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1.
J Infect Chemother ; 28(9): 1225-1230, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35637131

RESUMO

INTRODUCTION: The objectives of this study were to develop a stability-indicating high performance liquid chromatography (HPLC) assay for benzylpenicillin (BPC) in pharmaceutical fluids, and to investigate the stability of (i) isotonic citrate-buffered BPC solutions at the clinically relevant concentration of 30 mg/mL, and (ii) low concentration citrate-buffered BPC intravenous infusions (5-30 µg/mL). METHODS: The stability of isotonic BPC solutions containing 3.4 or 7.2 mg/mL sodium citrate was compared against contemporary hypertonic solutions. The HPLC assay was shown to be stability-indicating following acidic, alkali, oxidative and elevated temperature stress testing. RESULTS: After 7 d storage at 4 °C and 24 h at 35 °C, the concentrations of isotonic BPC 30 mg/mL solutions containing 3.4 and 7.2 mg/mL sodium citrate were 96% and 95% respectively, compared to day 0. After 3 d at 4 °C and 24 h at room temperature (22 °C), the concentrations of isotonic BPC solutions with 3.4 and 7.2 mg/mL sodium citrate were 99% and 96% respectively, compared to day 0. These data were comparable to the hypertonic solutions and meet pharmacopeial stability requirements. Low concentration BPC infusions showed 0.5% and 2.5% degradation after 24 h storage at 22 °C and 35 °C, respectively. CONCLUSIONS: The isotonic BPC 30 mg/mL formulation is simple to prepare and may offer clinical benefits in settings where hypertonic solutions are problematic. This study provides assurance that high- and low-dose isotonic BPC infusions are stable at room temperature and our findings may be applicable to in vitro studies of BPC.


Assuntos
Penicilina G , Estabilidade de Medicamentos , Humanos , Soluções Hipertônicas , Infusões Intravenosas , Soluções Isotônicas/química , Citrato de Sódio , Temperatura
2.
Pflugers Arch ; 474(6): 603-612, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35275260

RESUMO

The hypokalemic response to alkali infusion has been attributed to the resulting extracellular fluid (ECF) expansion, urinary potassium excretion, and internal potassium shifts, but the dominant mechanism remains uncertain. Hypertonic NaHCO3 infusion (1 N, 5 mmol/kg) to unanesthetized dogs with normal acid-base status or one of the four chronic acid-base disorders decreased plasma potassium concentration ([K+]p) at 30 min in all study groups (Δ[K+]p, - 0.16 to - 0.73 mmol/L), which remained essentially unaltered up to 90-min postinfusion. ECF expansion accounted for only a small fraction of the decrease in ECF potassium content, (K+)e. Urinary potassium losses were large in normals and chronic respiratory acid-base disorders, limited in chronic metabolic alkalosis, and minimal in chronic metabolic acidosis, yet, ongoing kaliuresis did not impact the stability of [K+]p. All five groups experienced a reduction in (K+)e at 30-min postinfusion, Δ(K+)e remaining unchanged thereafter. Intracellular fluid (ICF) potassium content, (K+)i, decreased progressively postinfusion in all groups excluding chronic metabolic acidosis, in which a reduction in (K+)e was accompanied by an increase in (K+)i. We demonstrate that hypokalemia following hypertonic NaHCO3 infusion in intact animals with acidemia, alkalemia, or normal acid-base status and intact or depleted potassium stores is critically dependent on mechanisms of internal potassium balance and not ECF volume expansion or kaliuresis. We envision that the acute NaHCO3 infusion elicits immediate ionic shifts between ECF and ICF leading to hypokalemia. Thereafter, maintenance of a relatively stable, although depressed, [K+]e requires that cells release potassium to counterbalance ongoing urinary potassium losses.


Assuntos
Doenças do Cão , Hipopotassemia , Bicarbonato de Sódio , Acidose/metabolismo , Acidose/veterinária , Animais , Doenças do Cão/induzido quimicamente , Cães , Soluções Hipertônicas , Hipopotassemia/induzido quimicamente , Hipopotassemia/veterinária , Infusões Intravenosas/veterinária , Potássio/metabolismo , Bicarbonato de Sódio/administração & dosagem , Bicarbonato de Sódio/toxicidade
3.
Sci Rep ; 12(1): 3035, 2022 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-35194150

RESUMO

Hypertonic lactate (HL) is emerging as alternative treatment of intracranial hypertension following acute brain injury (ABI), but comparative studies are limited. Here, we examined the effectiveness of HL on main cerebral and systemic physiologic variables, and further compared it to that of standard hypertonic saline (HS). Retrospective cohort analysis of ABI subjects who received sequential osmotherapy with 7.5% HS followed by HL-given at equi-osmolar (2400 mOsmol/L) and isovolumic (1.5 mL/kg) bolus doses-to reduce sustained elevations of ICP (> 20 mmHg). The effect of HL on brain (intracranial pressure [ICP], brain tissue PO2 [PbtO2], cerebral microdialysis [CMD] glucose and lactate/pyruvate ratio [LPR]) and blood (chloride, pH) variables was examined at different time-points (30, 60, 90, 120 min vs. baseline), and compared to that of HS. A total of 34 treatments among 17 consecutive subjects (13 traumatic brain injury [TBI], 4 non-TBI) were studied. Both agents significantly reduced ICP (p < 0.001, at all time-points tested): when comparing treatment effectiveness, absolute ICP decrease in mmHg and the duration of treatment effect (median time with ICP < 20 mmHg following osmotherapy 183 [108-257] vs. 150 [111-419] min) did not differ significantly between HL and HS (all p > 0.2). None of the treatment had statistically significant effects on PbtO2 and CMD biomarkers. Treatment with HL did not cause hyperchloremia and resulted in a more favourable systemic chloride balance than HS (Δ blood chloride - 1 ± 2.5 vs. + 4 ± 3 mmol/L; p < 0.001). This is the first clinical study showing that HL has comparative effectiveness than HS for the treatment of intracranial hypertension, while at the same time avoiding hyperchloremic acidosis. Both agents had no significant effect on cerebral oxygenation and metabolism.


