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1.
Ann Med ; 56(1): 2305309, 2024 12.
Article in English | MEDLINE | ID: mdl-38261566

ABSTRACT

BACKGROUND: This is the first study to examine the clinical utility of measuring plasma secretoneurin (SN) levels in patients with heart failure with reduced ejection fraction (HFrEF), as a predictor of unplanned hospitalization, and all-cause mortality independently, and as a composite endpoint at one-year follow-up. METHODS: The study group includes 124 caucasian patients in New York Heart Association (NYHA) classes II to IV. Plasma SN concentrations were statistically analyzed in relation to sex, age, BMI, etiology of HFrEF, pharmacotherapy, clinical, laboratory and echocardiographic parameters. Samples were collected within 24 h of admission to the hospital. KEY RESULTS: In the 12-month follow-up, high SN levels were noted for all three endpoints. CONCLUSIONS: SN positively correlates with HF severity measured by NYHA classes and proves to be a useful prognostic parameter in predicting unplanned hospitalizations and all-cause mortality among patients with HFrEF. Patients with high SN levels may benefit from systematic follow-up and may be candidates for more aggressive treatment.


Subject(s)
Heart Failure , Neuropeptides , Secretogranin II , Humans , Follow-Up Studies , Prognosis , Stroke Volume
2.
Int J Mol Sci ; 24(18)2023 Sep 06.
Article in English | MEDLINE | ID: mdl-37762023

ABSTRACT

Epigenetics is a rapidly developing science that has gained a lot of interest in recent years due to the correlation between characteristic epigenetic marks and cardiovascular diseases (CVDs). Epigenetic modifications contribute to a change in gene expression while maintaining the DNA sequence. The analysis of these modifications provides a thorough insight into the cardiovascular system from its development to its further functioning. Epigenetics is strongly influenced by environmental factors, including known cardiovascular risk factors such as smoking, obesity, and low physical activity. Similarly, conditions affecting the local microenvironment of cells, such as chronic inflammation, worsen the prognosis in cardiovascular diseases and additionally induce further epigenetic modifications leading to the consolidation of unfavorable cardiovascular changes. A deeper understanding of epigenetics may provide an answer to the continuing strong clinical impact of cardiovascular diseases by improving diagnostic capabilities, personalized medical approaches and the development of targeted therapeutic interventions. The aim of the study was to present selected epigenetic pathways, their significance in cardiovascular diseases, and their potential as a therapeutic target in specific medical conditions.


Subject(s)
Cardiovascular Diseases , Humans , Cardiovascular Diseases/genetics , Cardiovascular Diseases/therapy , Epigenesis, Genetic , Epigenomics , Exercise , Heart Disease Risk Factors
3.
J Clin Med ; 12(15)2023 Jul 28.
Article in English | MEDLINE | ID: mdl-37568371

ABSTRACT

Phase III clinical trials for individual direct oral anticoagulants (DOACs) contained a limited representation of subjects with abnormal body weight, which were mostly limited to a BMI > 40 kg/m2, or body weight > 120 kg for obese subjects, and <50 kg for underweight subjects. Although low or high body weight is not a contraindication to DOACs therapy, it can significantly affect the safety and effectiveness of treatment. Due to the limited amount of clinical data on the use of DOACs in extremely abnormal weight ranges, optimal pharmacotherapy in this group of patients is a matter of controversy. The objective of this study was to evaluate the pharmacokinetics of DOAC properties in patients with abnormal body weight beyond the established cut-off points in the phase III studies for rivaroxaban, apixaban, and dabigatran. In total, 38 patients took DOACs for at least 12 months for non-valvular atrial fibrillation in 2019-2021. Blood samples were collected before the planned intake of the drug and 4 h after its administration. The determined concentrations of DOACs were statistically analyzed in relation to body weight, age, and eGFR (estimated Glomerular Filtration Rate). Among subjects taking apixaban, rivaroxaban, and dabigatran, the smallest representation of patients who achieved therapeutic concentrations were those treated with dabigatran. The population of people with abnormal body weight is a potential risk group of patients, in which some of them do not reach the therapeutic range of DOACs.

