Quantitative Analysis of Cenobamate and Concomitant Anti-Seizure Medications in Human Plasma via Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry.

Cenobamate (CNB) is a new anti-seizure medication (ASM) recently introduced in clinical practice after approval by the FDA and EMA for the add-on treatment of focal onset seizures in adult patients. Although its mechanism of action has not been fully understood, CNB showed promising clinical efficacy in patients treated with concomitant ASMs. The accessibility of CNB could pave a way for the treatment of refractory or drug-resistant epilepsies, which still affect at least one-third of the patients under pharmacological treatment.

Posaconazole and midostaurin in patients with FLT3-mutated acute myeloid leukemia: Pharmacokinetic interactions and clinical facts in a real life study.

Midostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3-mutated acute myeloid leukemia. Chemotherapy-induced neutropenia exposes these patients to a significant risk of invasive fungal infections (IFIs). International guidelines recommend primary antifungal prophylaxis with posaconazole (PCZ) but nested analysis of a phase III trial showed that strong PCZ inhibition of CYP3A4 diminished midostaurin metabolism and increased midostaurin plasma levels; however, midostaurin-related adverse events (AEs) were only moderately exacerbated.

New Targeted Drugs for Acute Myeloid Leukemia and Antifungals: Pharmacokinetic Challenges and Opportunities.

Background: Acute myeloid leukemia (AML) is a life-threatening disease whose treatment is made difficult by a number of mutations or receptor overexpression in the proliferating cellular clones. Life expectancy of patients diagnosed with new, relapsed-refractory, or secondary AML has been improved by drugs targeted at such moieties. Regrettably, however, clinical use of new AML drugs is complicated by pharmacokinetic interactions with other drugs the patient is exposed to.

Ibrutinib and Bruton's Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia: Focus on Atrial Fibrillation and Ventricular Tachyarrhythmias/Sudden Cardiac Death.

Background: The natural history of chronic lymphocytic leukemia (CLL) was dramatically improved by the introduction of ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor. In this review, we aimed to summarize and critically evaluate the association between first- and second-generation BTK inhibitors and the risk of atrial fibrillation (AF) and ventricular arrhythmias (VA).

Summary: Since the first clinical experience, the development of AF was observed as the result of off-target effects that likely combined with patient's predisposing risk factors and concomitant cardiac morbidities.

Development and Validation of a UHPLC-MS/MS-Based Method to Quantify Cenobamate in Human Plasma Samples.

Cenobamate (CNB) is the newest antiseizure medication (ASM) approved by the FDA in 2019 to reduce uncontrolled partial-onset seizures in adult patients. Marketed as Xcopri in the USA or Ontozry in the EU (tablets), its mechanism of action has not been fully understood yet; however, it is known that it inhibits voltage-gated sodium channels and positively modulates the aminobutyric acid (GABA) ion channel. CNB shows 88% of oral bioavailability and is responsible for modifying the plasma concentrations of other co-administered ASMs, such as lamotrigine, carbamazepine, phenytoin, phenobarbital and the active metabolite of clobazam.

High Incidence of Invasive Fungal Diseases in Patients with FLT3-Mutated AML Treated with Midostaurin: Results of a Multicenter Observational SEIFEM Study.

The potential drug-drug interactions of midostaurin may impact the choice of antifungal (AF) prophylaxis in FLT3-positive acute myeloid leukemia (AML) patients. To evaluate the incidence of invasive fungal diseases (IFD) during the treatment of FLT3-mutated AML patients and to correlate it to the different AF prophylaxis strategies, we planned a multicenter observational study involving 15 SEIFEM centers. One hundred fourteen patients treated with chemotherapy + midostaurin as induction/reinduction, consolidation or both were enrolled.

Beyond hypertension: Diastolic dysfunction associated with cancer treatment in the era of cardio-oncology.

Cancer patients are at an increased risk of cardiovascular events. Both old-generation cytostatics/cytotoxics and new-generation "targeted" drugs can in fact damage cardiomyocytes, endothelial cells of veins and arteries, specialized cells of the conduction system, pericardium, and valves. A new discipline, cardio-oncology, has therefore developed with the aim of protecting cancer patients from cardiovascular events, while also providing them with the best possible oncologic treatment.

Infectious complications of targeted drugs and biotherapies in acute leukemia. Clinical practice guidelines by the European Conference on Infections in Leukemia (ECIL), a joint venture of the European Group for Blood and Marrow Transplantation (EBMT), the European Organization for Research and Treatment of Cancer (EORTC), the International Immunocompromised Host Society (ICHS) and the European Leukemia Net (ELN).