Assuntos
Lesões Encefálicas/complicações , Hipertensão Intracraniana/tratamento farmacológico , Hipertensão Intracraniana/etiologia , Lactatos/administração & dosagem , Adulto , Feminino , Humanos , Soluções Hipertônicas , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Solução Salina Hipertônica/administração & dosagem , Resultado do Tratamento , Adulto Jovem
4.
Acta pediátr. hondu ; 12(1): 1237-1240, abr.-sep. 2021. ilus
Artigo em Espanhol | LILACS, BIMENA | ID: biblio-1381266

RESUMO

En los ámbitos científico e institucional existe controversia sobre el manejo idóneo de la bron- quiolitis en pacientes pediátricos. El objetivo de este trabajo es valorar el nivel de evidencia cientí- fica que existe sobre el manejo de la bronquiolitis para determinar si las recomendaciones actuales son o no adecuadas. Se realizó una revisión sis- temática de artículos científicos consultando di- versas bases de datos, sin restricción de fecha, en los idiomas español e inglés. Se incluyó literatura gris mediante búsqueda manual. No se hicieron restricciones respecto al tipo de estudio. Se re- visaron los resúmenes y en los casos necesarios los artículos completos, teniéndose en cuenta fi- nalmente todos los artículos que incluían apor- tes sobre el manejo adecuado de la bronquiolitis. Como resultado la mayoría de las recomenda- ciones realizadas por las sociedades fueron a tra- vés de guías de práctica clínica o artículos de opinión, concluyendo que no se cuenta con un esquema de tratamiento adecuado para tratar la bronquiolitis aguda, existiendo un manejo erróneo con el uso de esteroides y antibióticos, mientras que uno de los tratamiento más viables y costo efectivos queda en el olvido como es la solución hipertónica al 3%, la cual ha demostra- do reducción de la estancia hospitalaria...(AU)


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Bronquite/diagnóstico , Broncodilatadores , Esteroides , Nebulizadores e Vaporizadores , Soluções Hipertônicas
5.
Physiol Behav ; 240: 113545, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34363817

RESUMO

OBJECTIVES: to investigate the effects of hyperosmolar state (HS) on immune response and inflammation via the NFAT5 pathway and examine whether immune-mediated conditions trigger autism-like behavior in offspring. METHODS: a pregnant rat model was performed by administering hyperosmotic solutions. Pregnant rats were divided into 2 main groups; control (group I) and hyperosmolar groups (group II). Control group rats were given % 0.25 NaCI (tap water) (n = 6), the Hyperosmolar (HO) group was further subdivided into 3 groups as; Group II a rats which were given % 3 hypertonic NaCl (n = 6), Group II b rats were given mineral water (% 3 NaHCO3+magnesium+calcium content) (n = 6), and Group II c rats were given Ayran (% 0.8 NaCl content) (n = 6). Their offspring were examined for behaviors, biochemical and histological abnormality. RESULTS: in offspring, TNF- α, IL-17, NFAT-5, and NGF levels in the brain were significantly higher in hyperosmotic solution groups than in control rats. Exposure of pregnant rats to hyperosmotic solution resulted in autism-like behaviors in their offspring. Through immunohistochemical methods, we found that CA1 and CA2 of the hippocampus indicated decreased number of neurons in hyperosmotic solution groups compared with the control group. CONCLUSIONS: our findings once again emphasized that the immune-mediated conditions involved in the pathophysiology of autism. NFAT5 pathway may be a key factor in the development of neuroinflammation by hyperosmotic solutions.


Assuntos
Transtorno Autístico , Efeitos Tardios da Exposição Pré-Natal , Animais , Transtorno Autístico/induzido quimicamente , Comportamento Animal , Feminino , Hipocampo , Soluções Hipertônicas , Neurônios , Gravidez , Ratos
6.
Cells ; 10(7)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34359883

RESUMO

While sudden loss of perfusion is responsible for ischemia, failure to supply the required amount of oxygen to the tissues is defined as hypoxia. Among several pathological conditions that can impair brain perfusion and oxygenation, cardiocirculatory arrest is characterized by a complete loss of perfusion to the brain, determining a whole brain ischemic-anoxic injury. Differently from other threatening situations of reduced cerebral perfusion, i.e., caused by increased intracranial pressure or circulatory shock, resuscitated patients after a cardiac arrest experience a sudden restoration of cerebral blood flow and are exposed to a massive reperfusion injury, which could significantly alter cellular metabolism. Current evidence suggests that cell populations in the central nervous system might use alternative metabolic pathways to glucose and that neurons may rely on a lactate-centered metabolism. Indeed, lactate does not require adenosine triphosphate (ATP) to be oxidated and it could therefore serve as an alternative substrate in condition of depleted energy reserves, i.e., reperfusion injury, even in presence of adequate tissue oxygen delivery. Lactate enriched solutions were studied in recent years in healthy subjects, acute heart failure, and severe traumatic brain injured patients, showing possible benefits that extend beyond the role as alternative energetic substrates. In this manuscript, we addressed some key aspects of the cellular metabolic derangements occurring after cerebral ischemia-reperfusion injury and examined the possible rationale for the administration of lactate enriched solutions in resuscitated patients after cardiac arrest.