4.
J Clin Med ; 12(13)2023 Jun 22.
Article in English | MEDLINE | ID: mdl-37445245

ABSTRACT

The primary objective of the study was to evaluate the prognostic value of measuring plasma catestatin (CST) concentration in patients with heart failure with reduced ejection fraction (HFrEF) as a predictor of unplanned hospitalization and all-cause death independently and as a composite endpoint at 2-year follow-up. The study group includes 122 hospitalized Caucasian patients in NYHA classes II to IV. Patients who died during the 24-month follow-up period (n = 44; 36%) were significantly older on the day of enrollment, were more likely to be in a higher NYHA class, had lower TAPSE, hemoglobin concentration, hematocrit, and platelet count, higher concentrations of CST, NT-proBNP, troponin T, creatinine, and glucose, and higher red cell distribution width value and leukocyte and neutrocyte count than patients who survived the follow-up period. Plasma catestatin concentration increased with NYHA class (R = 0.58; p <0.001) and correlated significantly with blood NT-proBNP concentration (R = 0.44; p <0.001). We showed that higher plasma catestatin concentration increased the risk of all-cause death by more than five times. Plasma CST concentration is a valuable prognostic parameter in predicting death from all causes and unplanned hospitalization in patients with HFrEF.

5.
Int J Mol Sci ; 24(11)2023 Jun 04.
Article in English | MEDLINE | ID: mdl-37298685

ABSTRACT

Pulmonary hypertension (PH) is characterized by a progressive increase in pulmonary arterial pressure and pulmonary vascular resistance. In a short time, it leads to right ventricular failure and, consequently, to death. The most common causes of PH include left heart disease and lung disease. Despite the significant development of medicine and related sciences observed in recent years, we still suffer from a lack of effective treatment that would significantly influence the prognosis and prolong life expectancy of patients with PH. One type of PH is pulmonary arterial hypertension (PAH). The pathophysiology of PAH is based on increased cell proliferation and resistance to apoptosis in the small pulmonary arteries, leading to pulmonary vascular remodeling. However, studies conducted in recent years have shown that epigenetic changes may also lie behind the pathogenesis of PAH. Epigenetics is the study of changes in gene expression that are not related to changes in the sequence of nucleotides in DNA. In addition to DNA methylation or histone modification, epigenetic research focuses on non-coding RNAs, which include microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Preliminary research results give hope that targeting epigenetic regulators may lead to new, potential therapeutic possibilities in the treatment of PAH.


Subject(s)
Hypertension, Pulmonary , MicroRNAs , Pulmonary Arterial Hypertension , RNA, Long Noncoding , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Pulmonary Arterial Hypertension/drug therapy , Pulmonary Arterial Hypertension/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Lung/pathology , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/genetics , Familial Primary Pulmonary Hypertension/metabolism , Pulmonary Artery/pathology
6.
Pharmaceutics ; 15(2)2023 Jan 18.
Article in English | MEDLINE | ID: mdl-36839644

ABSTRACT

Dyslipidemia is listed among important cardiovascular disease risk factors. Treating lipid disorders is difficult, and achieving desirable levels of LDL-cholesterol (LDL-C) is essential in both the secondary and primary prevention of cardiovascular disease. For many years, statins became the basis of lipid-lowering therapy. Nevertheless, these drugs are often insufficient due to their side effects and restrictive criteria for achieving the recommended LDL-C values. Even the addition of other drugs, i.e., ezetimibe, does not help one achieve the target LDL-C. The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) discovery has triggered intensive research on a new class of protein-based drugs. The protein PCSK9 is located mainly in hepatocytes and is involved in the metabolism of LDL-C. In the beginning, antibodies against the PCSK9 protein, such as evolocumab, were invented. The next step was inclisiran. Inclisiran is a small interfering RNA (siRNA) that inhibits the expression of PCSK9 by binding specifically to the mRNA precursor of PCSK9 protein and causing its degradation. It has been noticed in recent years that siRNA is a powerful tool for biomedical research and drug discovery. The purpose of this work is to summarize the molecular mechanisms, pharmacokinetics, pharmacodynamics of inclisiran and to review the latest research.

