Clavulanic Acid and its Potential Therapeutic Effects on the Central Nervous System.

Clavulanic acid (CLAV) is a non-antibiotic ß-lactam that has been used since the late 1970s as a ß-lactamase inhibitor in combination with amoxicillin, another ß-lactam with antibiotic activity. Its long-observed adverse reaction profile allows it to say that CLAV is a well-tolerated drug with mainly mild adverse reactions. Interestingly, in 2005, it was discovered that ß-lactams enhance the astrocytic expression of GLT-1, a glutamate transporter essential for maintaining synaptic glutamate homeostasis involved in several pathologies of the central nervous system (CNS). This finding, along with a favorable pharmacokinetic profile, prompted the appearance of several studies that intended to evaluate the effect of CLAV in preclinical disease models. Studies have revealed that CLAV can increase GLT-1 expression in the nucleus accumbens (NAcc), medial prefrontal cortex (PFC), and spinal cord of rodents, to affect glutamate and dopaminergic neurotransmission, and exert an anti-inflammatory effect by modulating the levels of the cytokines TNF-α and interleukin 10 (IL-10). CLAV has been tested with positive results in preclinical models of epilepsy, addiction, stroke, neuropathic and inflammatory pain, dementia, Parkinson's disease, and sexual and anxiety behavior. These properties make CLAV a potential therapeutic drug if repurposed. Therefore, this review aims to gather information on CLAV's effect on preclinical neurological disease models and to give some perspectives on its potential therapeutic use in some diseases of the CNS.

Study of Antispasmodic and Antidiarrheal Activities of Tagetes lucida (Mexican Tarragon) in Experimental Models and Its Mechanism of Action.

Tagetes lucida has been used in traditional medicine as a remedy to alleviate several gastrointestinal disorders that provoke stomachaches, abdominal cramps, and diarrhea. However, there is not enough scientific evidence that supports these effects. Therefore, the purpose of this study was to evaluate antispasmodic and antidiarrheal activities of aqueous extract of T. lucida (AqExt-TL) as well as its mechanism of action in experimental models. Antispasmodic activity and the mechanism of action of AqExt-TL were assessed on segments of the guinea pig ileum precontracted with KCl, acetylcholine (ACh), or electrical field stimulation (EFS). Furthermore, the antispasmodic effect of two coumarins (umbelliferone and herniarin) previously identified in this species was evaluated. Antidiarrheal activity of AqExt-TL was determined using the charcoal meal test in mice. AqExt-TL showed antispasmodic activity in segments of the guinea pig ileum precontracted with KCl (83.7 ± 1.9%) and ACh (77.2 ± 5.3%) at the maximal concentration; however, practically, it did not alter the contractions induced by EFS (10.1 ± 2.2%). Antispasmodic activity of AqExt-TL was not significantly altered by hexamethonium (a ganglionic blocker) or L-NAME (an inhibitor of nitric oxide synthase). However, this extract decreased the maximal contractile response to calcium (82.7 ± 8.5%), serotonin (68.1 ± 8.5%), and histamine (63.9 ± 5.9%) in their concentration-response curves. Umbelliferone and herniarin also induced an antispasmodic effect on tissues precontracted with KCl. In addition, low doses of AqExt-TL reduced to 50% the distance traveled by charcoal meal in the gastrointestinal transit model in mice as loperamide, an antidiarrheal agent, did. These results provided evidence of the antispasmodic and antidiarrheal activity of T. lucida, which supports its use in the folk medicine in relieving symptoms in some gastrointestinal disorders. In the antispasmodic effect, the blockade of histaminergic and serotoninergic pathway as well as the calcium channels seems to be involved. Finally, umbelliferone and herniarin could be partially responsible for the antispasmodic activity induced by T. lucida.

Potential pro-arrhythmic effects of pharmacotherapy against SARS-CoV-2.

