Pharmacokinetics and Safety of Lurbinectedin Administrated with Itraconazole in Cancer Patients: A Drug-Drug Interaction Study.

This open-label, two-part, phase Ib drug-drug interaction study investigated whether the pharmacokinetic (PK) and safety profiles of lurbinectedin (LRB), a marine-derived drug, are affected by co-administration of itraconazole (ITZ), a strong CYP3A4 inhibitor, in adult patients with advanced solid tumors. In Part A, three patients were sequentially assigned to Sequence 1 (LRB 0.8 mg/m2, 1-h intravenous [IV] + ITZ 200 mg/day oral in Cycle 1 [C1] and LRB alone 3.2 mg/m2, 1 h, IV in Cycle 2 [C2]). In Part B, 11 patients were randomized (1:1) to receive either Sequence 1 (LRB at 0.9 mg/m2 + ITZ in C1 and LRB alone in C2) or Sequence 2 (LRB alone in C1 and LRB + ITZ in C2). Eleven patients were evaluable for PK analysis: three in Part A and eight in Part B (four per sequence). The systemic total exposure of LRB increased with ITZ co-administration: 15% for Cmax, area under the curve (AUC) 2.4-fold for AUC0-t and 2.7-fold for AUC0-∞. Co-administration with ITZ produced statistically significant modifications in the unbound plasma LRB PK parameters. The LRB safety profile was consistent with the toxicities described in previous studies. Co-administration with multiple doses of ITZ significantly altered LRB systemic exposure. Hence, to avoid LRB overexposure when co-administered with strong CYP3A4 inhibitors, an LRB dose reduction proportional to CL reduction should be applied.

Impact of a Moderate CYP3A4 Inducer (Bosentan) on Lurbinectedin Pharmacokinetics and Safety in Patients with Advanced Solid Tumors: An Open-Label, Two-Way, Crossover, Phase Ib Drug-Drug Interaction Study.

This open-label, two-way, crossover, phase Ib drug-drug interaction study investigated whether the pharmacokinetics (PKs) and safety profile of lurbinectedin (LRB) are affected by co-administration of a moderate CYP3A4 inducer (bosentan, BOS) in adult patients with advanced solid tumors. Eleven patients were randomly assigned to Sequence 1 (LRB + BOS in Cycle 1 [C1] and LRB alone in Cycle 2 [C2]) or Sequence 2 (LRB alone in C1 and LRB + BOS in C2), and finally, eight patients (four per sequence) were considered evaluable for PK assessment. LRB (3.2 mg/m2, 1 h [h], intravenous) was administered alone or combined with multiple BOS administration (125 mg/12 h oral; 5.5 days). Co-administration with BOS decreased the systemic total exposure (area under the curve, AUC) of LRB by 21% for AUC0-t and 20% for AUC0-∞ and increased clearance by 25%. Co-administration with BOS did not significantly modify the unbound plasma LRB PK parameters. BOS increased the conversion of LRB to its metabolite M1, with no changes on its metabolite M4. The LRB safety profile was consistent with the toxicities previously described for this drug. No differences in terms of toxicity were found between LRB with and without BOS. In summary, the magnitude of the observed changes precludes a clinically relevant effect of BOS co-administration on LRB exposure and its safety profile.

fMRI Neurofeedback-Enhanced Cognitive Reappraisal Training in Depression: A Double-Blind Comparison of Left and Right vlPFC Regulation.

Affective disorders are associated with maladaptive emotion regulation strategies. In particular, the left more than the right ventrolateral prefrontal cortex (vlPFC) may insufficiently regulate emotion processing, e.g., in the amygdala. A double-blind cross-over study investigated NF-supported cognitive reappraisal training in major depression (n = 42) and age- and gender-matched controls (n = 39). In a randomized order, participants trained to upregulate either the left or the right vlPFC during cognitive reappraisal of negative images on two separate days. We wanted to confirm regional specific NF effects with improved learning for left compared to right vlPFC (ClinicalTrials.gov NCT03183947). Brain responses and connectivity were studied with respect to training progress, gender, and clinical outcomes in a 4-week follow-up. Increase of vlPFC activity was stronger after NF training from the left- than the right-hemispheric ROI. This regional-specific NF effect during cognitive reappraisal was present across patients with depression and controls and supports a central role of the left vlPFC for cognitive reappraisal. Further, the activity in the left target region was associated with increased use of cognitive reappraisal strategies (r = 0.48). In the 4-week follow-up, 75% of patients with depression reported a successful application of learned strategies in everyday life and 55% a clinically meaningful symptom improvement suggesting clinical usability.