7.
Biomed Pharmacother ; 156: 113957, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36411665

ABSTRACT

annually in Europe, 4 million people die from cardiovascular diseases, the main cause of which is atherosclerosis. In order to slow down the development of atherosclerotic plaques, the main therapeutic goal is to lower LDL cholesterol (LDL-C) level. Undoubtedly, statins are the basis of lipid-lowering therapy for many years. However, a European study shows that only 43% of statin-taking patients achieved their LDL-C targets. PCSK9 inhibitors are a new group of lipid-lowering drugs whose main point of action is the protein discovered in 2003 - the PCSK9 (proprotein convertase subtilisin/kexin 9). This protein is responsible for reducing the density of LDL receptors on the surface of hepatocytes, which increases the value of LDL-C. The discovery of this protein was soon after the basis for the start of research, thanks to which three monoclonal antibodies against PCSK9 were developed - evolocumab, alirocumab, bococizumab - and inclisiran, an inhibitor of PCSK9 synthesis in the liver. In addition to the mechanism of action of PCSK9 inhibitors, resulting in lowering LDL-C level, a number of pleiotropic mechanisms have also been identified, including effects on metabolic processes and inflammation. Until the registration and introduction of above-mentioned drugs into everyday clinical practice, many studies were carried out, in which, in addition to assessing the effectiveness of treatment, the safety and tolerability of the drug were also examined. The purpose of this review is to summarize information on the safety profile of PCSK9 inhibitors, which may help in making therapeutic decision.


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , PCSK9 Inhibitors , Humans , Proprotein Convertase 9 , Cholesterol, LDL/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
8.
Curr Issues Mol Biol ; 44(8): 3455-3464, 2022 Aug 01.
Article in English | MEDLINE | ID: mdl-36005134

ABSTRACT

The genetic factors of adult acute lymphoblastic leukemia (ALL) development are only partially understood. The Runt-Related Transcription Factor (RUNX) gene family play a crucial role in hematological malignancies, serving both a tumor suppressor and promoter function. The aim of this study was the assessment of relative RUNX1 and RUNX3 genes expression level among adult ALL cases and a geographically and ethnically matched control group. The relative RUNX1 and RUNX3 genes expression level was assessed by qPCR. The investigated group comprised 60 adult patients newly diagnosed with ALL. The obtained results were compared with a group of 40 healthy individuals, as well as clinical and hematological parameters of patients, and submitted for statistical analysis. ALL patients tend to have significantly higher RUNX1 gene expression level compared with controls. This observation is also true for risk group stratification where high-risk (HR) patients presented higher levels of RUNX1. A higher RUNX1 transcript level correlates with greater leukocytosis while RUNX3 expression is reduced in Philadelphia chromosome bearers. The conducted study sustains the hypothesis that both a reduction and increase in the transcript level of RUNX family genes may be involved in leukemia pathogenesis, although their interaction is complex. In this context, overexpression of the RUNX1 gene in adult ALL cases in particular seems interesting. Obtained results should be interpreted with caution. Further analysis in this research field is needed.

