Cyclic voltammetry as a sensitive approach in investigation of doxorubicin

Introduction and objective Doxorubicin is an anthracycline drug. Its chemotherapeutic effect is due to two possible mechanisms, 1)disruption of topoisomerase-II-mediated DNA repair due to its intercalation into DNA helix and 2)generation of free radicals and their damage to cellular membranes, DNA, and proteins. This can be a result of its planar aromatic chromophore which intercalates between two base pairs of DNA [1]. Therefore, its pharmacological/toxicological characteristics are largely dependent on its oxidative properties, and the aim of this study is to summarize the methods and data based on its еlectrochemical behavior of doxorubicin, obtained by the means of cyclic voltammetry (CV) [2]. Methods Cyclic voltammetry is a versatile electrochemical method where the redox reactions occurring at the working electrode result in a flow of current. The potentiostat measures this current and plots it as a function of the applied potential. Each successful forwards and backwards potential sweep produces a a cyclic voltammogram characterized by anodic and cathodic peak currents, peak potentials, and the oxidation and reduction onset potentials. Results Our research revealed several studies that feature the electrochemical behavior of doxorubicin. CV in pH~7.4 has shown that doxorubicin undergoes a reversible two-electron reduction with value E1/2 = -665 mV(versus Ag/AgCl, saturated KCl). This process was defined as quasi reversible, at low scan rates. Further, the interaction of doxorubicin hydrochloride with calf thymus DNA was studied by measuring cathodic peak current, which gradually decreased as more DNA was added into the cell [3]. The interaction of doxorubicin with calf thymus DNA, was mostly assessed by electrochemical sensors using surface modified working electrodes [4,5,6]. Electrochemical sensor based on multi-walled carbon nanotubes modified platinum electrode (Pt/MWCNTs) [4], electrodeposition of silver nanoparticles and electro-polymerization of alginate layers on the surface of a glassy carbon electrode have been also used in this purpose [5]. CV of doxorubicine on a screen-printed electrodes modified with single-wall carbon nanotubes (SPE/CNT) have shown linear dependence of the intensity of electro reduction/oxidation on the square root of the scan rate which proved that the process is a controlled by diffusion. Moreover, thay imployed differential pulse voltammetry to validate a sensitive method for doxorubicine quantification. The drug binding processes were examined by DPV via the registration of a decrease in peak current intensity of guanine, adenine, and thymine of DNA in the presence of doxorubicin [6]. Conclusion Cyclic voltammetry can be used as an efffective tool for quantification of doxorubicine and its interactions with DNA or other metals. Reverible oxidation of doxorubicin to semiquinone and back, releases reactive oxygen species that cause DNA damage and lipid peroxidation. The effectivness of the therapeutic effect of doxorubicine depends on its interaction with DNA. These interactions were mostly assessed by using an electrochemical surface modified sensor, in the presence of DNA. These data lead to a conclusion that electrochemical platforms represent a sensitive approach for the investigation of DNA–drug interaction in electrode systems. Examining the electrochemical signals doxorubicin or DNA–doxorubicin complex before and after binding establishes the interaction and helps in mechanism elucidation

Use of chronic lymphocytic leukemia-international prognostic index in patient risk stratification-single center experience

Background: Several prognostic factors have been identified to predict the outcome of patients with chronic lymphocytic leukemia (CLL). To predict the time to first treatment (TFT) we integrated the data of clinical and biological markers in CLL-International prognostic index (CLL-IPI). Aim of the study was the determination of the impact of CLL-IPI in prediction of TFS in CLL patents.Methods: The study was set up retrospectively and included 90 patients with CLL diagnosed and treated at the university clinic of hematology for a period of time from January 2012 to January 2020. We incorporated the data of Binet staging system, most adverse cytogenetic marker and mutational status of immunoglobulin heavy chain in CLL-IPI.Results: The statistical data of the 90 patients showed that the median TFS for low CLL-IPI (N=24), intermediate CLL-IPI (N=40), high risk CLL-IPI (N=17) and very high risk group (N=9) according to the CLL-IPI scoring system was 20.1, 17.6, 7.1 and 5.8 months, respectively. Multivariate analysis indicated that del 17p (p<0.008) was independent prognostic factors of TFS.Conclusions: CLL-IPI is a powerful risk stratification tool for CLL patients and this system has also provided treatment recommendations for different patient risk subgroups.