Assuntos
Acidose/prevenção & controle , Lesões Encefálicas Traumáticas/prevenção & controle , Parada Cardíaca/complicações , Hipóxia-Isquemia Encefálica/prevenção & controle , Ácido Láctico/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Acidose/etiologia , Acidose/patologia , Animais , Lesões Encefálicas Traumáticas/etiologia , Lesões Encefálicas Traumáticas/patologia , Morte Celular/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Parada Cardíaca/patologia , Parada Cardíaca/terapia , Humanos , Soluções Hipertônicas , Hipóxia-Isquemia Encefálica/etiologia , Hipóxia-Isquemia Encefálica/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Ressuscitação/métodos
7.
Exp Eye Res ; 211: 108741, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34425102

RESUMO

Retinal pigment epithelial (RPE) cells express different subtypes of inwardly rectifying potassium (Kir) channels. We investigated whether human and rat RPE cells express genes of strongly rectifying Kir2 channels. We also determined the hypoxic and hyperosmotic regulation of Kir2.1 gene expression in cultured human RPE cells and the effects of siRNA-mediated knockdown of Kir2.1 on VEGFA expression, VEGF secretion, proliferation, and viability of the cells. Extracellular hyperosmolarity was induced by addition of NaCl or sucrose. Hypoxia and chemical hypoxia were produced by cell culture in 0.25% O2 and addition of CoCl2, respectively. Gene expression levels were evaluated by real-time RT-PCR. Rat RPE cells contained Kir2.1, Kir2.2, Kir2.3, and Kir2.4 gene transcripts while human RPE cells contained Kir2.1, Kir2.2, and Kir2.4 transcripts. Immunocytochemical data may suggest that Kir2.1 protein in cultured human cells is expressed in both perinuclear and plasma membranes. Kir2.1 gene expression and Kir2.1 protein level in human cells increased under hypoxic and hyperosmotic conditions. The expression of the Kir2.1 gene was mediated in part by diverse intracellular signal transduction pathways and transcription factor activities under both conditions; the hyperosmotic, but not the CoCl2-induced Kir2.1 gene expression was dependent on intracellular calcium signaling. Autocrine/paracrine activation of purinergic receptors contributed to Kir2.1 gene expression under hyperosmotic (P2Y1, P2Y2, P2X7) and CoCl2-induced conditions (P2Y2, P2X7). Exogenous VEGF, TGF-ß1, and blood serum decreased Kir2.1 gene expression. Inhibition of VEGF receptor-2 increased the Kir2.1 gene expression under control conditions and in CoCl2-simulated hypoxia, and decreased it under high NaCl conditions. Knockdown of Kir2.1 by siRNA inhibited the CoCl2-induced and hyperosmotic transcription of the VEGFA gene and caused a delayed decrease of the constitutive VEGFA gene expression while VEGF protein secretion was not altered. Kir2.1 knockdown stimulated RPE cell proliferation under control and hyperosmotic conditions without affecting cell viability. The data indicate that Kir2.1 channel activity is required for the expression of the VEGFA gene and inhibits the proliferation of RPE cells. Under control and hypoxic conditions, the extracellular VEGF level may regulate the production of VEGF via its inhibitory effect on the Kir2.1 gene transcription; this feedback loop may prevent overproduction of VEGF.


Assuntos
Regulação da Expressão Gênica/fisiologia , Soluções Hipertônicas/farmacologia , Hipóxia/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/genética , Epitélio Pigmentado da Retina/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Western Blotting , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Diabetes Mellitus Experimental , Retinopatia Diabética/metabolismo , Endotélio Vascular , Ensaio de Imunoadsorção Enzimática , Inativação Gênica , Masculino , Concentração Osmolar , RNA Interferente Pequeno/genética , Ratos , Ratos Long-Evans , Reação em Cadeia da Polimerase em Tempo Real , Epitélio Pigmentado da Retina/metabolismo , Cloreto de Sódio/farmacologia , Sacarose/farmacologia
8.
Exp Eye Res ; 211: 108723, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34384756

RESUMO

PURPOSE: To develop an easy-to-perform combined model in human corneal epithelial cells (HCECs) and Balb/c mice macrophages J774.A1 (MP) for preliminary screening of potential ophthalmic therapeutic substances. METHODS: HCECs were exposed to different osmolarities (350-500 mOsm/L) and MTT assay was employed for cell survival and flow cytometry to assess apoptosis-necrosis and relative cell size (RCS) distribution. Effectiveness of Betaine, L-Carnitine, Taurine at different concentrations (ranging from 20 mM to 200 mM) was studied. Also, mucoadhesive polymers such as Hyaluronic acid (HA) and Hydroxypropylmethylcellulose (HPMC) (0.4 and 0.8%) were evaluated. Cells were pre-incubated with the compounds (8h) and then exposed to hyperosmotic stress (470 mOsm/L) for 16h. Moreover, anti-inflammatory activity was performed in LPS-stimulated MP. RESULTS: Exposure to hyperosmotic solutions between 450 and 500 mOsm/L promoted the highest cell death after 16h exposures (p < 0.0001) with a drop in viability to 34.96% ± 11.77 for 470 mOsm/L. Pre-incubation with Betaine at 150 mM and 200 mM provided the highest cell survival against hyperosmolarity (66.01% ± 3.65 and 65.90% ± 0.78 respectively) while HA 0.4% was the most effective polymer in preventing cell death (42.2% ± 3.60). Flow cytometry showed that Betaine and Taurine at concentrations between 150-200 mM and 20-80 mM respectively presented the highest anti-apoptotic activity. Also, HA and HPMC polymers reduced apoptotic-induced cell death. All osmoprotectants modified RCS, and polymers increased their value over 100%. L-Carnitine 50 mM, Taurine 40 mM and HA 0.4% presented the highest TNF-α inhibition activity (60%) albeit all of them showed anti-inflammatory inhibition percentages higher than 20% CONCLUSIONS: HCECs hyperosmolar model combined with inflammatory conditions in macrophages allows the screening of osmoprotectants by simulating chronic hyperosmolarity (16h) and inflammation (24h).