9.
Adv Clin Exp Med ; 31(9): 1023-1033, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35467089

ABSTRACT

BACKGROUND: Venetoclax (VEN), a highly selective BCL-2 inhibitor, is successfully used in the treatment of chronic lymphocytic leukemia (CLL). The purine analogue - cladribine (2-CdA) - is also administered to CLL patients, especially as a part of chemoimmunotherapy. OBJECTIVES: To compare the effects of the VEN+2-CdA regimen with that of the 2 drugs used alone on the apoptosis of CLL lymphocytes in vitro. MATERIAL AND METHODS: Mononuclear cells were collected from 103 previously untreated CLL patients. They were incubated with VEN (40 nM) or/and 2-CdA (16 µM) for 48 h. Cytotoxicity, overall apoptosis, mitochondrial transmembrane potential changes (ΔΨm), and expression of selected apoptosis-involved proteins were measured. RESULTS: The cytotoxicity, overall apoptosis, caspase-3 or caspase-9 expression, and ΔΨm were significantly higher after VEN+2-CdA addition compared to both drugs used alone, with a very strong synergistic effect observed. The percentage of BCL-2-positive cells decreased after VEN and VEN+2-CdA addition compared to controls. The TP53-expressing cells increased under the influence of all tested regimens. The VEN+2-CdA increased the expression of BIM, BAX and NOXA compared to either controls or VEN or 2-CdA alone. Similar increases in PUMA expression were observed after VEN, 2-CdA and VEN+2-CdA addition. The FAS-associated death-domain protein (FADD) expression was significantly higher after 2-CdA and 2-CdA+VEN addition as compared to control. CONCLUSIONS: Our results confirm the involvement of both VEN and 2-CdA in the intrinsic apoptotic pathway. They also demonstrate that these agents have a synergistic effect on CLL cells in vitro. Further studies are needed to assess the influence of VEN+2-CdA on the expression of apoptosis-involved genes.


Subject(s)
Antineoplastic Agents , Leukemia, Lymphocytic, Chronic, B-Cell , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis , Bridged Bicyclo Compounds, Heterocyclic , Caspase 3/metabolism , Caspase 3/pharmacology , Caspase 3/therapeutic use , Caspase 9/metabolism , Caspase 9/pharmacology , Cladribine/pharmacology , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Sulfonamides , bcl-2-Associated X Protein
10.
Front Pharmacol ; 13: 1043714, 2022.
Article in English | MEDLINE | ID: mdl-36699057

ABSTRACT

ß-blockers is a vast group of antiarrhythmic drugs which differ in their pharmacokinetic and chemical properties. Some of them block ß-adrenergic receptors selectively while the others work non-selectively. Consequently, they reduce the influence of the sympathetic nervous system on the heart, acting negatively inotropic, chronotropic, bathmotropic and dromotropic. Although they have been present in medicine since the beginning of the 1960s, they still play a crucial role in the treatment of cardiac arrhythmias. They are also first-line group of drugs used to control the ventricular rate in patients with the most common arrhythmia-atrial fibrillation. Previous reports indicate that infection with SARS-CoV-2 virus may constitute an additional risk factor for arrhythmia. Due to the aging of the population in developed countries and the increase in the number of patients with cardiac burden, the number of people suffering from cardiac arrhythmias will increase in the upcoming years. As a result the role of above-mentioned beta-blockers will remain significant. Particularly noteworthy is propranolol-the oldest beta adrenergic antagonist, which in recent years has found additional applications due to its unique properties. In this article, we reviewed the accessible literature and summarized the current guidelines on the use of beta-blockers in the treatment of cardiac arrhythmias.

11.
Expert Opin Drug Saf ; 19(11): 1377-1393, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32946324

ABSTRACT

INTRODUCTION: Conventional treatment for mantle cell lymphoma (MCL) patients includes regimens combining rituximab with other cytotoxic drugs, followed or not by consolidation with autologous stem cell transplantation and rituximab maintenance. However, older, unfit, and relapsed/refractory patients are often ineligible for intense treatment. Currently, available new targeted treatment options seem to offer hope in this group of patients. AREAS COVERED: This article reviews the safety profiles of new therapeutic chemotherapy-free options for MCL patients. Publications in English from 2010 through June 2020 were surveyed on the MEDLINE database for articles. Proceedings of the American Society of Hematology during the last 5 years were also included. EXPERT OPINION: MCL is a clinically heterogenous disease predominantly affecting elderly patients. Its variable clinical course requires personalization and individualization of treatment to achieve optimal survival and acceptable safety profiles, especially in poor prognosis patients. Results of clinical trials performed in the past decade indicated that novel drugs used as a single agent or as part of a conventional chemotherapeutic treatment offer promise in minimalizing the relapse rate for MCL and may allow more effective and safer treatment options by reducing the risk of adverse events, especially cytopenias and infections.