Безбедност на пациентите во клиничка пракса - програма за контролиран пристап до лекот леналидомид

Леналидомид е лек кој поседува антинеопластично, антиангиогено, проеритропоетско и имуномодулаторно дејство, но притоа поседува и изразено тератогено дејство. Клиничкиот фармацевт при ЈЗУ Универзитетска клиника за хематологија - Скопје е одговорен за спроведување на процесот на фармаковигиланца. Затоа, со цел подобрување на безбедноста на пациентите, на клиниката се спроведе контролирана дистрибуција на лекот таблети леналидомид од 5 mg. Kако мерка за минимализација на ризикот (ММР) за пациентите кои го примаат овој лек се спроведе програмата за контролиран пристап (CAP), според која пропишувањето на лекот го вршат исклучиво лекари кои се евидентирани во Регистарот на едуцирани лекари за спроведување на програмата за превенција на бременост (PPP). Со тоа се водеше грижа пациентот да го прими лекот само доколку се исполнети барањата од PPP. Бидејќи лекот се излачува и во спермата, во програмата покрај жени мораше да бидат вклучени и пациенти од машка популација. За лекот таблети леналидомид 5 mg, PPP е спроведена кај 36 пациенти (23 мажи и 13 жени), во тек на 18 месеци, започнувајќи од октомври 2021 година. Вo овој период лекот е издаден на 14 пациенти со мултипен миелом кои претходно примиле барем една линија на терапија (во комбинација со дексаметазон), 22 пациенти со терапија на одржување на новодијагностициран мултипен миелом кај кои е спроведена трансплантација на автологни матични клетки и 1 пациент со дијагноза Не-Хочкинов фоликуларен лимфом. Со едуцирање на пациентите и преземање на сите пропишани мерки од PPP, потенцијалниот ризик од тератогеното дејство на лекот беше сведен на минимум

Clinically significant drug interactions of Eltrombopag: a retrospective study from the clinical pharmacist perspective

Introduction: Thrombopoietin is the main cytokine regulating megakaryopoiesis and platelet production. Eltrombopag interacts with the transmembrane domain of thrombopoietin receptors and initiates signaling cascades inducing proliferation and differentiation from bone marrow progenitor cells. The aim of the study was to determine drug interaction at patients that are receiving Eltrombopag along with other medications. Materials and methods: A retrospective, longitudinal study was conducted at the Hematology Clinic in Skopje, N. Macedonia. A clinical pharmacist, focusing on Eltrombopag and concomitant medications interactions, reviewed a total number of 16 patient’s histories for the period of 6 months (January-June 2023). Anamnestic data on additional drugs, herbal supplements, vitamins, minerals were also taken. Potential drug interactions were identified using Stockley's interactions checker, categorized by severity and subclassified into co-administered drugs altering pharmacokinetics. Results: A total number of 73 interactions were identified, of which 23 (31.51%) were with moderate clinical relevance, 14 (19.18%) were with no clinical importance and required counseling about possible adverse effects and additional monitoring. The rest of 36 (49,32%) interactions were without clinical significance. Additionally, we determine that 7 (9.59%) of total interactions directly related to patients receiving Eltrombopag (ciclosporin, atorvastatin, rosuvastatin, dexamethasone, prednisolone, valsartan, and magnesium) and categorized as moderate and needs close monitoring. Conclusion: This study demonstrates toxicity potential of Eltrombopag at patients associated with concomitant medicines. Close collaboration of physicians and clinical pharmacists is necessary in all cases where patients are receiving Eltrombopag along with other medications in order all significant interactions to be identified, prevented and managed

Determination of non-adherence in patients receiving Eltrombopag

Eltrombopag, an orally administered thrombopoietin receptor agonist, selectively binds to the transmembrane domain of the thrombopoietin receptor on the surface of platelets, megakaryocytes and megakaryocyte precursor cells (1). The aim of our research is to determine patient non-adherence and its impact on the effectiveness and safety of prescribed therapy, as well as the possibility of treatment failure. The observational, longitudinal, and retrospective study was conducted in the PHO University Clinic of Hematology in Skopje, R.N.Macedonia. 17 patients (9 men and 8 women) were followed from January to August 2023. Five of them were with diagnose aplastic anemia and 12 with immune thrombocytopenia. All of them treated with Eltrombopag. We have systematically reviewed medical records from the Department of Hospital pharmacy, collected anamnestic data and determine non-adherence to therapy, followed by dose frequency, double taking therapy, omitted doses, drug-drug interactions and food/supplement-drug interactions. Thirteen types of non-adherence were identified, of which 3(23,08%) were related to dose frequency, 1(7,69 %) was related to double taking therapy, 5(38,46%) were related to the possibility of drug-drug interactions, 2(15,38%) with possibility for food/supplement-drug interactions and 2(15,38 %) were related with omitted doses. Failure to adherence is a serious problem which not only affects the patient but also the health care system. The clinical pharmacist intervention can improve patient adherencе, because the most important determinants effectiveness and safety are adherence to the prescribed therapy, multiple drug and food/supplement interactions which can vary on dose-response relationship, and risk of insufficient effectiveness of therapy (2)