Magnetic Control over the Fractal Dimension of Supramolecular Rod Networks.

Controlling supramolecular polymerization is of fundamental importance to create advanced materials and devices. Here we show that the thermodynamic equilibrium of Gd3+-bearing supramolecular rod networks is shifted reversibly at room temperature in a static magnetic field of up to 2 T. Our approach opens opportunities to control the structure formation of other supramolecular or coordination polymers that contain paramagnetic ions.

First-in-human phase I study of the microtubule inhibitor plocabulin in patients with advanced solid tumors.

Background Plocabulin (PM060184) is a novel marine-derived microtubule inhibitor that acts as an antitumor agent. This first-in-human study evaluated dose-limiting toxicities (DLT) to define the maximum tolerated dose (MTD) and phase II recommended dose (RD) of plocabulin given as a 10-min infusion on Day (D) 1, D8 and D15 every four weeks. Patients and methods Forty-four patients with advanced solid tumors received plocabulin following an accelerated titration design. Results Plocabulin was escalated from 1.3 mg/m2 to 14.5 mg/m2, which was defined as the MTD. No RD was confirmed, because frequent dose delays and omissions resulted in low relative dose intensity (66%) at the 12.0 mg/m2 expansion cohort. The main DLT was grade 3 peripheral sensory neuropathy (PSN); other DLTs were grade 4 tumor lysis syndrome, grade 4 cardiac failure and grade 3 myalgia. Toxicities were mainly mild to moderate, and included abdominal pain, myalgia, fatigue, nausea, and vomiting. Myelosuppression was transient and manageable. Plocabulin had a half-life of ~4 h and a wide diffusion to peripheral tissues. Antitumor response was observed in cervix carcinoma and heavily pretreated metastatic non-small cell lung cancer patients, and disease stabilization (≥3 months) in patients with colorectal, thymic, gastrointestinal stromal and breast tumors, among others. The clinical benefit rate was 33%. Conclusion The main DLT of plocabulin was PSN, as anticipated for a tubulin-binding agent. Since encouraging antitumor activity was observed, efforts to improve toxicity and to find the RD were planned in other trials evaluating D1&D8 and D1-D3 plus D15-D17 schedules.

Oscillations, travelling fronts and patterns in a supramolecular system.

Supramolecular polymers, such as microtubules, operate under non-equilibrium conditions to drive crucial functions in cells, such as motility, division and organelle transport1. In vivo and in vitro size oscillations of individual microtubules2,3 (dynamic instabilities) and collective oscillations4 have been observed. In addition, dynamic spatial structures, like waves and polygons, can form in non-stirred systems5. Here we describe an artificial supramolecular polymer made of a perylene diimide derivative that displays oscillations, travelling fronts and centimetre-scale self-organized patterns when pushed far from equilibrium by chemical fuels. Oscillations arise from a positive feedback due to nucleation-elongation-fragmentation, and a negative feedback due to size-dependent depolymerization. Travelling fronts and patterns form due to self-assembly induced density differences that cause system-wide convection. In our system, the species responsible for the nonlinear dynamics and those that self-assemble are one and the same. In contrast, other reported oscillating assemblies formed by vesicles6, micelles7 or particles8 rely on the combination of a known chemical oscillator and a stimuli-responsive system, either by communication through the solvent (for example, by changing pH7-9), or by anchoring one of the species covalently (for example, a Belousov-Zhabotinsky catalyst6,10). The design of self-oscillating supramolecular polymers and large-scale dissipative structures brings us closer to the creation of more life-like materials11 that respond to external stimuli similarly to living cells, or to creating artificial autonomous chemical robots12.

Non-equilibrium steady states in supramolecular polymerization.