Subject(s)
Antineoplastic Agents/administration & dosage , Lymphoma, Mantle-Cell/therapy , Molecular Targeted Therapy , Aged , Antineoplastic Agents/adverse effects , Humans , Lymphoma, Mantle-Cell/pathology , Precision Medicine , Prognosis , Recurrence , Survival Rate
12.
Expert Opin Drug Metab Toxicol ; 15(5): 353-366, 2019 May.
Article in English | MEDLINE | ID: mdl-30969139

ABSTRACT

INTRODUCTION: Venetoclax, an antagonist of BCL-2 protein plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). It has been approved by the FDA for the treatment of relapsed/refractory CLL with del17p, and by the EMA for patients with del17p/TP53 mutation who have failed a BCR inhibitor, or in patients without those aberrations who have failed previous therapy, regardless of their genetic/molecular profile. Venetoclax in combination with rituximab has been also approved for the treatment of CLL after at least 1 prior therapy, regardless of del17p. Areas covered: This article reviews the chemical structure, mechanisms of action, pharmacokinetic, and the clinical applications of venetoclax in monotherapy and in combined treatment of CLL. Publications dated 2010 through March 2019 were obtained from the MEDLINE database. The proceedings of the American Society of Hematology held during the last five years were also included. Expert opinion: Venetoclax shows high efficacy, a favorable toxicity profile, and a high rate of minimal residual disease negativity, which is thought to have an impact on overall survival. It is efficient in patients with del17p/TP53 mutations, the incidence of which increases during clonal CLL evolution, and after the failure of BCR pathway inhibitors.


Subject(s)
Antineoplastic Agents/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Sulfonamides/administration & dosage , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Rituximab/administration & dosage , Sulfonamides/pharmacology
13.
Leuk Lymphoma ; 60(6): 1409-1419, 2019 06.
Article in English | MEDLINE | ID: mdl-30187811

ABSTRACT

We studied whether bendamustine (BENDA) alone or with rituximab (RIT) modifies in vitro expression of apoptosis-involved genes and proteins of chronic lymphocytic leukemia (CLL) cells depending on IGVH mutational status. Circulating lymphocytes from 34 untreated patients (18 IGVH-MUT and 16 IGVH-UNMUT) were incubated with above drugs to evaluate proteins expression. Microarray analysis of 93 genes was performed in 14 patients. BENDA and BENDA + RIT increased expression of BAX and BBC3 in IGVH-MUT and IGVH-UNMUT groups, and significant differences in expression of above genes after BENDA + RIT were observed between both groups. Additionally, BENDA + RIT decreased NFκB and BCL-2 genes in IGVH-UNMUT patients and increased expression of P53, BAX and PUMA proteins in IGVH-MUT and UNMUT subjects. However, no significant differences were found between these groups. In conclusion, BENDA + RIT modified gene expression profile in CLL cells and affected expression of some apoptosis-regulating proteins in vitro. Expression of BAX and BBC3 depends on action of drugs and IGVH mutational status.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Apoptosis Regulatory Proteins/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Proto-Oncogene Proteins/metabolism , bcl-2-Associated X Protein/metabolism , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Immunological/administration & dosage , Apoptosis/drug effects , Apoptosis/genetics , Bendamustine Hydrochloride/administration & dosage , Female , Gene Expression Profiling , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Leukocytes, Mononuclear , Male , Middle Aged , Mutation , Primary Cell Culture , Rituximab/administration & dosage , Tumor Cells, Cultured , Young Adult
14.
Expert Opin Drug Saf ; 16(2): 185-201, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27880061

