Podophyllotoxin: Recent Advances in the Development of Hybridization Strategies to Enhance Its Antitumoral Profile.

Podophyllotoxin is a naturally occurring cyclolignan isolated from rhizomes of Podophyllum sp. In the clinic, it is used mainly as an antiviral; however, its antitumor activity is even more interesting. While podophyllotoxin possesses severe side effects that limit its development as an anticancer agent, nevertheless, it has become a good lead compound for the synthesis of derivatives with fewer side effects and better selectivity. Several examples, such as etoposide, highlight the potential of this natural product for chemomodulation in the search for new antitumor agents. This review focuses on the recent chemical modifications (2017-mid-2023) of the podophyllotoxin skeleton performed mainly at the C-ring (but also at the lactone D-ring and at the trimethoxyphenyl E-ring) together with their biological properties. Special emphasis is placed on hybrids or conjugates with other natural products (either primary or secondary metabolites) and other molecules (heterocycles, benzoheterocycles, synthetic drugs, and other moieties) that contribute to improved podophyllotoxin bioactivity. In fact, hybridization has been a good strategy to design podophyllotoxin derivatives with enhanced bioactivity. The way in which the two components are joined (directly or through spacers) was also considered for the organization of this review. This comprehensive perspective is presented with the aim of guiding the medicinal chemistry community in the design of new podophyllotoxin-based drugs with improved anticancer properties.

La regulación normativa como instrumento de apoyo al control de la pandemia / Normative regulation as an instrument to support the control of the pandemic

Una de las herramientas esenciales para combatir la pandemia ha sido la aprobación de normativa para dictar medidas sanitarias específicas de prevención, de carácter extraordinario,como consecuencia de la situación epidemiológica derivada de la COVID-19.Algunas de estas medidas tuvieron rango de ley, otras eran reglamentos de carácter ejecutivo y otras actos administrativos de carácter organizativo. Estaban dirigidas fundamentalmente a evitar la movilidad de las personas para reducir los contagios y contener lasatenciones médicas y hospitalizaciones, las cuales amenazaban con colapsar el sistema sanitario y comprometer la salud pública de la población. Eran normas de una extraordinariacomplejidad por la cantidad de ámbitos sociales y económicos en los que incidían y, sobretodo, por los derechos que limitaban: derechos fundamentales como la libertad de circulación de las personas o la libertad religiosa, derecho de reunión y de manifestación o derechoa la intimidad familiar.El objeto de este artículo es realizar un breve análisis de la actividad normativa llevada a caboen Navarra para dictar medidas sanitarias de carácter extraordinario entre marzo de 2020 einicios de 2022, recorriendo las distintas etapas con declaración de estado de alarma y aquellas en las que las comunidades autónomas ostentaban competencias para dictar normas. Sereflexiona sobre cómo la urgencia con la que hubo que dictarlas, su extrema complejidad técnica, la falta de experiencias previas, las dispares interpretaciones jurídicas sobre si el marconormativo existente avalaba su adopción, y la falta de referencias jurisprudenciales dificultaronsu aprobación.(AU)

1,3-Cyclohexadien-1-Als: Synthesis, Reactivity and Bioactivities.

In synthetic organic chemistry, there are very useful basic compounds known as building blocks. One of the main reactions wherein they are applied for the synthesis of complex molecules is the Diels-Alder cycloaddition. This reaction is between a diene and a dienophile. Among the most important dienes are the cyclic dienes, as they facilitate the reaction. This review considers the synthesis and reactivity of one of these dienes with special characteristics-it is cyclic and has an electron withdrawing group. This building block has been used for the synthesis of biologically active compounds and is present in natural compounds with interesting properties.

Zr-MOF-808 as Catalyst for Amide Esterification.