Assuntos
Síndromes do Olho Seco/tratamento farmacológico , Epitélio Corneano/efeitos dos fármacos , Soluções Hipertônicas/farmacologia , Inflamação/fisiopatologia , Macrófagos/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Betaína/farmacologia , Carnitina/farmacologia , Sobrevivência Celular , Células Cultivadas , Síndromes do Olho Seco/fisiopatologia , Epitélio Corneano/metabolismo , Citometria de Fluxo , Humanos , Ácido Hialurônico/farmacologia , Derivados da Hipromelose/farmacologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Concentração Osmolar , Taurina/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
9.
Am J Emerg Med ; 50: 224-231, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34392142

RESUMO

BACKGROUND: The effect of intravenous (IV) fluid administration type on cerebral perfusion pressure (CePP) during cardiopulmonary resuscitation (CPR) is controversial. The purpose of this study was to evaluate the association between IV fluid type and CePP in a porcine cardiac arrest model. METHODS: We randomly assigned 12 pigs to the hypertonic crystalloid, isotonic crystalloid and no-fluid groups. After 4 min of untreated ventricular fibrillation (VF), chest compression was conducted for 2 cycles (CC only). Chest compression with IV fluid infusion (CC + IV) was followed for 2 cycles. Advanced life support, including defibrillation and epinephrine, was added for 8 cycles (ALS phase). Mean arterial pressure (MAP), intracranial pressure (ICP) and CePP were measured. A paired t-test was used to measure the mean difference in CePP. RESULTS: Twelve pigs underwent the experiment. The hypertonic crystalloid group showed higher CePP values than those demonstrated by the isotonic crystalloid group from ALS cycles 2 to 8. The MAP values in the hypertonic group were higher than those in the isotonic group starting at ALS cycle 2. The ICP values in the hypertonic group were lower than those in the isotonic group starting at ALS cycle 4. From ALS cycles 2 to 8, the reduction in the mean difference in the isotonic group was larger than that in the other groups. CONCLUSION: In a VF cardiac arrest porcine study, the hypertonic crystalloid group showed higher CePP values by maintaining higher MAP values and lower ICP values than those of the isotonic crystalloid group.


Assuntos
Circulação Cerebrovascular , Soluções Cristaloides/farmacologia , Parada Cardíaca/terapia , Soluções Hipertônicas/farmacologia , Soluções Isotônicas/farmacologia , Animais , Reanimação Cardiopulmonar , Modelos Animais de Doenças , Feminino , Suínos
10.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208226

RESUMO

We investigated the role of nuclear factor of activated T cells 5 (NFAT5) under hyperosmotic conditions in human lens epithelial cells (HLECs). Hyperosmotic stress decreased the viability of human lens epithelial B-3 cells and significantly increased NFAT5 expression. Hyperosmotic stress-induced cell death occurred to a greater extent in NFAT5-knockout (KO) cells than in NFAT5 wild-type (NFAT5 WT) cells. Bcl-2 and Bcl-xl expression was down-regulated in NFAT5 WT cells and NFAT5 KO cells under hyperosmotic stress. Pre-treatment with a necroptosis inhibitor (necrostatin-1) significantly blocked hyperosmotic stress-induced death of NFAT5 KO cells, but not of NFAT5 WT cells. The phosphorylation levels of receptor-interacting protein kinase 1 (RIP1) and RIP3, which indicate the occurrence of necroptosis, were up-regulated in NFAT5 KO cells, suggesting that death of these cells is predominantly related to the necroptosis pathway. This finding is the first to report that necroptosis occurs when lens epithelial cells are exposed to hyperosmolar conditions, and that NFAT5 is involved in this process.


Assuntos
Células Epiteliais/metabolismo , Células Epiteliais/patologia , Cristalino/patologia , Pressão Osmótica , Estresse Fisiológico , Fatores de Transcrição/metabolismo , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Humanos , Soluções Hipertônicas/toxicidade , Inflamação/patologia , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Pressão Osmótica/efeitos dos fármacos , Proteínas de Ligação a RNA/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Estresse Fisiológico/efeitos dos fármacos
11.
BMC Microbiol ; 21(1): 175, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34103006

RESUMO

BACKGROUND: Menaquinones are constituents of prokaryote cell membranes where they play important functions during electron transport. Menaquinone profiles are strongly recommended for species classification when proposing a new Actinomycetes taxon. Presently, the most widely used methods to determine menaquinones are based on freeze-dried cells. Taxonomic research in our lab has revealed that menaquinone concentrations are low for some species of the genus Microbacterium, leading to difficulties in identifying menaquinones. RESULTS: Menaquinones extracted using the novel lysozyme-chloroform-methanol (LCM) method were comparable in quality to those obtained using the Collins method, the most widely used method. All tested strains extracted via the LCM method showed higher concentrations of menaquinones than those extracted via the Collins method. For some Microbacterium strains, the LCM method exhibited higher sensitivity than the Collins method, and more trace menaquinones were detected with the LCM method than the Collins method. In addition, LCM method is faster than the Collins method because it uses wet cells. CONCLUSION: The LCM method is a simple, rapid and efficient technique for the extraction and identification of menaquinones from Actinomycetes.