ABSTRACT

INTRODUCTION: Monoclonal antibodies (MoAbs), non-chemotherapeutic agents targeting the antigens present on chronic lymphocytic leukemia (CLL) lymphocytes, are being implemented increasingly more often as treatment options. Areas covered: This article reviews the similarities and differences in the structure, mechanism of action, efficacy and safety profile of commercially-available MoAbs and prevents new agents potentially useful for CLL treatment. Publications in English before June 2016 were surveyed on the MEDLINE database for articles. Proceedings of the American Society of Hematology held during the last five years were also included. Expert opinion: MoAbs, especially those targeting CD20, are highly effective biological options for first-line and salvage treatment of CLL, particularly in chemoimmunotherapy, and possibly also as maintenance therapy. Treatment with MoAbs is associated with reduced risk of such adverse events as cytopenias, infections and secondary neoplasias and is generally well tolerated. Depending on antibody type, the most common adverse events are usually transient and limited to grade 1 and 2 infusion-related reactions. In addition to commercially available MoAbs, several other antibodies exist which are targeted against different antigens studied in the clinical trials.


Subject(s)
Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/adverse effects , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Antibodies, Monoclonal/therapeutic use , Antigens/immunology , Antineoplastic Agents/therapeutic use , Humans , Immunotherapy/methods , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Salvage Therapy/adverse effects , Salvage Therapy/methods
15.
Expert Opin Drug Saf ; 14(12): 1945-59, 2015.
Article in English | MEDLINE | ID: mdl-26566719

ABSTRACT

INTRODUCTION: Ofatumumab, the first fully human IgG1κ, belongs to the second generation of the first class of anti-CD20 monoclonal antibodies. The drug used alone and in combination with drugs having different mechanisms of action has shown a favorable toxicity profile and significant benefit especially in relapsed/refractory chronic lymphocytic leukemia (CLL) patients in doses up to 2000 mg. AREAS COVERED: This article reviews pharmacokinetic, clinical application for CLL treatment, and safety profile of ofatumumab as well as differences and similarity between ofatumumab and rituximab. Publications in English from 2010 through October 2015 were surveyed on the MEDLINE database for articles. Proceedings of the American Society of Hematology held during the last 5 years were also included. EXPERT OPINION: Ofatumumab more effectively than rituximab enhanced complement-dependent cytotoxicity playing the crucial role for its therapeutic activity. The drug is highly effective in the first-line and salvage treatment of CLL, essentially as a part of immunochemotherapy, and probably also as maintenance therapy. Its safety profile is very advantageous, since adverse events are usually limited to grade 1 and 2 infusion-related reactions, which tend to decrease throughout the treatment. Its advantage over the other anti-CD20 monoclonal antibodies in the treatment of CLL remains to be determined in the direct head-to-head trials.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Antigens, CD20/immunology , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Humans , Immunotherapy/methods , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Rituximab/adverse effects , Rituximab/therapeutic use , Salvage Therapy/methods
16.
Expert Opin Drug Metab Toxicol ; 11(9): 1371-91, 2015.
Article in English | MEDLINE | ID: mdl-26156752

ABSTRACT

INTRODUCTION: Small molecule inhibitors are currently in various stages of preclinical and clinical trials and are expected to revolutionize the treatment of many neoplastic diseases, including B-cell lymphoid malignancies. AREAS COVERED: This article reviews the chemical structure, mechanisms of action, pharmacodynamic and pharmacokinetic properties, as well as clinical applications of small molecules in the treatment of elderly patients with B-cell hematological malignancies. Bibliographic research covering mainly the period from 2010 until February 2015 was conducted on the MEDLINE database for articles in English. Proceedings of the American Society of Hematology, European Hematology Association and American Society of Clinical Oncology conferences held during the last 5 years were also included. EXPERT OPINION: In the last few years, several preclinical and clinical trials have evaluated many small weight organic molecules which downregulate B-cell receptor (BCR) signaling and act via inhibition of either BCR-associated kinases or cyclin-dependent kinases, or which are antagonists of members of the B-cell lymphoma 2 protein family. Pharmacokinetic profiles of these agents as well as dosage used and adverse events in patients with lymphoid malignancies have been established. Some of these inhibitors satisfy therapeutic modalities as suitable for the elderly patients, including those with chronic lymphocytic leukemia and non-Hodgkin's lymphoma.