In this work, zirconium-based metal-organic framework Zr-MOF-808-P has been found to be an efficient and versatile catalyst for amide esterification. Comparing with previously reported homogeneous and heterogeneous catalysts, Zr-MOF-808-P can promote the reaction for a wide range of primary, secondary and tertiary amides with n-butanol as nucleophilic agent. Different alcohols have been employed in amide esterification with quantitative yields. Moreover, the catalyst acts as a heterogeneous catalyst and could be reused for at least five consecutive cycles. The amide esterification mechanism has been studied on the Zr-MOF-808 at molecular level by in situ FTIR spectroscopic technique and kinetic study.

Tianeptina, un abordaje farmacológico atípico de la depresión / Tianeptine, an atypical pharmacological approach to depression

La introducción de los primeros antidepresivos en la década de los cincuenta del sigloxx modificó de forma radical el tratamiento de la depresión, a la vez que aportó información sobre aspectos fisiopatológicos de esta enfermedad. Los nuevos fármacos antidepresivos (agomelatina, tianeptina, vortioxetina) están aportando datos que dan lugar a hipótesis fisiopatológicas de la depresión que difieren de la clásica teoría monoaminérgica. En este sentido, la tianeptina, un fármaco atípico por su mecanismo de acción diferencial, contribuye a clarificar que en la fisiopatología de la depresión hay algo más que monoaminas. Así, la tianeptina no modifica la tasa de serotonina extracelular, por lo que no aumenta ni disminuye la recaptación de serotonina. La administración crónica de tianeptina no altera la densidad ni la afinidad de más de un centenar de receptores clásicos relacionados con la depresión. Recientemente se ha descrito una acción débil de la tianeptina sobre receptores opioidesMu que podría explicar la liberación de dopamina en el sistema límbico y su participación en la modulación de mecanismos glutamatérgicos. Estos mecanismos sustentan la hipótesis del posible mecanismo de acción de este antidepresivo. La tianeptina es un antidepresivo con propiedades ansiolíticas que puede mejorar síntomas somáticos. La tianeptina como modulador glutamatérgico, entre otros mecanismos, permite abordar la depresión desde un punto de vista diferente al del resto de antidepresivos

The introduction of the first antidepressants in the 50s of the 20th century radically changed the treatment of depression, while providing information on pathophysiological aspects of this disease. New antidepressants drugs (agomelatine, tianeptine, vortioxetine) are providing data that give rise to pathophysiological hypotheses of depression that differ from the classic monoaminergic theory. In this sense, tianeptina, an atypical drug by its mechanism of differential action, contributes to clarify that in depression there is more than monoamines. Thus, tianeptine does not modify the rate of extracellular serotonin, so it does not increase or decrease the reuptake of serotonin. Chronic administration of tianeptine does not alter the density or affinity of more than a hundred classical receptors related to depression. Recently, a weak action of tianeptine on Mu opioid receptors has been described that could explain the release of dopamine in the limbic system and its participation in the modulation of glutamatergic mechanisms. These mechanisms support the hypothesis of the possible mechanism of action of this antidepressant. Tianeptine is an antidepressant, with anxiolytic properties, that can improve somatic symptoms. Tianeptine as a glutamatergic modulator, among other mechanisms, allows us to approach depression from a different point of view than other antidepressants

Tianeptine, an atypical pharmacological approach to depression. / Tianeptina, un abordaje farmacológico atípico de la depresión.

The introduction of the first antidepressants in the 50s of the 20th century radically changed the treatment of depression, while providing information on pathophysiological aspects of this disease. New antidepressants drugs (agomelatine, tianeptine, vortioxetine) are providing data that give rise to pathophysiological hypotheses of depression that differ from the classic monoaminergic theory. In this sense, tianeptina, an atypical drug by its mechanism of differential action, contributes to clarify that in depression there is more than monoamines. Thus, tianeptine does not modify the rate of extracellular serotonin, so it does not increase or decrease the reuptake of serotonin. Chronic administration of tianeptine does not alter the density or affinity of more than a hundred classical receptors related to depression. Recently, a weak action of tianeptine on Mu opioid receptors has been described that could explain the release of dopamine in the limbic system and its participation in the modulation of glutamatergic mechanisms. These mechanisms support the hypothesis of the possible mechanism of action of this antidepressant. Tianeptine is an antidepressant, with anxiolytic properties, that can improve somatic symptoms. Tianeptine as a glutamatergic modulator, among other mechanisms, allows us to approach depression from a different point of view than other antidepressants.

