and may lead to ineffective therapy, while a high-dose CsA (>240 mg/day) is related to greater than 10 mg/L MPA Cmax and increases the likelihood of adverse events.

Cisplatin-induced sudden cardiac death with hemodynamic collapse: a severe adverse drug reaction: Case report.

RATIONALE: Cisplatin is responsible for a significant percentage of adverse drug reactions (ADRs) in oncology setting. A great proportion of cisplatin-induced severe adverse events are difficult to foresee, and giving premedication does not always prevent the occurrence of such events. PATIENT CONCERNS: A 53-year-old woman with progressive T4 N0 M0 stage IV pleural mesothelioma experienced cardiac arrest with hemodynamic collapse after cisplatin and pemetrexed chemotherapy administration. DIAGNOSES: Progressive pleural T4 N0 M0 stage IV mesothelioma of the right lung, primary arterial hypertension, and cardiac arrest with hemodynamic collapse. INTERVENTIONS: The cisplatin and pemetrexed chemotherapy was administered intravenously for progressive pleural T4 N0 M0 stage IV mesothelioma of the right lung. During infusion of cisplatin the patient developed cardiac arrest, and cardiopulmonary resuscitation was initiated. OUTCOMES: The patient was treated in intensive care unit and recovered successfully. Further chemotherapy with cisplatin and pemetrexed was withheld due to this severe adverse reaction to cisplatin. LESSONS: Cisplatin therapy should be thoroughly monitored including electrolyte, especially magnesium levels. Absence of previous ADRs to cisplatin and premedication should not give false sense of security.

Cyclosporine therapeutic window evaluation by Chebyshev's inequality method in kidney recipients.

OBJECTIVE: The aim of this study was to identify a cyclosporine therapeutic range for kidney recipients. MATERIALS AND METHODS: The cyclosporine exposure level was based on the calculation of the mean area under the concentration-time curve AUC(0-12). The AUC(0-12) was estimated using a Bayesian estimator and a 3-point limited sampling strategy. Cyclosporine exposure levels were obtained from 3 blood samples: 0, 1, and 3h postdose; and analyses were performed using a liquid chromatography-tandem mass spectrometry method. The therapeutic window of cyclosporine was calculated by the Chebyshev's inequality method with a 99% guarantee (α=0.01) using the IBM SPSS Statistics 20 software. RESULTS: It was found that the therapeutic window of cyclosporine estimated by the Chebyshev's inequality method and put on the AUC(0-12) exposure lies in the ranges from 2.84-3.13 mg h/L with the 99% confidence for the patients with the target AUC(0-12) exposure of 3.8 mg h/L (posttransplantation time >1 year). The therapeutic window of cyclosporine differs in different posttransplantation time groups: the estimated AUC exposure range in the group of patients who have a graft longer than 5 years is 2.70-2.98 mg h/L, and the estimated AUC exposure range in the group of patients who have a graft for 1-5 years is 3.05-3.75 mg h/L. CONCLUSIONS: Chebyshev's inequality could be an appropriate and more precise method to determine the therapeutic window for cyclosporine in kidney recipients than the target AUC(0-12) value and further studies should be conducted to evaluate patients with postoperative time <1 year.

Influence of coadministration of antithrombotic medicines, warfarin, and NSAIDs on heparin safety: data from a prospective observational study.