Living systems use fuel-driven supramolecular polymers such as actin to control important cell functions. Fuel molecules like ATP are used to control when and where such polymers should assemble and disassemble. The cell supplies fresh ATP to the cytosol and removes waste products to sustain steady states. Artificial fuel-driven polymers have been developed recently, but keeping them in sustained non-equilibrium steady states (NESS) has proven challenging. Here we show a supramolecular polymer that can be kept in NESS, inside a membrane reactor where ATP is added and waste removed continuously. Assembly and disassembly of our polymer is regulated by phosphorylation and dephosphorylation, respectively. Waste products lead to inhibition, causing the reaction cycle to stop. Inside the membrane reactor, however, waste can be removed leading to long-lived NESS conditions. We anticipate that our approach to obtain NESS can be applied to other stimuli-responsive materials to achieve more life-like behaviour.

Non-equilibrium supramolecular polymerization.

Supramolecular polymerization has been traditionally focused on the thermodynamic equilibrium state, where one-dimensional assemblies reside at the global minimum of the Gibbs free energy. The pathway and rate to reach the equilibrium state are irrelevant, and the resulting assemblies remain unchanged over time. In the past decade, the focus has shifted to kinetically trapped (non-dissipative non-equilibrium) structures that heavily depend on the method of preparation (i.e., pathway complexity), and where the assembly rates are of key importance. Kinetic models have greatly improved our understanding of competing pathways, and shown how to steer supramolecular polymerization in the desired direction (i.e., pathway selection). The most recent innovation in the field relies on energy or mass input that is dissipated to keep the system away from the thermodynamic equilibrium (or from other non-dissipative states). This tutorial review aims to provide the reader with a set of tools to identify different types of self-assembled states that have been explored so far. In particular, we aim to clarify the often unclear use of the term "non-equilibrium self-assembly" by subdividing systems into dissipative, and non-dissipative non-equilibrium states. Examples are given for each of the states, with a focus on non-dissipative non-equilibrium states found in one-dimensional supramolecular polymerization.

Phase I study of lurbinectedin, a synthetic tetrahydroisoquinoline that inhibits activated transcription, induces DNA single- and double-strand breaks, on a weekly × 2 every-3-week schedule.

Background Lurbinectedin administered as a 1-h intravenous infusion every 3 weeks induces neutropenia, with the nadir usually occurring during the second week. This phase I study evaluated an alternative lurbinectedin dosing schedule consisting of a 1-h infusion on days 1 and 8 every 3 weeks. Patients and methods Twenty-one patients with advanced cancer received lurbinectedin using a standard cohort dose escalation design. Results Three dose levels of 3, 4, and 5 mg of lurbinectedin were explored. The recommended phase II dose was 5 mg, with 3 of 13 patients having dose-limiting toxicity (DLT), although grade 4 neutropenia occurred in 50% of patients. Other frequent toxicities were mild to moderate nausea and vomiting, fatigue, decreased appetite, stomatitis and asymptomatic creatinine and transaminase increases. No objective responses occurred, but prolonged stable disease was observed in 7 patients, including 3 with soft tissue sarcoma. Conclusion The recommended phase II dose of lurbinectedin is 5 mg, administered as a 1-h infusion on days 1 and 8 every 3 weeks. These data support further testing of this dose and schedule, particularly in soft tissue sarcoma.

Supramolecular pathway selection of perylenediimides mediated by chemical fuels.

We demonstrate supramolecular pathway selection of a perylenediimide derivative in aqueous solution using chemically fueled redox reactions to control assembly/disassembly cycles. The number and frequency of cycles affect the nucleation and growth process, providing control over the size and internal order of the resulting self-assembled structures.

First-in-human, phase I study of elisidepsin (PM02734) administered as a 30-min or as a 3-hour intravenous infusion every three weeks in patients with advanced solid tumors.