Catalytic Transfer Hydrogenation of Biomass-Derived Carbonyls over Hafnium-Based Metal-Organic Frameworks.

A series of highly crystalline, porous, hafnium-based metal-organic frameworks (Hf-MOFs) have been shown to catalyze the transfer hydrogenation reaction of levulinic ester to produce γ-valerolactone by using isopropanol as a hydrogen donor. The results are compared with their zirconium-based counterparts. The role of the metal center in Hf-MOFs has been identified and reaction parameters optimized. NMR studies using isotopically labeled isopropanol provide evidence that the transfer hydrogenation occurs through a direct intermolecular hydrogen transfer route. The catalyst, Hf-MOF-808, can be recycled several times with only a minor decrease in catalytic activity. The generality of the procedure has been demonstrated by accomplishing the transformation with aldehydes, ketones, and α,ß-unsaturated carbonyl compounds. The combination of Hf-MOF-808 with the Brønsted-acidic Al-Beta zeolite gives the four-step one-pot transformation of furfural to γ-valerolactone in good yield of 75 %.

Tianeptina, antidepresivo con perfil beneficio/riesgo positivo / Tianeptine, antidepressant with positive benefit/risk

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Adhesión al tratamiento con levetiracetam: estudio observacional retrospectivo no intervencionista / Treatment adherence with levetiracetam: a non-interventionist retrospective observation-based study

Introducción. La adhesión al tratamiento es un factor que está repercutiendo en la eficacia de los fármacos antiepilépticos. El levetiracetam es un principio activo cuya eficacia y seguridad están ampliamente demostradas y que está disponible en diferentes formulaciones orales (sobres, comprimidos y solución oral), pero la información sobre la adhesión/cumplimiento del tratamiento con estas formulaciones orales es escasa. Objetivo. Conocer la adhesión al tratamiento con formulaciones de levetiracetam (granulado en sobre y comprimidos) en adultos y ancianos. Pacientes y métodos. Estudio observacional retrospectivo no intervencionista. Durante los tres meses previos al estudio debía estar en tratamiento con levetiracetam (granulado en sobre o comprimidos), bien en monoterapia o en combinación. Se valoraron los tests de cumplimiento (cuestionario de Morisky-Green modificado), así como un cuestionario de satisfacción del investigador y del paciente/cuidador. Los datos se analizaron con el programa SPSS v. 21.0. Resultados. Un total de 466 pacientes completaron el estudio. La edad media fue de 52,75 ± 19,17 años, y la media en los mayores de 65 años fue de 72,79 ± 6,15 años. Un 55,4% eran hombres. El cumplimiento se relaciona con la variable ‘formulación galénica’ y con la edad (p = 0,031). El riesgo de incumplimiento es un 86,4% mayor entre los que toman comprimidos frente a granulado de levetiracetam (odds ratio: 1,864). Asimismo, el incumplimiento es mayor entre los pacientes mayores de 65 años. El incumplimiento se relaciona con la atribución de fallos de memoria. Conclusiones. Los pacientes más mayores presentan más dificultades en el cumplimiento. El granulado de levetiracetam en sobres favorece el cumplimiento (AU)