Subject(s)
Antineoplastic Agents/pharmacology , Lymphoproliferative Disorders/drug therapy , Molecular Targeted Therapy , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Down-Regulation/drug effects , Drug Design , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lymphoproliferative Disorders/pathology , Receptors, Antigen, B-Cell/genetics , Signal Transduction/drug effects
17.
Postepy Hig Med Dosw (Online) ; 68: 1433-43, 2014 Dec 05.
Article in English | MEDLINE | ID: mdl-25531707

ABSTRACT

AIM: The aim of our study was to compare the cytotoxic effects of bendamustine (BENDA) and rituximab (RIT) used either alone or in combination and to evaluate the influence of the above mentioned drugs on apoptosis measured as changes in mitochondrial transmembrane potential (Δψm), expression of caspases and selected apoptosis-regulating proteins in freshly isolated peripheral blood mononuclear cells of chronic lymphocytic leukemia (CLL) patients. MATERIALS/METHODS: Cytotoxic effect of tested drugs, as well as induction of apoptosis, drop in Δψm and expression of selected proteins involved in regulation of apoptosis were assessed in 48 hour cultures containing autologous serum (AS) using flow cytometry. BENDA was used at the concentration of 40 µg/ml and RIT at the concentration of 10 µg/ml. Control cultures were incubated without drugs. RESULTS: BENDA used either alone or in combination with RIT strongly induced apoptosis as well as enhanced expression of selected apoptotic proteins, especially those involved in the intrinsic apoptotic pathway: P53, PUMA and BAX, which cause mitochondrial transmembrane potential changes leading to activation of caspase-9 and -3. CONCLUSIONS: Our results indicate that both BENDA and RIT participate in the induction of apoptosis of CLL lymphocytes in vitro in the presence of AS in the culture medium. The drug-induced apoptosis occurs mainly via intrinsic pathway and activation of P53 and PUMA proteins, however the extrinsic pathway is likely to be involved as well. We also found that the combination of these drugs induces the expression of P53, caspase-8 and -9 more potently than either of them used separately.


Subject(s)
Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Membrane Potential, Mitochondrial/drug effects , Nitrogen Mustard Compounds/administration & dosage , Bendamustine Hydrochloride , Caspases/drug effects , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/enzymology , Leukemia, Lymphocytic, Chronic, B-Cell/physiopathology , Leukocytes, Mononuclear/drug effects , Rituximab , Tumor Cells, Cultured/drug effects
18.
Eur J Haematol ; 92(2): 91-101, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24138550

ABSTRACT

The acquisition of new aberrations during the course of chronic lymphocytic leukemia (CLL) named clonal evolution (CE) is usually detected by one of the two methods: chromosome banding analysis (CBA) and interphase fluorescence in situ hybridization (I-FISH). The purpose of this study was to compare the usefulness of FISH and CBA for detecting CE and to evaluate its influence on clinical outcome. FISH and CBA were performed at two time points: baseline and follow-up. Thirty-eight previously untreated patients with CLL were included in this study. CBA and I-FISH revealed CE in 15 (39.5%) and 10 (26.3%) patients, respectively. High-risk CE was detected in six cases by CBA and in five cases by I-FISH. In four cases with CE-dependent 17p abnormalities detected by CBA, metaphase FISH was needed for the confirmation of 17p13.1 deletion. Time from first-line to second-line treatment (TTST) and overall survival (OS) did not differ between patients with and without CE, irrespective of the CE-detecting method used. However, shorter OS (P = 0.043) and TTST (P = 0.006) were observed for the patients with potentially relevant CE (rCE) detected by CBA, in which acquired aberrations were present in at least 20% of undivided cells and/or changed baseline karyotype to abnormal or complex and were not resulting from 13q deletion. Our results suggest that some, but not all, CE-dependent aberrations detected by CBA influence clinical outcome. Moreover, I-FISH, which was aimed at detecting aberrations of prognostic significance, was found to be more precise than CBA in their detection, especially TP53 deletion.