This first-in-human, phase I clinical trial was designed to determine the dose-limiting toxicities (DLTs) and the dose for phase II trials (P2D) of elisidepsin (PM02734) administered as a 30-min or as a 3-h intravenous infusion every 3 weeks (q3wk). Between March 2006 and April 2011, 53 patients with advanced malignant solid tumors were enrolled and treated with elisidepsin on the two different q3wk infusion schedules: 22 (30-min) and 31 (3-h), respectively. Doses evaluated ranged from 0.1 to 1.6 mg/m(2) (30-min q3wk) and from 2.0 to 11.0 mg flat dose (FD) (3-h q3wk). In the 30-min q3wk schedule, transient grade 3/4 increases in hepatic transaminases were the DLT, which appeared at the highest doses tested (from 1.1 to 1.6 mg/m(2)). No DLTs were observed on the 3-h schedule at doses up to 11.0 mg q3wk. Common adverse events were grade 1/2 pruritus, nausea, fatigue and hypersensitivity. Of note, myelotoxicity was not observed. Plasma maximum concentration and total drug exposure increased linearly with dose. Prolonged (≥3 months) disease stabilization was observed in pretreated patients with pleural mesothelioma (n = 1) in the 30-min q3wk arm, and with colorectal adenocarcinoma (n = 3), esophagus adenocarcinoma, endometrium adenocarcinoma, pleural mesothelioma, and head and neck carcinoma (n = 1 each) in the 3-h q3wk arm. In conclusion, elisidepsin doses of 1.1 mg/m(2) (equivalent to a FD of 2.0 mg) and 11.0 mg FD are the dose levels achieved for further phase II trials testing the 30-min q3wk and 3-h q3wk schedules, respectively.

Role of the plasma membrane transporter of organic cations OCT1 and its genetic variants in modern liver pharmacology.

Changes in the uptake of many drugs by the target cells may dramatically affect the pharmacological response. Thus, downregulation of SLC22A1, which encodes the organic cation transporter type 1 (OCT1), may affect the response of healthy hepatocytes and liver cancer cells to cationic drugs, such as metformin and sorafenib, respectively. Moreover, the overall picture may be modified to a considerable extent by the preexistence or the appearance during the pathogenic process of genetic variants. Some rare OCT1 variants enhance transport activity, whereas other more frequent variants impair protein maturation, plasma membrane targeting or the function of this carrier, hence reducing intracellular active drug concentrations. Here, we review current knowledge of the role of OCT1 in modern liver pharmacology, which includes the use of cationic drugs to treat several diseases, some of them of great clinical relevance such as diabetes and primary liver cancer (cholangiocarcinoma and hepatocellular carcinoma). We conclude that modern pharmacology must consider the individual evaluation of OCT1 expression/function in the healthy liver and in the target tissue, particularly if this is a tumor, in order to predict the lack of response to cationic drugs and to be able to design individualized pharmacological treatments with the highest chances of success.

Phase I clinical and pharmacokinetic study of trabectedin and cisplatin given every three weeks in patients with advanced solid tumors.

The aim of this phase I study was to identify a feasible dose and schedule for the combination of cisplatin and trabectedin. The regimen evaluated consisted of cisplatin at a fixed dose of 75 mg/m(2) 1-hour intravenous (i.v.) infusion followed by escalating doses of trabectedin 3-hour i.v. infusion, both administered on day 1 every 3 weeks (q3wks). Two dose-limiting toxicities (DLTs), grade 4 neutropenia longer than 7 days duration and grade 3 vomiting despite standard antiemetic therapy, occurred at the starting dose of trabectedin (0.75 mg/m(2)). The immediately lower dose (trabectedin 0.60 mg/m(2)) was evaluated in a total of 8 patients; no DLTs occurred and this was declared the recommended dose (RD). The safety profile of the combination at this dose and schedule was consistent with the known side effects of each agent alone: nausea, fatigue, transient transaminase elevations and neutropenia. No new or unexpected adverse reactions were observed. Two partial responses were reported at the RD in patients with pretreated ovarian cancer. Comparison with population pharmacokinetic data suggests a PK interaction between trabectedin and cisplatin leading to increased plasma exposure of trabectedin in the first 48 h, lower platinum clearance and longer half-life. In conclusion, although the trabectedin dose achieved with this combination was low (50 % of single-agent when given q3wks), this day 1 q3wks trabectedin plus cisplatin combination showed a feasible administration, a tolerable safety profile and some antitumor activity.

Changes in reading strategies in school-age children.