Introduction. Treatment adherence is a factor that is affecting the effectiveness of antiepileptic drugs. Levetiracetam is a drug whose effectiveness and safety is well established and is available in different oral formulations (granulates in sachets, tablets, oral solution), but information on treatment adherence/compliance with these oral formulations is limited. Aim. To determine treatment adherence with levetiracetam formulations (granulates in sachets, tablets) in adult and elderly people. Patients and methods. Retrospective observational non-interventionist study. During the three months before the study patients should be treated with levetiracetam (granulates in sachets or tablets), either alone or in combination. Compliance tests (Green-Morisky modified test) as well as a satisfaction questionnaire investigator and patient/caregiver is assessed. Data were analyzed using SPSS v. 21.0 program. Results. A total of 466 patients completed the study. The average age was 52.75 ± 19.17 years old and the average over 65 years of 72.79 ± 6.15. 55.4% were men. Compliance is related to the variable ‘pharmaceutical formulation’ and with age (p = 0.031). The risk of non-compliance was 86.4% higher among those taking tablets versus granulates in sachets of levetiracetam (odds ratio: 1.864). Likewise, the non-compliance was greater among patients over 65 years. The noncompliance was related to attributing of memory failures. Conclusions. Patients older are more difficult to compliance. The granulates levetiracetam in sachets improves compliance (AU)

Organic-inorganic supramolecular solid catalyst boosts organic reactions in water.

Coordination polymers and metal-organic frameworks are appealing as synthetic hosts for mediating chemical reactions. Here we report the preparation of a mesoscopic metal-organic structure based on single-layer assembly of aluminium chains and organic alkylaryl spacers. The material markedly accelerates condensation reactions in water in the absence of acid or base catalyst, as well as organocatalytic Michael-type reactions that also show superior enantioselectivity when comparing with the host-free transformation. The mesoscopic phase of the solid allows for easy diffusion of products and the catalytic solid is recycled and reused. Saturation transfer difference and two-dimensional (1)H nuclear Overhauser effect NOESY NMR spectroscopy show that non-covalent interactions are operative in these host-guest systems that account for substrate activation. The mesoscopic character of the host, its hydrophobicity and chemical stability in water, launch this material as a highly attractive supramolecular catalyst to facilitate (asymmetric) transformations under more environmentally friendly conditions.

Psychiatric Comorbidity at the Time of Diagnosis in Adults With ADHD: The CAT Study.

OBJECTIVE: The CAT (Comorbilidad en Adultos con TDAH) study aimed to quantify and characterize the psychiatric comorbidity at the time of diagnosis of ADHD in adult outpatients. METHOD: Cross-sectional, multicenter, observational register of adults with ADHD diagnosed for the first time. RESULTS: In this large sample of adult ADHD (n = 367), psychiatric comorbidities were present in 66.2% of the sample, and were more prevalent in males and in the hyperactive-impulsive and combined subtypes. The most common comorbidities were substance use disorders (39.2%), anxiety disorders (23%), and mood disorders (18.1%). In all, 88.8% patients were prescribed pharmacological treatment for ADHD (in 93.4% of cases, modified release methylphenidate capsules 50:50). CONCLUSION: A high proportion of psychiatric comorbidity was observed when adult outpatients received a first-time diagnosis of ADHD. The systematic registering of patients and comorbidities in clinical practice may help to better understand and manage the prognostic determinants in adult ADHD.

Quo Vadis Clozapine? A Bibliometric Study of 45 Years of Research in International Context.

We have carried out a bibliometric study about the international scientific publications on clozapine. We have used the EMBASE and MEDLINE databases, and we applied bibliometric indicators of production, as Price's Law on the increase of scientific literature. We also calculated the participation index (PI) of the different countries. The bibliometric data have also been correlated with some social and health data from the 12 most productive countries in biomedicine and health sciences. In addition, 5607 original documents dealing with clozapine, published between 1970 and 2013, were downloaded. Our results state non-fulfilment of Price's Law, with scientific production on clozapine showing linear growth (r=0.8691, vs. r=0.8478 after exponential adjustment). Seven of the 12 journals with the highest numbers of publications on clozapine have an Impact Factor>2. Among the countries generating clozapine research, the most prominent is the USA (PI=24.32), followed by the UK (PI=6.27) and Germany (PI=5.40). The differences among countries on clozapine research are significantly related to economic variables linked to research. The scientific interest in clozapine remains remarkable, although after the application of bibliometric indicators of production, a saturation point is evident in the growth of scientific literature on this topic.