Assuntos
Actinobacteria/química , Fracionamento Químico/métodos , Vitamina K 2/isolamento & purificação , Actinobacteria/crescimento & desenvolvimento , Actinobacteria/metabolismo , Biomassa , Clorofórmio/química , Soluções Hipertônicas/química , Metanol/química , Vitamina K 2/química , Vitamina K 2/metabolismo
12.
Rev. costarric. cardiol ; 23(1)jun. 2021.
Artigo em Espanhol | LILACS-Express | LILACS, SaludCR | ID: biblio-1389028

RESUMO

Resumen La insuficiencia cardíaca aguda descompensada (ICAD) es una causa común de hospitalización, con repercusiones significativas en los sistemas de salud. El manejo agudo se basa en la reducción de la volemia con diuréticos de asa, sin embargo, un porcentaje de pacientes presenta resistencia o no logra la respuesta clínica esperada con este tratamiento. Una de las medidas que ha comprobado ser efectiva en este contexto, es el uso de solución salina hipertónica (SSH) en conjunto con dosis altas de diuréticos de asa, como medida terapéutica temida por sus posibles repercusiones sobre la función renal y posible sobrecarga de sodio. Objetivos: Determinar si el uso de solución salina hipertónica en pacientes con falla cardiaca aguda e hipervolemia genera un deterioro de la función renal. Determinar la respuesta del Pro-BNP ante el uso de la solución salina hipertónica en pacientes con falla cardiaca aguda como marcador de respuesta terapéutica. Determinar si el uso de solución salina hipertónica aumenta la diuresis sin generar cambios importantes en el sodio. Se muestran datos de pacientes con insuficiencia cardiaca aguda descompensada, que tras no presentar mejoría con altas dosis de diurético de asa en bolo, se les aplicó la solución hipertónica como adyuvante a este tratamiento. Se toma un total de 26 pacientes analizando datos generales clínicos y de laboratorio, se valoran curvas con la respuesta diurética y por parámetros de laboratorio a las 48 y 72 horas. El uso de solución salina hipertónica consigue un aumento de más de un 200% de la diuresis en 24 horas, con un descenso del Pro BNP de más de un 60% a las 48 horas, sin mostrar un cambio importante en los niveles de creatinina, nitrógeno ureico y sodio. Se requirió reposición de potasio en la totalidad de los pacientes. Se concluye que la infusión de furosemida más solución hipertónica es efectiva tanto en disminuir niveles de NT Pro-BNP en los pacientes, como en generar un aumento en el volumen de diuresis. La principal complicación fue la hipokalemia, sin cambios considerables en el valor de sodio, creatinina y nitrógeno ureico séricos.


Abstract Uso de Solución Hipertónica en pacientes con insuficiencia cardiaca aguda como terapia adyuvante a altas dosis de diuréticos Acute decompensated heart failure (AHF) is a common cause of hospitalization, with significant repercussions on health systems. Acute management is based on the reduction of blood volume with loop diuretics; however, a percentage of patients show resistance or do not achieve the expected clinical response with this treatment. One of the measures that has proven to be effective in this context is the use of hypertonic saline (HSS) in conjunction with high doses of loop diuretics, as a therapeutic measure feared due to its possible repercussions on kidney function and possible sodium overload. Objetives: To determine if the use of hypertonic saline in patients with acute heart failure and hypervolemia leads to a deterioration in renal function. To determine the response of Pro-BNP to the use of hypertonic saline in patients with acute heart failure as a marker of therapeutic response. Determine if the use of hypertonic saline increases urine output without causing significant changes in sodium. Data are shown from patients with acute decompensated heart failure, who after not presenting improvement with high doses of bolus loop diuretic, the hypertonic solution was applied as an adjunct to this treatment. A total of 26 patients are taken analyzing general clinical and laboratory data, curves with the diuretic response and by laboratory parameters are evaluated at 48 and 72 hours. The use of hypertonic saline solution achieves an increase of more than 200% in diuresis in 24 hours, with a decrease in Pro BNP of more than 60% at 48 hours, without showing a significant change in creatinine levels, urea nitrogen and sodium. Potassium replacement was required in all patients. It is concluded that the infusion of furosemide plus hypertonic solution is effective both in reducing levels of NT Pro-BNP in patients, and in generating an increase in the volume of diuresis. The main complication was hypokalemia, without significant changes in serum sodium, creatinine, and urea nitrogen.


Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Diuréticos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Soluções Hipertônicas/uso terapêutico , Costa Rica
13.
J Neurosci ; 41(16): 3579-3587, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33707294

RESUMO

The magnocellular neurosecretory cells (MNCs) of the hypothalamus play a vital role in osmoregulation, but the mechanisms underlying MNC osmosensitivity are not fully understood. We showed previously that high osmolality activates phospholipase C (PLC) in rat MNCs in a Ca2+-dependent manner and that PLC activation is necessary for full osmotic activation of an N-terminal variant of the TRPV1 (ΔN-TRPV1) channel. We therefore hypothesized that the Ca2+-dependent δ1 isoform of PLC contributes to ΔN-TRPV1 activation and tested whether MNC function is defective in a transgenic PLCδ1 KO mouse. Water deprivation for 24 h caused greater increases in serum osmolality and losses in body weight in PLCδ1 KO mice than it did in control mice. Action potentials and ΔN-TRPV1 currents were measured in acutely isolated mouse MNCs using whole-cell patch clamp before and after exposure to hypertonic solutions. This treatment elicited a significant activation of ΔN-TRPV1 currents and an increase in firing rate in MNCs isolated from control mice, but not from PLCδ1 KO mice. Submembranous filamentous actin was measured in isolated MNCs before and after treatment with angiotensin II and hypertonic solution. Both treatments caused an increase in filamentous actin fluorescence in MNCs isolated from control mice, but both responses were significantly attenuated in MNCs from PLCδ1 KO mice. Our data demonstrate that the PLCδ1 isoform plays a key role in the activation of ΔN-TRPV1 channels and in osmosensory transduction in MNCs. This study advances our understanding of the molecular mechanisms underlying mammalian osmoregulation.SIGNIFICANCE STATEMENT Magnocellular neurosecretory cells (MNCs) of the hypothalamus play a central role in osmoregulation. We have identified a key role for the PLCδ1 isoform in the activation of ΔN-TRPV1 channels and osmosensory transduction in MNCs. The data indicate that the PLCδ1 isoform is activated by the Ca2+ influx occurring during MNC action potentials and exerts a positive feedback on ΔN-TRPV1 channels to enhance MNC excitability. This study provides evidence that PLCδ1 is a key molecule underlying osmosensory transduction, the regulation of VP release, and osmoregulation.


Assuntos
Neurônios/metabolismo , Osmorregulação/fisiologia , Fosfolipase C delta/fisiologia , Núcleo Supraóptico/metabolismo , Canais de Cátion TRPV/metabolismo , Actinas/metabolismo , Potenciais de Ação/fisiologia , Angiotensina II/farmacologia , Animais , Fenômenos Eletrofisiológicos , Soluções Hipertônicas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sistemas Neurossecretores/metabolismo , Osmose , Fosfolipase C delta/genética , Canais de Cátion TRPV/genética , Privação de Água
14.
Neurocrit Care ; 34(3): 795-803, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32901380

RESUMO

BACKGROUND: There has been growing interest in the use of hypertonic sodium lactate (HSL) solution following traumatic brain injury (TBI) in humans. However, little is known about the effects of HSL on functional deficits with respect to the hyperosmotic nature of HSL. METHODS: We have compared the effects of HSL solution and isotonic saline solution using sensorimotor and cognitive tests for 14 days post-trauma in animals. Thirty minutes after trauma (impact-acceleration model), anesthetized rats were randomly allocated to receive a 2-h infusion of isotonic saline solution (TBI-saline group) or HSL (TBI-HSL group) (n = 10 rats per group). In another series of experiments using a similar protocol, the effects of equiosmolar doses of HSL and hypertonic saline solution (HSS) were compared in TBI rats (n = 10 rats per group). Blood lactate and ion concentrations were measured during the 2-h infusions. RESULTS: Compared to the TBI-saline group, the TBI-HSL group had a reduced latency to complete the adhesive removal test: 6 s (5-9) (median [25-75th centiles]) versus 13 s (8-17) on day 7, and 5 s (5-9) versus 11 s (8-26) on day 14 (P < 0.05), respectively, and a shorter delay to complete the radial arm maze test on day 7: 99 s (73-134) versus 176 s (127-300), respectively (P < 0.05). However, no differences were found between the TBI-HSL and TBI-HSS groups in neurocognitive tests performance. Compared to the TBI-saline group, the HSL and HSS groups had higher serum osmolality: 318 mOsm/Kg (315-321) and 315 mOsm/Kg (313-316) versus 307 mOsm/Kg (305-309), respectively (P < 0.05), and the HSL group had a higher serum lactate concentration: 6.4 mmol/L (5.3-7.2) versus 1.5 mmol/L (1.1-1.9) and 1.6 mmol/L (1.5-1.7), respectively (P < 0.05). CONCLUSIONS: These results indicate that improvements in cognitive and sensorimotor tests with HSL infusion post-TBI could be related to elevation of serum osmolality, not to exogenous administration of lactate.


Assuntos
Lesões Encefálicas Traumáticas , Lactato de Sódio , Animais , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Soluções Hipertônicas , Ácido Láctico , Ratos , Solução Salina Hipertônica/farmacologia , Lactato de Sódio/farmacologia
15.
Am J Physiol Cell Physiol ; 320(2): C225-C239, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33206547

RESUMO

There is growing evidence that microRNAs (miRNAs) are implicated in cellular adaptation to osmotic stress, but the underlying osmosignaling pathways are still not completely understood. In this study, we found that a passenger strand miRNA, miR-23a-5p, was significantly downregulated in response to high NaCl treatment in mouse inner medullary collecting duct cells (mIMCD3) through an miRNA profiling assay. The decrease of miR-23a-5p is hypertonicity-dependent and osmotolerant cell type-specific. Knockdown of miR-23a-5p increased cellular survival and proliferation in mIMCD3. In contrast, miR-23a-5p overexpression repressed cell viability and proliferation under hypertonic stress. RNA deep-sequencing revealed that a heat shock protein 70 (HSP70) isoform, HSP70 member 1B (HSPA1B), was significantly increased under hypertonic treatment. Based on the prediction analysis by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and TargetScan, and a further validation via a dual-luciferase assay, HSPA1B was identified as a potential target of miR-23a-5p. Overexpressed miR-23a-5p suppressed HSPA1B, whereas downregulated miR-23a-5p promoted HSPA1B expression in mIMCD3. In addition, an in vivo study demonstrated that there is a reverse correlation between the levels of miR-23a-5p and HSPA1B in mouse renal inner medulla (papilla) that is exposed to extremely high osmolality. In summary, this study elucidates that passenger strand miR-23a-5p is a novel tonicity-responsive miRNA. The downregulation of miR-23a-5p facilitates cellular adaptation to hypertonic stress in mammalian renal cells through modulating HSPA1B.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Proteínas de Choque Térmico HSP70/metabolismo , Soluções Hipertônicas/toxicidade , MicroRNAs/metabolismo , Pressão Osmótica/fisiologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células HEK293 , Humanos , Masculino , Camundongos , MicroRNAs/antagonistas & inibidores , Pressão Osmótica/efeitos dos fármacos
16.
ACS Appl Mater Interfaces ; 12(50): 56216-56221, 2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33327057

