PurposeThe aims of this study were to characterize the concentration–time course of cladribine (CdA) and its main metabolite 2-chloroadenine (CAde), estimate interindividual variability in pharmacokinetics (PK), and identify covariates explaining variability in the PK of CdA.MethodsThis population PK analysis was based on the combined dataset from four clinical studies in patients with multiple sclerosis (MS): three phase I studies, including one food and one drug–drug interaction study, and one phase III clinical study. Plasma and urine concentration data of CdA and CAde were modeled simultaneously.ResultsThe analysis comprised a total of 2619 CdA and CAde plasma and urine concentration observations from 173 patients with MS who received an intravenous infusion or oral tablet doses of CdA as a single agent or in combination with interferon (IFN) β-1a. CdA PK data were best described by a three-compartment model, while a one-compartment model best described the PK of CAde. CdA renal clearance (CLR) was correlated with creatinine clearance (CLCR), predicting a decrease in the total clearance of 19%, 30% and 40% for patients with mild (CLCR = 65 ml/min), moderate (CLCR = 40 ml/min) and severe (CLCR = 20 ml/min) renal impairment, respectively. Food decreased the extent of CdA absorption by 11.2% and caused an absorption delay. Coadministration with IFNβ-1a was found to increase non-CLR (CLNR) by 21%, resulting in an increase of 11% in total clearance.ConclusionsBoth CdA and CAde displayed linear PK after intravenous and oral administration of CdA, with CdA renal function depending on CLCR.Trial registration number for study 25643: NCT00213135.

Introduction Chronic right ventricular pacing can deteriorate cardiac function. Consequently, pacemaker system upgrades are more frequently indicated. These interventions can be hindered by venous thrombosis. In literature, it is rarely described that this problem is resolved by implanting a new lead for left ventricle (LV) stimulation on the opposite side of the previously implanted pacemaker and then subcutaneously transferring it to the old pocket. Case outline A 75-year-old male patient was hospitalized due to a planned pacemaker upgrade in December 2015. A dual-chamber pacemaker had been implanted due to sinus node dysfunction in 2011. During the previous 18 months he had been complaining about symptoms of heart failure. An upgrade to the cardiac resynchronization therapy (CRT) with a new CRT-P device was indicated due to the LV dilatation with the ejection fraction decrease, clinical deterioration, and the presence of high percentage of ventricular pacing. In October 2015, the mentioned intervention was unsuccessful due to total left subclavian vein thrombosis on the side of the previously implanted pacemaker. Anticoagulation therapy was ordinated and the reevaluation was postponed. During this hospitalization, venography confirmed total left subclavian vein thrombosis despite the anticoagulation therapy. It was decided to implant a new LV lead on the right side and then subcutaneously shift it by pre-sternal tunneling to the previous left prepectoral pocket. The intervention was uneventful. The first controls have shown stable pacemaker parameters. Conclusion This case report confirms that contralateral lead placement and subcutaneous pre-sternal tunneling of the lead is feasible and safe in patients with an implanted pacemaker, an indication for system upgrade and ipsilateral vein obstruction.

Introduction/Objective Pneumothorax is one of the most common complications of cardiac rhythm management (CRM) devices implantation. We aimed to assess the incidence of pneumothorax after implantation of these devices and to determine risk factors for this complication. Methods A retrospective, observational study included patients in whom CRM devices were implanted, pacing system was upgraded, or lead revision was performed during 2012 at the Pacemaker Center, Clinical Center of Serbia. We determined the connection between different variables, including sex, age, type of implanted device, prior history of chronic obstructive pulmonary disease, operator experience, venous access, the use of intravenous contrast during procedure, and the development of pneumothorax as the procedure-related complication, using multiple logistic regression. Results A total of 999 patients were included in this study. The patients’ mean age was 68.1 ± 9.2 years; 665 (66.6%) patients were male. The incidence of pneumothorax was 1.8% and an invasive treatment of this complication was required in 13 (72.2%) patients. Pneumothorax was more frequent in women (B = -2.136, p = 0.015), in patients with age > 75 years (B = 4.315, p = 0.001), venous access with subclavian vein puncture (B = 2.672, p = 0.045), and use of intravenous contrast during procedure (B = 3.155, p = 0.007). Conclusion Pneumothorax is a relatively rare complication of CRM device implantation, and for reducing its incidence, cephalic vein cut-down should be preferred to subclavian or axillary vein puncture as venous access, axillary vein puncture should not be avoided when cephalic vein cannot be found or used, and in the case of difficult vein puncture, contrast venography should be done immediately, before risky punctures.