Subject(s)
Chromosome Banding , Clonal Evolution/genetics , In Situ Hybridization, Fluorescence , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Adult , Aged , Aged, 80 and over , Chromosome Aberrations , Female , Follow-Up Studies , Humans , Karyotyping , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Male , Middle Aged , Neoplasm Staging , Prognosis , Young Adult
19.
ISRN Oncol ; 2013: 740615, 2013 Aug 22.
Article in English | MEDLINE | ID: mdl-24027642

ABSTRACT

Chronic lymphocytic leukemia (CLL) is characterized by the clonal proliferation and accumulation of mature B lymphocytes. CLL cells show an antiapoptotic profile, suggesting the important role of apoptosis inhibition in the disease development. However, there is some population of proliferating CLL cells, which may also play a role in progression of the disease. There are several newer, biological prognostic factors in CLL. Currently, cytogenetic abnormalities with different prognostic values seem to be the most biologically relevant. During the last decades, the treatment of CLL has been significantly changed. Different strategies such as monotherapy with chlorambucil and purine nucleoside analogues (PNA) used alone or in combination with cyclophosphamide have been introduced. Most recently, immunochemotherapy with anti-CD20 monoclonal antibody, rituximab, combined with fludarabine and cyclophosphamide, became a gold standard of first-line treatment in eligible CLL patients. Currently, new treatment strategies including new monoclonal antibodies, bendamustine, lenalidomide, or inhibitors of several cell signaling pathways are under clinical studies in resistant/relapsed CLL patients. Moreover, allogeneic stem cell transplantation has to be considered, especially in younger high risk patients, for example, those who are resistant to PNA or those with 17p deletion. In this paper, we present the most important recent advances in CLL biology and treatment.

20.
Eur Cytokine Netw ; 24(1): 60-8, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23661335

ABSTRACT

Systemic lupus erythematosus (SLE) is an autoimmune disease of multifactorial pathoaetiology. Different organs and blood vessels may be affected by chronic inflammation. A direct cause of the disease has not yet been found, so research is being carried out to this effect. The role of the recently identified helper T lymphocyte CD4+, described as Th17, and its dependent cytokines have been of particular interest. The aim of the study was to evaluate IL-17A, IL-17B, IL-17F and IL-23 in 60 SLE patients and 26 age-matched, healthy volunteers and also to investigate the correlation between levels of the investigated cytokines and VEGF, PIGF, as well as number of endothelial cells. IL-17A, IL-17B, IL-17BR and IL-17F levels were found to be higher in SLE patients than in the control group. However, only IL-17F levels showed a statistically significant correlation with the number of endothelial cells (aCEC) and disease activity. Correlations between levels of IL-17F and VEGF and PIGF as well as VEGF and IL-17A and IL-23 were statistically significant. Increased levels of the selected cytokines from the IL-17 family in SLE patients suggest a role for them not only in the inflammatory process but also in angiogenesis. This also highlights the role of IL-17F in activating vascular endothelial cells and consequently blood vessel formation, and in the relationship between the inflammatory reaction and angiogenesis in the development of SLE.


Subject(s)
Angiogenesis Inducing Agents/blood , Endothelial Cells/metabolism , Interleukin-17/blood , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/pathology , Membrane Proteins/blood , Vascular Endothelial Growth Factor A/blood , Adult , Case-Control Studies , Female , Humans , Interleukin-23/blood , Male , Middle Aged , Young Adult
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