BACKGROUND: Utilization of heparins has been increasing in the last decade, thus, in-depth analysis is needed to assess heparins safety monitoring patterns, incidence rates of adverse drug reactions (ADR), and frequency of coadministration with other medicines.  OBJECTIVE: To investigate the safety monitoring of heparin in hospitals and the influence of coadministration of nonsteroidal anti-inflammatory drugs (NSAIDs), antithrombotic medicines, and warfarin on heparin safety.  METHODS: We reviewed hospital records of 339 patients who had orders for heparin or low molecular weight heparin from May 2009 to May 2010. IBM SPSS Statistics version 18.0 was used to perform statistical analysis.   RESULTS: Dalteparin (n=238, 70.21%) was the most frequently prescribed heparin. The most frequent indications given were for prophylaxis of venous thrombosis (n=135, 39.82%) and treatment of unstable coronary artery disease and myocardial infarction (n=166, 48.97%). ADRs were reported for 75 patients (22.12%), including coagulation abnormalities in 25 patients (7.37%), renal dysfunctions in 24 patients (7.08%), and thrombocytopenia in 10 patients (2.95%). 256 patients (75.52%) had relative contraindications. ADRs were associated with the previously reported relative contraindications (Spearman's rank correlation coefficient [rS] = 0.261, Pearson's chi-squared test [χ2]= 45.5, P less than 0.0005) and with prolonged treatment with heparins (rS=0.279 and χ2=74.7, P less than 0.0005). ADRs were not related to heparin use but indicated increased risk for negative treatment outcomes. Coadministration of heparin with warfarin, acetylsalicylic acid, clopidogrel, ketorolac, and NSAIDs was associated with the increased risk of adverse drug reactions. The relationship was low but statistically significant. The strongest relationship was with coadministration of aspirin (rS=0.283, χ2=21.42, P less than 0.0005), while the coadministration of NSAIDs showed only a very weak relationship to the development of ADRs (rS=0.133, χ2=21.01, P less than 0.0005). For the development of thrombocytopenia, the strongest risk was calculated for coadministration of warfarin (rS=0.248, χ2=28.14, P less than 0.0005), while coadministration of medicines from the list did not have a relationship with the risk of thrombocytosis.   CONCLUSIONS: Safety monitoring of heparin orders is essential, especially for patients with relative contraindications during long-term treatment and in case of coadministration of oral anticoagulants, platelet inhibitors, and NSAIDs.

Cognitive failure evaluation and therapy based on pharmacy practice - utilization of anti-dementia drugs and food supplements in Lithuania.

OBJECTIVE: To evaluate cognitive failures of patients visiting pharmacies and to study utilization of drugs for dementia therapy in Lithuania. METHODS: 153 patients completed a Cognitive Failure Questionnaire (CFQ) at pharmacy. The ATC/DDD method was used to evaluate utilization of drugs licensed for dementia treatment, including C04AE (peripheral vasodilators), N04BD (MAO inhibitors), N06D (anti-dementia drugs), N06BX (nootropics), N07C (anti-vertigo), and A11HA (plain vitamin E) preparations. RESULTS: 53 of 153 study participants (34.6%) scored over 45 CFQ points and reported cognitive failure, assessed by three factors: F1 - forgetfulness, F2 - distractibility and F3 - false triggering. All three factors correlate with age and the most significant extent has memory performance (Spearman's rank correlation coefficient (rs) F1 - rs = 0.85, p < 0.01; F3 - rs = 0.79, p < 0.01, and F2 - rs = 0.4, p < 0.01) and do not depend on gender or educational background. Total use of anti-dementia drugs and food supplements decreased from 27.08 DDD/1,000 inhabitants/day in 2006 to 26.46 DDD/1,000 inhabitants/day in 2011. Nicergoline 6.26 DDD/1,000 inhabitants/day and cinnarizine 6.16 DDD/1,000 inhabitants/ day - were the most prescribed medications in 2011. Total costs for anti-dementia drugs increased from EUR 8.91 million to EUR 11.63 million during the same period. The largest amount of EUR 3.166 million was spent on nicergoline. Older people were more likely than younger people to report using prescription drugs (rs = 0.468; p < 0.01), while younger population used more supplements (rs = -0.227; p = 0.005). CONCLUSIONS: Trend of anti-dementia drugs use in Lithuania is similar to other EU countries; however, there are some deviations from dementia treatment guidelines, particularly in terms of nicergoline and cinnarizine recommendations.

Evolution of Helicobacter pylori susceptibility to antibiotics during a 10-year period in Lithuania.

The study evaluated the changes in the prevalence of Helicobacter pylori strains with primary resistance to antibiotics during the last 10 years in Lithuania. H. pylori susceptibilities to antibiotics were tested in 89 patients in 1998, in 81 patients in 2001 and in 90 patients in 2007/2008. Susceptibility to metronidazole, clarithromycin, amoxicillin and tetracycline was tested using E-test or agar dilution method. Susceptibility to ciprofloxacin was only tested in 2007/2008. Data about utilization of all authorized and available on market macrolides and clindamycin in Lithuania during 2003-2007 were evaluated using WHO ATC/DDD methodology. A total of 260 H. pylori strains cultured from untreated adult patients were investigated. Primary resistance rates (1998, 2001 and 2007/2008) for metronidazole were 24.7%, 33.3%, and 35.6%, for clarithromycin 1.1%, 3.7%, and 3.3% and for tetracycline 0%, 2.5% and 0% respectively. No cases of amoxicillin resistance have been detected. The resistance rate for ciprofloxacin was 5.6% in 2007/2008. Data of total macrolides and clarithromycin utilization in Lithuania revealed that despite an increase of consumption of these drugs in Lithuania during 2003-2007 in 1.5 times, the total macrolide consumption remains one of the lowest in Europe. We have not observed any significant changes in the susceptibility of H. pylori to the most widely used antibiotics during the recent 10-year period. The low resistance rate to clarithromycin might be related to the policy to avoid use of macrolides as first-line treatment for pulmonary and other infections.