Evaluación de la calidad de vida en la mujer menopáusica mediante la escala Cervantes: impacto del tratamiento en la práctica clínica / Assessment of quality of life in postmenopausal women through the Cervantes scale: impact of treatment in clinical practice

Objetivo: Evaluar la calidad de vida actual de las mujeres menopáusicas y conocer el efecto del tratamiento instaurado. Sujetos y métodos: El estudio epidemiológico transversal y multicéntrico que incluyó a 1.344 mujeres menopáusicas. Se empleó la escala Cervantes para valorar la calidad de vida. Resultados: La puntuación global de la calidad de vida fue mejor en los grupos con tratamiento (terapia hormonal e isoflavonas, diferencia puntuación total: 13,62 y 7,93 puntos, respectivamente; p < 0,001) versus las que no recibían terapia. Factores que influyen en la calidad de vida son: el alcohol, los antecedentes de enfermedad y el tiempo de evolución de la menopausia. Conclusiones: Las mujeres menopáusicas pueden mejorar su calidad de vida con el tratamiento con terapia hormonal y con isoflavonas, siendo la escala Cervantes una herramienta clínica muy útil (AU)

Objective: To assess the current quality of life of menopausal women and determine the effect of treatment. Subjects and methods: This multicenter, cross-sectional, epidemiological study included 1344 postmenopausal women. The Cervantes scale was used to assess quality of life. Results: The overall quality of life score was better in the treatment groups (hormonal therapy and isoflavones, with differences in total scores of 13.62 and 7.93 points, respectively; P<.001) versus those not receiving therapy. Factors influencing quality of life were alcohol, history of disease, and time since onset of menopause. Conclusions: Menopausal women can improve their quality of life with treatment with hormonal therapy and isoflavones. The Cervantes scale is a useful clinical tool (AU)

Risk-benefit analysis of antidepressant drug treatment in the elderly.

Depression in the elderly is a significant health issue that has the potential to seriously affect physical and emotional well-being. Therefore, the treatment of geriatric depression is necessary. Antidepressant treatment in older depressed patients is efficacious, but differences in the effectiveness of different classes of antidepressants have not been demonstrated. However, differences in tolerability profile are most recognizable in the elderly. With ageing, a series of changes occur in the elderly that modify both the pharmacokinetics and pharmacodynamics of antidepressants and may influence the efficacy, tolerability and safety of treatment in the elderly. Comorbidities require the use of other drugs, which increases the possibility of drug-drug interactions. Given these aspects, individualized therapy for each elderly patient is needed to achieve acceptable risk-benefit ratio. Effective treatment of depression in the elderly, which may require combined pharmacological with psychosocial treatment, can decrease both morbidity and mortality; it also may lead to reduced demands on family members and on health-care and social services.

Multisite organic-inorganic hybrid catalysts for the direct sustainable synthesis of GABAergic drugs.

Multisite organic-inorganic hybrid catalysts have been prepared and applied in a new general, practical, and sustainable synthetic procedure toward industrially relevant GABA derivatives. The domino sequence is composed of seven chemical transformations which are performed in two one-pot reactions. The method produces both enantiomeric forms of the product in high enantiopurity as well as the racemate in good yields after a single column purification step. This protocol highlights major process intensification, catalyst recyclability, and low waste generation.

The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder.

The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients, caregivers, and society and accounts for the largest part of the morbidity-mortality of the illness. Lurasidone is an atypical antipsychotic with a potent binding affinity as antagonist for D2, 5-HT2A, 5-HT7, and partial agonist at 5-HT1A receptors. Affinity for other receptors as H1 and muscarinic were negligible. Lurasidone was approved in 2010 for the treatment of schizophrenia and recently, 2013, for bipolar depression in monotherapy and an adjunct to lithium or valproate. Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose, lipids, or the QT interval. Additional studies are desirable to know the clinical profile of lurasidone in long-term treatment, in patients with bipolar II disorders, and versus other antipsychotic agents.