The pandemic caused by the SARS-COV-2 or COVID-19 virus has been a global challenge given its high rate of transmission and lack of effective therapy or vaccine. This scenario has led to the use of various drugs that have demonstrated a potential effect against the virus in vitro. However, time has not been enough to properly evaluate their clinical effectiveness. The use of chloroquine/hydroxychloroquine, azithromycin and antiviral treatment and has been proposed by various groups, supported by in-vitro studies and limited patient series, without the adequate scientific rigor that precedes drug prescription. Although it may represent the only hope for many patients, it is important to know the main adverse effects associated with the use of these drugs and to better select patients who may benefit from them.

La pandemia por el virus SARS-COV-2 causante de la enfermedad COVID-19 representa un reto mundial dada su alta tasa de transmisión y ausencia de una terapia efectiva o vacuna. Este escenario ha propiciado el uso de diversos fármacos que in vitro han demostrado un potencial efecto contra el virus. Sin embargo, el tiempo no ha sido suficiente para evaluar su efectividad clínica con el adecuado rigor científico que precede a la prescripción de medicamentos. El uso de cloroquina/hidroxicloroquina, azitromicina y esquemas antivirales ha sido propuesto por diversos grupos, apoyado por series de pacientes limitada en número. Si bien puede representar la única esperanza para muchos enfermos, es importante conocer los principales efectos adversos asociados al uso de estas drogas y seleccionar mejor a los pacientes que puedan beneficiarse de ellas. El riesgo de arritmias ventriculares incrementa tanto por el uso de fármacos como por la gravedad de la propia enfermedad viral.

Panorama histórico de la enfermedad diarreica aguda en México y el futuro de su prevención / Historical overview of acute infectious diarrhea in Mexico and future preventive strategies

Resumen: Objetivo: Revisar los aspectos epidemiológicos de la enfermedad diarreica aguda (EDA) a través de la historia de México y analizar las estrategias que potencialmente podrán prevenir su aparición en la población mexicana. Material y métodos: Se realizó una búsqueda sistematizada utilizando los siguientes descriptores de las ciencias de la salud: diarrea, morbilidad, mortalidad, México y promoción de la salud de los últimos 20 años (1878-2018). Resultados: Se obtuvieron más de 8 600 artículos que fueron evaluados en función de los objetivos de la presente publicación. Conclusión: Como resultado de una revisión sistemática se observó que, gracias a las estrategias implementadas a lo largo del tiempo, se ha logrado graduar los matices de riesgo de la EDA; ello permite ahora plantear estrategias que guiarán a la prevención de ese padecimiento, de la mano de políticas que incluyan aspectos higiénico-dietéticos, innovaciones farmacéuticas y aplicaciones tecnológicas en medidas sanitarias.

Abstract: Objective: To analyze the epidemiological aspects of AID through Mexican history and the potential strategies to prevent AID in Mexican population. Materials and methods: A systematic review was performed exploring the key words, diarrhea, morbidity, mortality, Mexico, health promotion for the last 20 years (1978-2018). Results: Over 8 600 articles were obtained; all of them were evaluated to consider those follow the aim of the present work. Conclusion: The result of the performed systematic review denoted the influence of AID in Mexican public health policy the adopted actions diminished the AID's associated risks and allowed future strategies to prevent it; those actions must include hygienic and dietetic measures, pharmaceutical innovations and technological tools applied to health policies.

Crossing event boundaries changes prospective perceptions of temporal length and proximity.