Learning to read is one of the most important cognitive milestones in the human social environment. One of the most accepted models explaining such process is the Double-Route Cascaded Model. It suggests the existence of two reading strategies: lexical and sublexical. In the Spanish language there are some contradictions about how these strategies are applied for reading. In addition, there are only a few studies dealing with the analysis of shifts between them, achieving a fluent reading process. In this paper we use a reading task including words and pseudowords for characterizing the cost of shifting between reading strategies in children with developmental dyslexia and normal controls. Our results suggest the presence of both strategies in these two experimental groups. In controls, both strategies become more efficient in correspondence to the increased exposition to written material. However, in children with developmental dyslexia only the lexical strategy exhibits such improvement. Their also point to a low cost for shifting between strategies in controls and a much more significant one in children with developmental dyslexia, differentiating subgroups with distinct shifting patterns.

Changes in Reading Strategies in School-Age Children

Learning to read is one of the most important cognitive milestones in the human social environment.One of the most accepted models explaining such process is the Double-Route Cascaded Model. It suggests the existence of two reading strategies: lexical and sublexical. In the Spanish language there are some contradictions about how these strategies are applied for reading. In addition, there are only a few studies dealing with the analysis of shifts between them, achieving a fluent reading process. In this paper we use a reading task including words and pseudowords for characterizing the cost of shifting between reading strategies in children with developmental dyslexia and normal controls. Our results suggest the presence of both strategies in these two experimental groups. In controls, both strategies become more efficient in correspondence to the increased exposition to written material. However, in children with developmental dyslexia only the lexical strategy exhibits such improvement. Their also point to a low cost for shifting between strategies in controls and a much more significant one in children with developmental dyslexia, differentiating subgroups with distinct shifting patterns (AU)

El aprendizaje de la lectura constituye uno de los hitos cognitivos más importantes del entorno social humano. Uno de los modelos de lectura más aceptados ha sido el Modelo de Doble Ruta en Cascada que sugiere la existencia de dos estrategias de lectura: lexical y sublexical. En el idioma español existen datos contradictorios acerca de cómo se aplican estas estrategias y no hay estudios que describan cómo se realizan los cambios de una a otra para lograr una lectura fluida. En este trabajo utilizamos una tarea de lectura de palabras y pseudopalabras para caracterizar el costo de cambio de una a otra estrategia en niños buenos lectores y niños con dislexia del desarrollo. Nuestros resultados sugieren la presencia de ambas estrategias en los dos grupos. En los niños buenos lectores ambas estrategias se hacen más eficientes con el grado de exposición a la lectura. Sin embargo, en los niños disléxicos esto solo ocurre en la estrategia lexical. Además, indican que los niños buenos lectores desarrollan un bajo costo en el cambio de estrategia de lectura mientras que un subgrupo de niños disléxicos presenta un costo mayor, conformándose subgrupos con patrones diferentes de afectación selectiva (AU)

Pathological personality traits and suicidal ideation among older adolescents and young adults with alcohol misuse: a pilot case-control study in a primary care setting.

OBJECTIVE: To compare the clinical and demographic characteristics of older adolescents and young adults with and without alcohol misuse in a primary care setting. METHODS: This study is a case-control study. Eighty-one 18-30 year old adolescents and young adults attending a primary care center were assessed with the CAGE questionnaire, the PRIME-MD instrument and the IPDE screening questionnaire. Sub-samples of positive screen for alcohol misuse (n = 21) and a negative age- and gender matched group (n = 21) were compared. RESULTS: Of those with alcohol misuse, 71.9% had a comorbid psychiatric diagnosis. Depressive and anxiety disorders appeared to be more prevalent among the subjects with alcohol misuse than among controls. Among those patients with depressive or anxiety disorders and alcohol misuse, 22.2% reported suicidal ideation as compared to none among the controls suffering from depressive or anxiety disorders. 69.1% of subjects with alcohol misuse had a comorbid personality disorder. Significantly more adolescents and young adults with alcohol misuse exhibited borderline personality traits (p = 0.03) and there was also a trend towards a greater proportion exhibiting histrionic traits (p = 0.07) than among those without alcohol misuse. CONCLUSIONS: Adolescents and young adults with alcohol misuse in a primary care center have a high prevalence of psychiatric comorbidity. Cluster B personality disorders may be more prevalent in the population with alcohol misuse. Adolescents and young adults with alcohol misuse may be more likely to report suicidal ideation while suffering from depressive or anxiety disorders. Further studies that evaluate the clinical and demographic characteristics of adolescents and young adults with alcohol misuse attended in a primary care center are needed.