Tretatment Approach of Nontransplant Patients with Multiple Myeloma

Multiple myeloma is still an incurable disease with pattern of regression and remission followed by multiple relapses raising from the residual myeloma cells surviving even in the patients who achieve complete clinical response to treatment. In recent years there is a huge improvement in treatment of patients with multiple myeloma. The milestones of these improvement are: autologous transplantation and high-dose melphalan, imunomodulating drugs (thalidomide, lenalidomide), proteosom inhibitors (bortesomib, carfilzomib). The most significant improvement in overall survival has been achieved in the patients younger than 65 years. So, the major challenge for hematologist is to translate this improvement in the elderly patients with multiple myeloma. Today, physicians are able to offer wider variety of treatment options for elderly patients with multiple myeloma. Therapeutic options should be tailored and personalized according to patient’s characteristics by balancing efficacy and toxicity of each drug which is especially important for elderly patients. In the mode of sequencing treatment for elderly patients with multiple myeloma, our goal is to achieve and maintain maximal response while limiting treatment -related toxicities as much as possible. Second-generation novel agent, such as carfilzomib, pomalidomide, elotuzumab, bendamustine are currently being evaluated as an option to improve treatment outcome in elderly patients

Adverse Effects of Thalidomide Administration, in Patients with Myeloma Multiplex?

Myeloma multiplex is defined by the presence of monoclonal plasma cell population in the bone marrow>10%,M protein in the serum and/or urine ,and clinical evidence of end organ damage like hypercalcemia ,renal failure, anemia, or bone lesions. In the most hematologic malignancies the role of induction treatment is to achieve complete remission (CR). Thalidomide became a new therapeutic approach but use of Thalidomide as a single agent or combination with steroids or chemotherapy is associated with several side effects like deep vein thrombosis (DVT), peripheral neuropathy (PN), constipation, somnolence, pyrexia, pain, fatigue osteonecrosis of jaw, and teratogenicity that is the most worrying adverse event. Risk of appearance of DVT increased if we use combination of Thalidomide plus Dexamethasone plus cytotoxic chemotherapy such Cyclophosphamide. >30% DVT usually occurs during the first months of treatment and is more frequent in newly diagnosed patients with a high tumor burden. The second side effect is peripheral neuropathy (PN) which occurs in 50% of patients with MM treated with Thalidomide plus Dexamethasone and chemotherapy. Eighty patients of both sexes (43 males and 37 females) at the age of 31-81 (median range 58 years) with MM, were treated–one group with combinations of Thalidomide plus Dexamethasone plus Cyclophosphamide (CyThalDex) 4 cycle( >4months), and the other group with Thalidomide plus Dexamethasone plus Melphalan (MPT), ( >4month) and third group with high dose of chemotherapy and continue with ThalDex (TD), the fourth group with CyThalDex, > than 5 cycles, and the fifth group with ThalDex (TD) only. It is obvious while myelo-suppression is very rare, the incidence of nonhematologic side effects is high and dose dependent. Eight ( or 10% ) patients that developed DVT and CVI were initially treated with antiaggregation therapy of Aspirin 100mg per day, but those that already developed were treated with low dose of Heparin 40000 iE per day in ten days and continued with oral anticoagulans therapy. However, besides the given therapy in four (or 5 %) patients there was exitus letalis. PN was developed in twentyone patients (or 26.25%) from the total number of patients treated with Thalidomide, in ten patients the dosage of Thalidomide was decreased to 50mg per day, in one patient with Epi attacks it was interrupted and the other was with paresis n.occulomotorius and n.abducens. Patients treated with thalidomide have an increased risk of arterial thromboembolism, including myocardial infarction and cerebrovascular events, in addition to the established risk of venous thromboembolism, but most patients who presenting DVT or some of thromboembolic events have had identifiable risk factors. The prolonged exposure to Thalidomide seems to induce resistance of MM reducing overall survival (OS). We must evaluate consolidation and maintenance therapies with Thalidomide, determinate which regimens provide a highness benefit with favorable side effect profiles in specific subgroups of patients