We conducted two experiments to investigate how crossing a single naturalistic event boundary impacted two different types of temporal estimation involving the same target duration - one where participants directly compared marked temporal durations and another where they judged the temporal proximity of stimuli. In Experiment 1, participants judged whether time intervals presented during movies of everyday events were shorter or longer than a previously encoded 5-s reference interval. We examined how the presence of a transition between events (event boundary) in the movie influenced people's judgments about the length of the comparison interval. Comparison intervals presented during a portion of the movie containing an event boundary were judged as shorter than the reference interval more often than comparison intervals that contained no boundary. Working-memory updating at the event boundary may have directed attention away from the concurrent timing task. In Experiment 2, participants judged whether the second of three tones presented during everyday movies was closer to the first or the third tone presented. Tones separated by an event boundary were judged as farther apart than tones contained within the same event. When judging temporal proximity, attention directed to processing information at an event boundary between two stimuli may disrupt the formation of temporal associations between those stimuli. Overall, these results demonstrate that crossing a single event boundary can impact people's prospective perceptions of the temporal characteristics of their experience and suggest that the episodic memory updating that occurs during an event boundary both captures timing-relevant attentional resources and plays a role in the temporal binding of information.

[Historical overview of acute infectious diarrhea in Mexico and future preventive strategies]. / Panorama histórico de la enfermedad diarreica aguda en México y el futuro de su prevención.

OBJECTIVE: To analyze the epidemiological aspects of AID through Mexican history and the potential strategies to pre- vent AID in Mexican population. MATERIALS AND METHODS: A systematic review was performed exploring the key words, diarrhea, morbidity, mortality, Mexico, health promotion for the last 20 years (1978-2018). RESULTS: Over 8 600 articles were obtained; all of them were evaluated to consider those follow the aim of the present work. CONCLUSIONS: The result of the performed systematic review denoted the influence of AID in Mexican public health policy; the adopted actions diminished the AID's associated risks and allowed future strategies to prevent it; those actions must include hygienic and dietetic measures, pharmaceutical innovations and technological tools applied to health policies.

OBJETIVO: Revisar los aspectos epidemiológicos de la enfermedad diarreica aguda (EDA) a través de la historia de México y analizar las estrategias que potencialmente podrán prevenir su aparición en la población mexicana. MATERIAL Y MÉTODOS: Se realizó una búsqueda sistematizada utilizando los siguientes descriptores de las ciencias de la salud: diarrea, morbilidad, mortalidad, México y promoción de la salud de los últimos 20 años (1878-2018). RESULTADOS: Se obtuvieron más de 8 600 artículos que fueron evaluados en función de los objetivos de la presente publicación. CONCLUSIONES: Como resultado de una revisión sistemática se observó que, gracias a las estrategias implementadas a lo largo del tiempo, se ha logrado graduar los matices de riesgo de la EDA; ello permite ahora plantear estrategias que guiarán a la prevención de ese padecimiento, de la mano de políticas que incluyan aspectos higiénico-dietéticos, innovaciones farmacéuticas y aplicaciones tecnológicas en medidas sanitarias.

Potenciales efectos pro-arrítmicos de la farmacoterapia contra SARS-CoV-2 / Potential pro-arrhythmic effects of pharmacotherapy against SARS-CoV-2

Resumen La pandemia por el virus SARS-COV-2 causante de la enfermedad COVID-19 representa un reto mundial dada su alta tasa de transmisión y ausencia de una terapia efectiva o vacuna. Este escenario ha propiciado el uso de diversos fármacos que in vitro han demostrado un potencial efecto contra el virus. Sin embargo, el tiempo no ha sido suficiente para evaluar su efectividad clínica con el adecuado rigor científico que precede a la prescripción de medicamentos. El uso de cloroquina/hidroxicloroquina, azitromicina y esquemas antivirales ha sido propuesto por diversos grupos, apoyado por series de pacientes limitada en número. Si bien puede representar la única esperanza para muchos enfermos, es importante conocer los principales efectos adversos asociados al uso de estas drogas y seleccionar mejor a los pacientes que puedan beneficiarse de ellas. El riesgo de arritmias ventriculares incrementa tanto por el uso de fármacos como por la gravedad de la propia enfermedad viral.