The 9th web-based European Conference on Infections in Leukemia (ECIL-9), held September 16-17, 2021, reviewed the risk of infections and febrile neutropenia associated with more recently approved immunotherapeutic agents and molecular targeted drugs for the treatment of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Novel antibody based treatment approaches (inotuzumab ozogamicin, gemtuzumab ozogamicin, flotetuzumab), isocitrate dehydrogenases inhibitors (ivosidenib, enasidenib, olutasidenib), FLT3 kinase inhibitors (gilteritinib, midostaurin, quizartinib), a hedgehog inhibitor (glasdegib) as well as a BCL2 inhibitor (venetoclax) were reviewed with respect to their mode of action, their immunosuppressive potential, their current approval and the infectious complications and febrile neutropenia reported from clinical studies. Evidence-based recommendations for prevention and management of infectious complications and specific alerts regarding the potential for drug-drug interactions were developed and discussed in a plenary session with the panel of experts until consensus was reached.

Choosing Antifungals for the Midostaurin-Treated Patient: Does CYP3A4 Outweigh Recommendations? A Brief Insight from Real Life.

Introduction: Patients treated with midostaurin and chemotherapy are at risk of invasive fungal disease. Prophylactic posaconazole is recommended for these patients, but posaconazole strongly inhibits the CYP3A4 isozyme that metabolizes midostaurin. Posaconazole therefore introduces a risk of patient's overexposure to midostaurin.

Rational design of PIN1 inhibitors for cancer treatment based on conformational diversity analysis and docking based virtual screening.

The parvulin PIN1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1), is the only enzyme capable of isomerizing prolines of phospho-Serine/Threonine-Proline motifs. PIN1 binds to a subset of proteins and plays an essential role in regulating protein function post-phosphorylation control. Furthermore, the activity of PIN1 regulates the outcome of the signalling of proline-directed kinases (e.

In ®Entresto we trust.

Sacubitril/Valsartan (S/V) is a novel and remarkably effective opportunity to treat heart failure with reduced ejection fraction (HFrEF). However, patients with HFrEF induced by cancer therapy were a priori excluded from the registration study. The value of S/V in this important subgroup of patients needs to be firmly established.

RepeatsDB in 2021: improved data and extended classification for protein tandem repeat structures.

The RepeatsDB database (URL: https://repeatsdb.org/) provides annotations and classification for protein tandem repeat structures from the Protein Data Bank (PDB). Protein tandem repeats are ubiquitous in all branches of the tree of life.

Predictors of Early or Delayed Diastolic Dysfunction After Anthracycline-Based or Nonanthracycline Chemotherapy: A Pharmacological Appraisal.

Diastolic dysfunction (DD) is an early manifestation of cancer drug cardiotoxicity. Anthracyclines are considered as more cardiotoxic than other chemotherapeutics, but previous studies have shown that both anthracycline-based and nonanthracycline chemotherapy can cause an early DD, detected 1 week after the end of chemotherapy. Here we characterized if DD also occurred in a delayed form, detected 6 months after chemotherapy.

Further Analytical, Pharmacokinetic, and Clinical Observations on Low-Dose Ponatinib in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

Introduction: Ponatinib (PNT) is a tyrosine kinase inhibitor approved for treating patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL), or chronic myeloid leukemia, resistant or intolerant to other tyrosine kinase inhibitor or showing T315I mutation of BCR-ABL. Unfortunately, the clinical use of PNT is limited by the possible occurrence of vascular occlusive events. The incidence of vascular events seems to correlate with PNT dose intensity and plasma exposure.

Safety and tolerability of a novel oral nutritional supplement in healthy volunteers.

Background And Objective: Foods for Special Medical Purposes (FSMPs) are formulated to support the nutritional needs of subjects with impaired capacity to ingest, digest or absorb ordinary food or nutrients. Polglumyt® is a proprietary highly purified, high quality glycogen obtained from mussels. Here we report the results of a single-center, single dose, open label, single arm study carried out to investigate acceptance (i.

Cardio-oncology in clinical studies and real life.

Session V of the Colloquium was chaired by Professors Teresa López-Fernández of Spain and Grzegorz Opolski of Poland. The 3 speakers addressed cardio-oncology issues as they relate to both clinical studies and real life situations. Professor Susan Dent discussed cardio-oncology networks for patients, emphasizing the importance of establishing a framework where the expertise of the cardiology consultant can supplement and reinforce the goals of optimal cancer therapy.

Pharmacology of Ranolazine versus Common Cardiovascular Drugs in Patients with Early Diastolic Dysfunction Induced by Anthracyclines or Nonanthracycline Chemotherapeutics: A Phase 2b Minitrial.

We have reported that anthracyclines and nonanthracycline chemotherapeutics caused diastolic dysfunction in cancer patients without cardiovascular risk factors. Diastolic dysfunction occurred as early as 1 week after the last chemotherapy cycle and manifested as impaired myocardial relaxation at echocardiography or persistent elevations of B-type natriuretic peptide (BNP) or troponin. The antianginal drug ranolazine shows cardiac relaxant effects that we considered of value to treat early diastolic dysfunction induced by cancer drugs; therefore, 24 low-risk patients with post-chemotherapy diastolic dysfunction were randomized (1:1) to ranolazine or the investigator's choice of common cardiovascular drugs, such as -blockers and/or angiotensin-converting enzyme inhibitors or loop diuretics (best standard therapy, BST).