La investigación sobre fármacos antipsicóticos atípicos en España: una evaluación bibliométrica / Mapping the scientific research on atypical antipsychotic drugs in Spain: a bibliometric assessment

Objetivos: Se llevó a cabo un estudio bibliométrico de las publicaciones sobre fármacos antipsicóticos atípicos (AA) realizadas en España. Método: Se usaron las bases de datos EMBASE y MEDLINE y se aplicaron indicadores bibliométricos de productividad y dispersión de artículos (leyes de Price y de Bradford, respectivamente).También se calculó el índice de participación (IP)de los diferentes países y se buscaron correlaciones entre los datos bibliométricos y algunos datos sociales y de salud(gasto total per capita en salud y gasto interior bruto en investigación y desarrollo).Resultados: Se recopilaron 656 artículos originales publicados entre 1988 y 2011. Nuestros resultados constatan el cumplimiento de la ley de Price en la producción científica sobre AA, mostrando un crecimiento exponencial (coeficiente de correlación r = 0,9693 vs. r = 0,9177 después del ajuste lineal).Los fármacos más estudiados fueron la risperidona (181 artículos), la olanzapina (143), la clozapina (94) y la quetiapina (74). La división en zonas de Bradford dio lugar a un núcleo ocupado por las revistas European Psychiatry y European Neuropsychopharmacology (70 artículos). En total se publicaron artículos en 194 revistas diferentes, de las cuales 5de las 10 primeras tenían un factor de impacto mayor de 4.Conclusión: Las publicaciones sobre AA en España han experimentado un crecimiento exponencial en el período estudiado, sin evidencia de que se haya alcanzado un punto de saturación (AU)

Objectives: We carried out a bibliometric study on the scientific publications in relation to atypical antipsychotic drugs (AADs) in Spain. Methods: We used the EMBASE and MEDLINE databases and we applied some bibliometric indicators of paper production and dispersion (Price’s law and Bradford’s law, respectively). We also calculated the participation index of the different countries and correlated the bibliometric data with some social and health data (total per capita expenditure on health and gross domestic expenditure on research and development).Results: We collected 656 original papers published between 1988 and 2011. Our study results fulfilled Price’s law with scientific production on AADs showing exponential growth (correlation coefficient r = 0.9693, vs. r = 0.9177 after linear adjustment). The most widely studied drugs were risperidone (181 papers), olanzapine (143), clozapine (94),and quetiapine (74). Division into Bradford zones yielded a nucleus occupied by the European Psychiatry and European Neuropsychopharmacology (70 articles). Totally 194 different journals were published, with 5 of the first 10 usedj ournals having an impact factor being greater than 4.Conclusion: The publications on AADs in Spain have undergone exponential growth over the studied period, without evidence of reaching a saturation point (AU)

Mapping the scientific research on atypical antipsychotic drugs in Spain: a bibliometric assessment.

OBJECTIVES: We carried out a bibliometric study on the scientific publications in relation to atypical antipsychotic drugs (AADs) in Spain. METHODS: We used the EMBASE and MEDLINE databases and we applied some bibliometric indicators of paper production and dispersion (Price's law and Bradford's law, respectively). We also calculated the participation index of the different countries and correlated the bibliometric data with some social and health data (total per capita expenditure on health and gross domestic expenditure on research and development). RESULTS: We collected 656 original papers published between 1988 and 2011. Our study results fulfilled Price's law with scientific production on AADs showing exponential growth (correlation coefficient r = 0.9693, vs. r = 0.9177 after linear adjustment). The most widely studied drugs were risperidone (181 papers), olanzapine (143), clozapine (94), and quetiapine (74). Division into Bradford zones yielded a nucleus occupied by the European Psychiatry and European Neuropsychopharmacology (70 articles). Totally 194 different journals were published, with 5 of the first 10 used journals having an impact factor being greater than 4. CONCLUSION: The publications on AADs in Spain have undergone exponential growth over the studied period, without evidence of reaching a saturation point.