Abstract The pandemic caused by the SARS-COV-2 or COVID-19 virus has been a global challenge given its high rate of transmission and lack of effective therapy or vaccine. This scenario has led to the use of various drugs that have demonstrated a potential effect against the virus in vitro. However, time has not been enough to properly evaluate their clinical effectiveness. The use of chloroquine/hydroxychloroquine, azithromycin and antiviral treatment and has been proposed by various groups, supported by in-vitro studies and limited patient series, without the adequate scientific rigor that precedes drug prescription. Although it may represent the only hope for many patients, it is important to know the main adverse effects associated with the use of these drugs and to better select patients who may benefit from them.

Validación del índice pronóstico de Mannheim para mortalidad en pacientes con peritonitis generalizada en el hospital de alta complejidad / Validation of the Mannheim forecast index for mortality in patients with generalized peritonitis in the high-complexity hospital

Objetivos: Estimar el mejor punto de corte del Índice Pronóstico de Mannheim (IPM) para predecir mortalidad según curva de ROC en pacientes con peritonitis generalizada. Material y Métodos: Estudio observacional, descriptivo transversal, retrospectivo, en 53 pacientes operados con el diagnóstico de peritonitis generalizada, en el HRL durante el periodo 2013 al 2016. Se revisaron historias clínicas para la obtención de datos, se analizaron utilizando el programa Microsoft Excel 2010, SPSS y EPIDAT 3.1. Resultados: Se trabajó con 53 historias clínicas encontrándose 41,5% de sexo femenino y 58,49% de sexo masculino. El 54,72% =de 50 años. El 86,79% presentó tiempo de enfermedad >24 horas. El 37,74% presentó falla multiorgánica, y el 9,43% malignidad. Con peritonitis generalizada representa el 88,68%, siendo de origen colónico un 54,72%; con apendicitis aguda un 37,73%. Se encontró una mortalidad de 18,86%. Estableciendo el mejor punto de corte para el IPM mayor igual a 27 puntos, con S=100%, E=67,44%, VPP=41,67%, VPN=100%, CP+= 3,07%, y un IY=0,67%; no se registró valor de CP- a este nivel de punto de corte. IPM <27 se encontró que el 54,72% presentaron sobrevida; mientras que IPM >= 27 el 71,14% con sobrevida. La curva de ROC para IPM mostró un área bajo la curva=0,8523, con un valor significativo p<0,05, EE= 0,0526, e IC al 95% (0,749 a 0,955). Conclusión: El mejor punto de corte según curva ROC para predecir mortalidad es 27, siendo una buena herramienta para el pronóstico de mortalidad en pacientes con peritonitis generalizada.

Exploratory studies of some Mexican medicinal plants: Cardiovascular effects in rats with and without hypertension.

BACKGROUND: Papaveraceae Argemone mexicana L., Burseraceae Bursera simaruba (L.) Sarg., Acanthaceae Justicia spicigera Schltdl. and Selaginellaceae Selaginella lepidophylla (Hook. & Grev.) Spring., have been used in Mexican traditional medicine to treat hypertension. The objective of this study was to further characterize the cardiovascular effects of the methanol extracts of such plants. METHODS: The medicinal plants were collected and taxonomically identified; the methanol extract of each explored plant were administrated to conscious and unconscious male Wistar rats with and without glucose-induced hypertension. The blood pressure (BP) and heart rate (HR) were evaluated before and after the extract administration. Vascular reactivity experiments were conducted in rat aortic rings obtained from rats with and without sugar-induced hypertension, a model widely used to study such effects with cardiovascular agents. RESULTS: After oral administration in normotensive conscious rats all tested extracts decreased the HR, such effect was only observed in hypertensive conscious rats after the administration of B. simaruba; only A. mexicana and B. simaruba decreased the BP after oral administration. All extracts administrated by intravenous injection diminished the mean arterial pressure. Dose-response curves to cumulative concentrations of all the extracts promote vascular relaxation in precontracted aortas from rats with and without sugar-induced hypertension. CONCLUSIONS: The present study indicated that B. simaruba is worthy of further investigation as a potential phytotherapeutic agent for treating hypertension.