Low-molecular-weight heparins: pharmacoeconomic decision modeling based on meta-analysis data.

OBJECTIVES: The aim of this study was to compare efficacy, safety, and consumption of low-molecular-weight heparins with unfractionated heparin, and to develop a pharmacoeconomic decision model based on meta-analysis data. METHODS: Review and meta-analysis were performed of published randomized control trials directly comparing the safety and efficacy of low-molecular-weight heparins (LMWHs)-that is, nadroparin, enoxaparin, and dalteparin-and unfractionated heparin (UFH) was performed by two reviewers using inclusion/exclusion criteria based on the research objectives. The value of fixed effects and random effects odds ratio (95 percent confidence interval) was calculated for each trial for the composite end point. Subsequently, a pharmacoeconomic decision modeling based on reference pricing methodology was implemented. RESULTS: In comparison to UFH, all LMWHs have independently demonstrated greater safety and effectiveness. None of the LMWHs demonstrated a significant superiority over each other; therefore, the group of LMWHs was interchangeable and suitable for cost minimization analysis and reference price implementation. Being the least expensive option, dalteparin single DDD price was set as the reference. Introduction of reference pricing for LMWHs would decrease the total expenditure on LMWHs of approximately 30 percent and would result in total savings of 1.830-2.070 thousand LTL in the country of Lithuania (approximately 0.8 million USD) per year. CONCLUSIONS: The meta-analysis results of LMWHs could be used to support a policy on reference-based pricing and pharmacoeconomic decision modeling in healthcare institutions, which would allow a decrease in healthcare expenditures.

Severe vancomycin-induced anaphylactic reaction.

Vancomycin is widely used against methicillin-resistant Staphylococcus aureus infections, but it is associated with many adverse effects such as nephrotoxicity, ototoxicity, gastrointestinal disturbances, blood disorders, and two types of hypersensitivity reactions - an anaphylactoid reaction known as "red man syndrome" and anaphylaxis. We report a case of a 23-year-old man who developed a vancomycin-induced anaphylactic reaction in the treatment of methicillin-resistant Staphylococcus aureus infection.

Policy implications of rationalization of statin use in Lithuania.

OBJECTIVES: The aim of this study was to assess the trends and costs of statin use in Lithuania over a 3-year period and perform a cost-minimization and reference price analysis to rationalize the use of financial resources of the National Health Care System. METHODS: The defined daily dose (DDD) methodology was applied for assessment of statin use, which was expressed in DDD/1,000 inhabitants/day. Cost minimization and reference price calculations were used in the economic analysis. RESULTS: Over the 3-year period (2005-2007), the consumption and expenditures of statins in Lithuania doubled. The consumption went up from 3.87 DDD/1,000 inhabitants/day (in 2005) to 8.35 DDD/1,000 inhabitants/day (in 2007). Total expenses of statins increased during the same period from LTL6.186 million in 2005 to LTL12.418 million in 2007. Approximately 68 percent of the estimated costs for statins in 2007 were for atorvastatin. Provided that the calculated reference prices were fixed, the estimated savings would amount to a minimum of LTL1.371 million per year and could reach yearly savings in the order of LTL3.163 million. The total expenses would drop by at least 11 percent, and the decrease in costs could be as high as 25 percent (1 euro = LTL3.4528). CONCLUSIONS: Statins consumption is still very low in Lithuania in comparison with other European Union countries. Implementation of cholesterol education programs and changing reimbursement profile for statins therapy will increase consumption and expenditures. The introduction of reference-based pricing as an indirect cost control policy would help rationalizing the use of statins and their expenditures.