RESUMO

Electrolyte-gated organic field-effect transistors (EGOFETs) are emerging as a new frontier of organic bioelectronics, with promising applications in biosensing, pharmaceutical testing, and neuroscience. However, the limited charge carriers' mobility and well-known environmental instability of conjugated polymers constrain the real applications of organic bioelectronics. Here, we comparatively studied the electrochemical stability of p-type conjugated polymer films in the EGOFET configuration. By combining electrochemical stability tests, morphology characterization, and EQCM-D monitoring, we find that a donor-acceptor copolymer, poly(N-alkyldiketopyrrolo-pyrrole-dithienylthieno[3,2-b]thiophene) (DPP-DTT) shows improved mobility and electrochemical stability under an electrolyte, which may benefit from the ordered morphology and close alkyl side-chains' interdigitation preventing water diffusion and ion doping during long-term operation under an electrolyte. Based on the DPP-DTT EGOFETs, we have demonstrated a low-cost drug toxicity test platform that is sensitive enough to distinguish the cytotoxicity of different chemicals. This study overall pushes forward the development of organic bioelectronics with enhanced stability and sensitivity and presents successful exploitation of EGOFET in pharmaceutical research.


Assuntos
Eletrólitos/química , Transistores Eletrônicos , Apoptose/efeitos dos fármacos , Técnicas de Cultura de Células/instrumentação , Técnicas de Cultura de Células/métodos , Linhagem Celular , Eletrodos , Humanos , Soluções Hipertônicas/farmacologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Polímeros/química , Técnicas de Microbalança de Cristal de Quartzo , Tripsina/farmacologia
17.
Genes (Basel) ; 11(12)2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33261148

RESUMO

Erythritol is a polyol produced by Yarrowia lipolytica under hyperosmotic stress. In this study, the osmo-sensitive strain Y. lipolytica yl-hog1Δ was subjected to stress, triggered by a high concentration of carbon sources. The strain thrived on 0.75 M erythritol medium, while the same concentrations of glucose and glycerol proved to be lethal. The addition of 0.1 M erythritol to the medium containing 0.75 M glucose or glycerol allowed the growth of yl-hog1Δ. Supplementation with other potential osmolytes such as mannitol or L-proline did not have a similar effect. To examine whether the osmoprotective effect might be related to erythritol accumulation, we deleted two genes involved in erythritol utilization, the transcription factor Euf1 and the enzyme erythritol dehydrogenase Eyd1. The strain eyd1Δ yl hog1Δ, which lacked the erythritol utilization enzyme, reacted to the erythritol supplementation significantly better than yl-hog1Δ. On the other hand, the strain euf1Δ yl-hog1Δ became insensitive to supplementation, and the addition of erythritol could no longer improve the growth of this strain in hyperosmotic conditions. This indicates that Euf1 regulates additional, still unknown genes involved in erythritol metabolism.


Assuntos
Eritritol/farmacologia , Pressão Osmótica/efeitos dos fármacos , Yarrowia/efeitos dos fármacos , Cromossomos Fúngicos/genética , Eritritol/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/fisiologia , Genes Fúngicos , Glucose/farmacologia , Glicerol/farmacologia , Soluções Hipertônicas/farmacologia , Manitol/farmacologia , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Família Multigênica , Pressão Osmótica/fisiologia , Prolina/farmacologia , Transdução de Sinais , Yarrowia/genética
18.
Nat Cell Biol ; 22(8): 947-959, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32753669

RESUMO

The plasma membrane tension strongly affects cell surface processes, such as migration, endocytosis and signalling. However, it is not known whether the membrane tension of organelles regulates their functions, notably intracellular traffic. The endosomal sorting complexes required for transport (ESCRT)-III complex is the major membrane remodelling complex that drives intra-lumenal-vesicle (ILV) formation on endosomal membranes. Here we used a fluorescent membrane-tension probe to show that ESCRT-III subunits are recruited onto endosomal membranes when the membrane tension is reduced. We find that tension-dependent recruitment is associated with ESCRT-III polymerization and membrane deformation in vitro and correlates with increased ILV formation in ESCRT-III-decorated endosomes in vivo. Finally, we find that the endosomal membrane tension decreases when ILV formation is triggered by EGF under physiological conditions. These results indicate that membrane tension is a major regulator of ILV formation and endosome trafficking, leading us to conclude that membrane tension can control organelle functions.


Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Endossomos/metabolismo , Membranas Intracelulares/metabolismo , Biogênese de Organelas , Endossomos/fisiologia , Corantes Fluorescentes , Células HeLa , Humanos , Soluções Hipertônicas , Tensão Superficial
19.
Crit Care ; 24(1): 354, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546181

RESUMO

BACKGROUND: Hypertonic sodium lactate (HSL) may be of interest during inflammation. We aimed to evaluate its effects during experimental sepsis in rats (cecal ligation and puncture (CLP)). METHODS: Three groups were analyzed (n = 10/group): sham, CLP-NaCl 0.9%, and CLP-HSL (2.5 mL/kg/h of fluids for 18 h after CLP). Mesenteric microcirculation, echocardiography, cytokines, and biochemical parameters were evaluated. Two additional experiments were performed for capillary leakage (Evans blue, n = 5/group) and cardiac hemodynamics (n = 7/group). RESULTS: HSL improved mesenteric microcirculation (CLP-HSL 736 [407-879] vs. CLP-NaCl 241 [209-391] UI/pixel, p = 0.0006), cardiac output (0.34 [0.28-0.43] vs. 0.14 [0.10-0.18] mL/min/g, p < 0.0001), and left ventricular fractional shortening (55 [46-73] vs. 39 [33-52] %, p = 0.009). HSL also raised dP/dtmax slope (6.3 [3.3-12.1] vs. 2.7 [2.0-3.9] 103 mmHg/s, p = 0.04), lowered left ventricular end-diastolic pressure-volume relation (1.9 [1.1-2.3] vs. 3.0 [2.2-3.7] RVU/mmHg, p = 0.005), and reduced Evans blue diffusion in the gut (37 [31-43] vs. 113 [63-142], p = 0.03), the lung (108 [82-174] vs. 273 [222-445], p = 0.006), and the liver (24 [14-37] vs. 70 [50-89] ng EB/mg, p = 0.04). Lactate and 3-hydroxybutyrate were higher in CLP-HSL (6.03 [3.08-10.30] vs. 3.19 [2.42-5.11] mmol/L, p = 0.04; 400 [174-626] vs. 189 [130-301] µmol/L, p = 0.03). Plasma cytokines were reduced in HSL (IL-1ß, 172 [119-446] vs. 928 [245-1470] pg/mL, p = 0.004; TNFα, 17.9 [12.5-50.3] vs. 53.9 [30.8-85.6] pg/mL, p = 0.005; IL-10, 352 [267-912] vs. 905 [723-1243] pg/mL) as well as plasma VEGF-A (198 [185-250] vs. 261 [250-269] pg/mL, p = 0.009). CONCLUSIONS: Hypertonic sodium lactate fluid protects against cardiac dysfunction, mesenteric microcirculation alteration, and capillary leakage during sepsis and simultaneously reduces inflammation and enhances ketone bodies.


Assuntos
Inflamação/tratamento farmacológico , Microcirculação/efeitos dos fármacos , Sepse/tratamento farmacológico , Lactato de Sódio/farmacologia , Análise de Variância , Animais , Modelos Animais de Doenças , Ecocardiografia/métodos , Fatores de Crescimento Endotelial/análise , Fatores de Crescimento Endotelial/sangue , Testes de Função Cardíaca/métodos , Soluções Hipertônicas/uso terapêutico , Inflamação/fisiopatologia , Interleucina-10/análise , Interleucina-10/sangue , Interleucina-1beta/análise , Interleucina-1beta/sangue , Microcirculação/fisiologia , Estudos Prospectivos , Ratos , Sepse/fisiopatologia , Lactato de Sódio/uso terapêutico , Sindecana-1/análise , Sindecana-1/sangue , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/sangue
20.
Am J Rhinol Allergy ; 34(6): 725-733, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32403941

RESUMO

BACKGROUND: Nasal solutions are part of the recommended therapy of chronic rhinosinusitis (CRS). Formulations containing hyaluronic acid (HA) may represent a promising topical treatment in CRS patients in light of the anti-inflammatory and protective effect of HA on the sinonasal mucosa. OBJECTIVE: Primary aim was to evaluate the performance of a new nebulized HA nasal hypertonic solution in the relief of symptoms of CRS. Secondarily, evaluation of symptoms improvement, endoscopic nasal findings, and safety profile were assessed. METHODS: A monocenter, single arm, not controlled, premarket clinical trial on a new nasal solution containing HA was performed. All the included patients had a history of previously diagnosed or recurrent CRS or they had received a clinical diagnosis of CRS defined, according to the European Position Paper on Rhinosinusitis and Nasal Polyps 2012. Each patient was evaluated on 3 visits. Endoscopic nasal examination and Nasal Obstruction Symptom Evaluation Instrument questionnaire filling were performed during each visit. Patients' adherence to treatment and overall satisfaction, patients' and investigator's global evaluation of performance, and safety parameters were also assessed. RESULTS: Eighty patients were enrolled. The use of the investigated HA nasal solution revealed to be significantly effective in the relief of symptoms of CRS. According to daily patients' diaries, several signs and symptoms significantly improved after therapy. The comparison between endoscopic assessments before and after treatment confirmed improvement of the condition in at least 75% of patients. Seventy-four percent of the patients were quite or very satisfied with the treatment and 80% reported an improvement. The investigator's global assessment of performance was in agreement with this view, as more than 80% of the patients were considered clinically improved. CONCLUSIONS: The use of the investigated new nebulized HA nasal hypertonic solution is an effective and safe the treatment of CRS.


Assuntos
Pólipos Nasais , Rinite , Sinusite , Doença Crônica , Humanos , Ácido Hialurônico , Soluções Hipertônicas , Rinite/tratamento farmacológico , Sinusite/tratamento farmacológico
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