Prevalence of alcohol misuse among adolescents and young adults evaluated in a primary care setting.

OBJECTIVE: To determine the prevalence of alcohol misuse among older adolescents and young adults evaluated in a primary care setting using the CAGE questionnaire. METHODS: In this crossover descriptive study, a general practitioner, using the CAGE questionnaire, interviewed consecutive primary care patients aged 18-30 years. RESULTS: 29.5% of adolescents and young adults answered "yes" to at least one question of the CAGE questionnaire. However, only 7.4% of study participants gave an affirmative answer to at least two CAGE questions. There were more males than females among subjects who answered "yes" to at least one question. Furthermore, males more commonly gave an affirmative answer to at least two CAGE questions. CONCLUSIONS: A substantial number of older adolescents and young adults evaluated at a primary care center may have alcohol misuse. Instruments with higher sensitivity may be preferable in screening procedures for alcohol misuse. Responses suggestive of problematic drinking should be confirmed during the second post-screening stage with a more detailed discussion about patterns of use, problems related to drinking, and symptoms of alcohol use disorder. Further studies of prevention interventions in adolescents and young adults are needed.

Quiste broncogénico (a propósito de un caso) / Bronchogenic cyst (a propos of a case)

Antecedentes: los quistes broncogénicos son una malformación congénita del árbol bronquial que a menudo son asintomáticos. Frecuentemente se manifiestan como un hallazgo radiológico. Objetivo: presentar un caso de quiste broncogénico sintomático en un adulto, tratado quirúrgicamente en nuestro hospital. Se hacen consideraciones etiológicas y clínico-quirúrgicas. Lugar de aplicación: Servicio de Cirugía General, Hospital Interzonal General de Agudos Presidente Perón, Avellaneda. Material y métodos: se presenta un paciente de sexo femenino de 42 años de edad, intervenido quirúrgicamente en nuestro hospital. Se utilizan para la recolección de datos la historia clínica, estudios de imágenes (radiografía de tórax, TAC de tórax, RMN de tórax) y los protocolos quirúrgicos. Resultados: se expone el tratamiento quirúrgico, los controles postoperatorios, la mejoría de la función, la desaparición de los síntomas. Conclusiones: si bien, generalmente son asintomáticos, y en los adultos se presentan como hallazgos radiológicos, en ciertos casos por su localización pueden dar origen a importantes síntomas funcionales y respiratorios, por lo cual se sugiere tratamiento quirúrgico una vez realizado el diagnóstico, ya que las cirugías de las complicaciones revelan mayor dificultad y resultados ominosos

Quiste broncogénico (a propósito de un caso) / Bronchogenic cyst (a propos of a case)

Antecedentes: los quistes broncogénicos son una malformación congénita del árbol bronquial que a menudo son asintomáticos. Frecuentemente se manifiestan como un hallazgo radiológico. Objetivo: presentar un caso de quiste broncogénico sintomático en un adulto, tratado quirúrgicamente en nuestro hospital. Se hacen consideraciones etiológicas y clínico-quirúrgicas. Lugar de aplicación: Servicio de Cirugía General, Hospital Interzonal General de Agudos Presidente Perón, Avellaneda. Material y métodos: se presenta un paciente de sexo femenino de 42 años de edad, intervenido quirúrgicamente en nuestro hospital. Se utilizan para la recolección de datos la historia clínica, estudios de imágenes (radiografía de tórax, TAC de tórax, RMN de tórax) y los protocolos quirúrgicos. Resultados: se expone el tratamiento quirúrgico, los controles postoperatorios, la mejoría de la función, la desaparición de los síntomas. Conclusiones: si bien, generalmente son asintomáticos, y en los adultos se presentan como hallazgos radiológicos, en ciertos casos por su localización pueden dar origen a importantes síntomas funcionales y respiratorios, por lo cual se sugiere tratamiento quirúrgico una vez realizado el diagnóstico, ya que las cirugías de las complicaciones revelan mayor dificultad y resultados ominosos