In this study, we report the development of the first item response theory (IRT) model within a pharmacometrics framework to characterize the disease progression in multiple sclerosis (MS), as measured by Expanded Disability Status Score (EDSS). Data were collected quarterly from a 96-week phase III clinical study by a blinder rater, involving 104,206 item-level observations from 1319 patients with relapsing-remitting MS (RRMS), treated with placebo or cladribine. Observed scores for each EDSS item were modeled describing the probability of a given score as a function of patients’ (unobserved) disability using a logistic model. Longitudinal data from placebo arms were used to describe the disease progression over time, and the model was then extended to cladribine arms to characterize the drug effect. Sensitivity with respect to patient disability was calculated as Fisher information for each EDSS item, which were ranked according to the amount of information they contained. The IRT model was able to describe baseline and longitudinal EDSS data on item and total level. The final model suggested that cladribine treatment significantly slows disease-progression rate, with a 20% decrease in disease-progression rate compared to placebo, irrespective of exposure, and effects an additional exposure-dependent reduction in disability progression. Four out of eight items contained 80% of information for the given range of disabilities. This study has illustrated that IRT modeling is specifically suitable for accurate quantification of disease status and description and prediction of disease progression in phase 3 studies on RRMS, by integrating EDSS item-level data in a meaningful manner.

Introduction: Diabetes mellitus (DM) is one of the most common endocrine disease of modern life. Diabetic foot (DF) is the term for a foot of a patient suffering from DM with the potential risk of a number of pathological sequels, including infection, ulceration and/or destruction of deep tissue. Goal: To determine the importance of preventive measures to prevent the development of diabetic foot. Results: The gender structure of respondents categorized by the complication of DF (yes/no) was uniform. The average age was 60.15±12.2 years. Respondents without DF, 63% had 2 visits to the doctor a month, while in the group of those with DF, 39% of them had 3 visits to a doctor and 33% four or more times. Wearing comfortable shoes and foot hygiene in relation to the development of the DF are interdependent: c2=4,409; c2 = 12.47 (p <0.0005). Also, recurrent foot injury, and slow healing of sores in comparison to the development of the DF are mutually dependent; c2=13,195; c2=14 (p <0.0005). Conclusion: We found that there is a significant statistical relationship between preventive measures and development of the DF.

Introduction: The occurrence of hyperglycemia in non-diabetics during development of acute coronary ischemia (ACI) indicates latent glucose metabolism disorder, or is a case of newly discovered diabetes mellitus (DM) as a result of stress. Acute coronary syndrome refers to a group of clinical syndromes caused by a sudden circulatory disorder in coronary arteries, resulting in the corresponding myocardial ischemia. It covers range from unstable angina and myocardial infarction (MI) without Q wave in the electrocardiogram finding (NSTEMI) up to myocardial infarction with Q wave in the electrocardiogram finding (STEMI). Goal: To determine the incidence of hyperglycemia in non-diabetics immediately after the occurrence of acute coronary ischemia and assess its risk factors. Results: The sample included 80 respondents. Men dominated with a total prevalence of 77.5%. The respondent was at mean age of 62.8±13.8 years. During the first measurement, immediately after hospital admission, 50% of respondents had increased blood glucose value and during the second measurement 62%. Hypertension as a risk factor has 54% and 56% smoking. The incidence of stress diabetes after ACI does not depend on the diagnosis of hypertension, χ2=0.050; p=0.823. The differences of mean values (median) BMI between examined persons with/without stress DM are not statistically significant p=0.402. Independent t-test showed that there was no statistically significant difference in the average values of HDL and LDL in patients with stress diabetes than in patients without diabetes stress after ACI p>0.05. For each year of age odds ratio for “stress diabetes” increases by 7% and 95% CI is 2% -12%. Conclusion: The incidence of stress diabetes ACI is not dependent on the working diagnosis (MI or angina pectoris). As risk factors we set hypertension and current smoking. There were no statistically significant associations between active smoking and hypertension as a risk factor in relation to occurrence of stress diabetes.