Anti Citrullinated Protein / Peptide Antibody Assay, Rheumathoid Factor or Both as Shifted Test in Diagnostic and Prognostic Evaluation in Patients with Rheumathoid Arthritis

The aim of this study was to compare the diagnostic values of laboratory variables, to present quantitative evaluations of the anti citrullinated protein / peptide antibody (ACPA), or anti CCP ( anti-cyclic citrullinated peptide, anti-CCP 2) antibodies in second generation antibody assay diagnostic test with reference to sensitivity and specificity, the predictive value of the positive and negative test and precision of the test for ACPA antibodies, rheumatoid factor, C-reactive protein and DAS 28 index, in the early diagnosis of untreated rheumatoid arthritis

Influence of Prognostic Factors on Overall Survival in Myelodysplastic Syndromes

Accurate prediction of a patient’s prognosis is useful to define the risk posed by the disease. Age, gender, peripheral blood cytopenia, proportion of bone marrow (BM) blasts, performance status, comorbidities, transfusion dependence, specific karyotype abnormalities and molecular biomarkers can refine the prediction of prognosis in MDS. The aim was to assess the influence of the some prognostic factors like age, gender, cytopenia, BM blast percentage, transfusion dependence, ferritin, hemoglobin (Hb), lactate dehydrogenase (LDH), albumin and specific karyotype abnormalities in myelodysplastic syndromes on overall survival (OS). We retrospectively analyzed the cohort of 108 patients diagnosed between 1.1.2011 and 31.12.2013 at the University Clinic of Hematology, Ss Cyril and Methodius University, Skopje, Macedonia. They were evaluated for clinical and hematologic features at diagnosis and at leukemic transformation. In the study group 62 were man and 46 women. Male to female ratio was 1.35 to 1. The differences in OS between men and women were significant (p = .03015). The mean age at diagnosis was 66,6 years. According to the age OS was 16,4 months. FAB subtypes influenced OS significantly (p = .03015). OS uinversely correlated with BM blast percentage (p= .02327). Cytopenia had no impact on OS (p=.33755). Hb as a whole and groups with different levels of Hb had no influence on OS (p= .12142) and (p= .07535), respectively. The group with ferritin <500 µg/L had better OS (p=.04720). Transfusion dependence, LDH and albumin had no impact on OS. Leukemic transformation was noticed in 10 (9,3%) patients. Mortality was 36,1%. Conclusion: gender, FAB subtypes, BM blast percentage and the serum levels of ferritin had an influence on OS, while age, hemoglobin level, transfusion dependence, LDH and albumin had no impact on OS

Osteonecrosis of the Jaw After Bisphosphonates Treatment in Patients with Multiple Myeloma

Bone lytic lesion in Multiple myeloma are the most commonly presented symptoms which require treatment with bisphosphonates (BPs). BPs are providing supportive care, reducing the rate of skeletal morbidity but evidently not abolishing it, the criteria for stopping their administration have to be different from those used for classic antineoplastic drugs, and they should not be stopped when metastatic bone disease is progressing. Osteonecrosis of the jaw (ONJ) has been associated recently with the use of BPs. The aim of these study is to evaluate the incidence of ONJ in patients with MM treated with mixed biphosphonates. We analyzed total 296 myeloma patients (150 male and 146 female). Mostly effected age group with 58,1% is age more than 60 years up to 88 years, diagnosed in our institution in the period 2005-2015. We used intravenous or oral forms of biphosphonates such as pamidronate, ibandronate, clodronate and zolendronic acid. The patients were evaluated for ONJ. The incidence of ONJ in our group of patients treated with Bps was 4,6% from our group of 260 patients 87,8% received BPs therapy and patients which haven’t received BPs 12,2%. From this group, 95,4% (248) didn’t show ONJ, and 4,6% (12) showed ONJ. The period of this treatment with BPs is an important risk factor for development of ONJ, average duration of BPs therapy in patients which show adverse effects is 26.8±13.7 months, from the total number of 12 patients that developed ONJ adverse effects, we have 8 patients which received treatment with Zolendronic acid and the remaining 4 patients which were treated with other BPs combinations without Zolendronic acid. All patients treated for MM must continue with the therapy with Zolendronic acid and Pamidronate, each patient must be individually treated according to his response of the treatment (dose, frequency and duration of therapy)