Endothelial function impairment in chronic venous insufficiency: effect of some cardiovascular protectant agents.

In segments of human varicose veins, endothelial function was assessed by measuring relaxation induced by acetylcholine in noradrenaline-precontracted preparations. In addition, concentration-response curves to acetylcholine were obtained before and after incubation with the arterial endothelium protectant agents captopril, losartan, troglitazone, pravastatin, or simvastatin. The antivaricose agent escin was also tested. Mean acetylcholine-induced relaxation of varicose venous rings was about 13%, approximately one third of that reported for control saphenous veins. Concentration-response curves to acetylcholine were ''u'' shaped, the result of endothelium-mediated relaxation at low concentrations, superseded by subsequent smooth muscle contractile responses. Relaxation was enhanced by the endothelium-protecting agents and by escin, troglitazone being the least, and simvastatin the most effective. It was concluded that endothelial dysfunction is present in varicose veins, that this anomaly can be reverted by cardiovascular protecting agents, and that it can play a role in the pathogenesis and treatment of chronic venous insufficiency.

Endothelium protectant and contractile effects of the antivaricose principle escin in rat aorta.

The triterpene saponin escin is the active component of the extract of seeds of Aesculus hippocastanum used in the treatment of chronic venous insufficiency. Escin is also used experimentally to increase membrane permeability in isolated cells. Since endothelial dysfunction is postulated to be involved in venous insufficiency, the possible endothelium-protectant effect of escin was explored in rat aortic rings, a model widely used to study such effects with cardiovascular agents. Escin enhanced endothelium-dependent relaxation induced by acetylcholine when such relaxation had been reduced by exposure to the superoxide ion generator pyrogallol. This effect was attributed to enhanced nitric oxide production by endothelial nitric oxide synthase, a calcium-dependent enzyme, activated by the increased endothelial cell permeability to calcium induced by escin. Another effect of escin thought to contribute to its therapeutic activity is its ability to produce venous contraction. The compound was found to induce concentration-related contraction also in rat aortic rings. This response was partially inhibited by removal of the endothelium or by preincubation with indomethacin, and was completely abolished by incubation in a calcium-free perfusion fluid. Contraction was considered to be due mainly to the aforementioned effect on calcium permeability, with some mediation by release of endothelial vasoconstrictor prostanoids. It was concluded that, in rat aorta, escin possesses an endothelium-protectant action and a direct contractile effect. The former could contribute to its beneficial effect in the treatment of venous insufficiency, while the latter could constitute a limiting side effect.

Antivasoconstrictor effect of the neuroprotective agent dexrazoxane in rat aorta.

Dexrazoxane is used clinically to reduce the cardiotoxicity of anthracycline cancer chemotherapeutic agents, acting by an iron-chelating antioxidant mechanism. In a study designed to explore the possible mechanism of the recently described neuroprotective effect of the drug in cerebral ischemia, its influence on vascular reactivity was determined in rat aortic rings. Dexrazoxane was found to be devoid of direct contractile or relaxant activity and to have no influence on responses to acetylcholine or histamine (relaxation), or to angiotensin or serotonin (contraction). In contrast, it decreased contractions to norepinephrine, as evidenced by rightward displacement of the concentration-response curves. The effect was prevented by the removal of the endothelium and by the alpha(2)-adrenoceptor antagonist yohimbine; it was partially antagonized by the endothelium-derived depolarizing factor inhibitor clotrimazole, but was not affected by L-NAME or indomethacin, inhibitors of endothelial nitric oxide and prostacyclin production. The anti-contractile effect did not occur in rings stimulated with the alpha(1)-adrenoceptor agonist phenylephrine. It was concluded that dexrazoxane opposes norepinephrine vascular contraction by enhancing endothelial alpha(2)-adrenoceptor-mediated release of relaxing factor(s). The drug could thus offset the deleterious vasoconstriction elicited by the increased circulating catecholamines present during cerebral ischemia, and by this mechanism produce neuroprotection.