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BACKGROUND: The ultra-short-acting benzodiazepine remimazolam, approved for procedural sedation and general anesthesia, is inactivated by carboxylesterase 1 (CES1). OBJECTIVE: Remimazolam´s involvement in CES1-mediated drug-drug interactions (DDIs) was investigated. METHODS: Possible interactions of remimazolam were studied in co-exposure experiments with eleven different drugs. Further, substrates and inhibitors of CES1, identified in the literature, were evaluated for possible in-vivo inhibition using pharmacokinetic and Ki or IC50 values. Compounds with only one published inhibitory concentration and CES1 substrates lacking inhibition data were assigned conservative Ki values. RESULTS: In human liver homogenates and/or blood cells, remimazolam showed no significant inhibition of esmolol and landiolol metabolism, which, in turn, at up to 98 and 169 µM, respectively, did not inhibit remimazolam hydrolysis by human liver homogenates. In human liver S9 fractions, IC50 values ranged from 0.69 µM (simvastatin) and 57 µM (diltiazem) to > 100 µM (atorvastatin) and, for the remaining test items (bupropion, carvedilol, nelfinavir, nitrendipine, and telmisartan), they ranged from 126 to 658 µM. Remifentanil was ineffective even at 1250 µM. Guidance-conforming evaluation revealed no relevant drug-drug interactions with remimazolam via CES1. The algorithm-based predictions were consistent with human study data. Among CES1 inhibitors and substrates identified in the literature, only dapsone and rufinamide were found to be possible in-vivo inhibitors of remimazolam metabolism. CONCLUSION: Data and analyses suggest a very low potential of remimazolam for pharmacokinetic DDIs mediated by CES1. The theoretical approach and compiled data are not specific to remimazolam and, hence, applicable in the evaluation of other CES1 substrates.
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BACKGROUND: The ultra-short-acting benzodiazepine, remimazolam, is a new treatment modality for procedural sedation and general anesthesia. Its activity is terminated by carboxylesterase 1 (CES1). OBJECTIVE: The objective of this study was to determine the drug-drug interaction (DDI) potential of remi-mazolam through mechanisms unrelated to its metabolizing enzyme, CES1. METHODS: Conventional in vitro co-exposure experiments were conducted to study possible interactions of remimazolam and its primary metabolite, CNS7054, mediated by competitive binding to plasma protein or competition for reactions with cytochrome P450 isoforms or drug transporters. RESULTS: No relevant interactions of remimazolam or its metabolite with cytochrome P450 (CYP) isoforms at clinically relevant concentrations were identified. Likewise, standard experiments revealed no clinically relevant interactions with drug transporters and plasma proteins. CONCLUSION: The present data and analyses suggest a very low potential of remimazolam for pharmacoki-netic DDIs mediated by CYP isoforms, drug transporters, and protein binding.
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BACKGROUND: Remimazolam (RMZ) is a novel ultrashort-acting benzodiazepine used for sedation by intravenous administration. The pharmacophore of RMZ includes a carboxyl ester group sensitive to esterase- mediated hydrolysis, which is the primary path of metabolic elimination. However, for the sake of drug safety, a deeper and broader knowledge of the involved metabolic pathways and the evolving metabolites is required. Information is needed on both humans and experimental animals to evaluate the possibility that humans form harmful metabolites not encountered in animal toxicity studies. OBJECTIVE: The current study aimed at identifying the mechanisms of remimazolam's metabolism and any potential clinically significant metabolites. METHODS: Using tissue homogenates from various animals and humans, the liver was identified as the tissue primarily responsible for the elimination of RMZ. CNS7054, the hydrolysis product of remimazolam, was identified as the only clinically relevant metabolite. Using bacterial or eukaryotic over-expression systems, carboxylesterase 1 (CES1) was identified as the iso-enzyme predominantly involved in RMZ metabolism, with no role for carboxylesterase 2. Using a variety of inhibitors of other esterases, the contribution to elimination mediated by esterases other than CES1 was excluded. RESULTS: Besides tissue carboxylesterases, rodents expressed an RMZ esterase in plasma, which was not present in this compartment in other laboratory animals and humans, hampering direct comparisons. Other pathways of metabolic elimination, such as oxidation and glucuronidation, also occurred, but their contribution to overall elimination was minimal. CONCLUSION: Besides the pharmacologically non-active metabolite CNS7054, no other clinically significant metabolite of remimazolam could be identified.
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Benzodiazepinas , Benzodiazepinas/farmacocinética , Benzodiazepinas/metabolismo , Animales , Humanos , Hipnóticos y Sedantes/farmacocinética , Hipnóticos y Sedantes/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Masculino , Hidrolasas de Éster Carboxílico/metabolismo , RatasRESUMEN
While lipase content and appropriate acid protection of pancreatin preparations (PP) are well defined determinants of an effective therapy of exocrine pancreatic insufficiency, the optimal sphere size of PP has remained a matter of discussion. We performed a systematic review to assess the optimal sphere size of enteric coated pancreatin products that may best guarantee coordinated delivery of PP and food to the duodenum. PubMed was searched for studies on gastric emptying of indigestible spheres in the digestive phase, using overlapping search algorithms; identified sources were searched for further leads, extending the investigation to Google Scholar. Of 739 screened publications, 26 were included in the final assessment. Contrary to current guideline recommendations, no scientific evidence was found to support a 2 mm diameter threshold for gastric emptying of indigestible particles. There is no documented advantage of ≤2 mm spheres regarding duodenal delivery and restoring maldigestion. The evolving picture is that of a gradation of sizes, over which gastric emptying becomes slower and more variable as particle size increases. Even 7 mm particles may be emptied from the stomach in conjunction with nutrient uptake. In conclusion sphere size of PP is not the essential parameter for selecting an effective PP fitting all patients. A variety of brands offer different lipase contents and sphere sizes that allow the physician to tailor treatment to the individual patient`s needs.
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Insuficiencia Pancreática Exocrina , Pancreatina , Duodeno , Insuficiencia Pancreática Exocrina/diagnóstico , Insuficiencia Pancreática Exocrina/tratamiento farmacológico , Vaciamiento Gástrico , Humanos , LipasaRESUMEN
As a new and ultra fast-acting IV benzodiazepine, pharmacological tolerance may be anticipated during long-term treatment with remimazolam e.g. in intensive care. In this context, tolerance is particularly relevant for withdrawal syndrome. However, apart from primates, existing models of sedative tolerance are unsuitable for remimazolam due to its excessive metabolic clearance (i.e. in rodents) or paradoxical responses (in dogs). Pigs are a well-established model species, especially for in-vivo drug safety studies, and appear a well suited as model for evaluation of remimazolam. In a series of experiments from dose-range-finding bolus and infusion studies through to 28-day continuous level sedation, we established a viable model of intravenous benzodiazepine sedation in NIBS micropigs to compare tolerance development during 28 days sedation with either midazolam or remimazolam. Dose increases after 28 days were lower for remimazolam (0 to 3-fold) than for midazolam (2 to 4-fold) and recovery times were approximately 40% faster for remimazolam vs midazolam. Tolerance to remimazolam is therefore likely in long-term human sedation and may be less than that seen for midazolam.
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Benzodiazepinas/administración & dosificación , Estado de Conciencia/efectos de los fármacos , Tolerancia a Medicamentos , Hipnóticos y Sedantes/administración & dosificación , Midazolam/administración & dosificación , Administración Intravenosa , Animales , Relación Dosis-Respuesta a Droga , Masculino , Modelos Animales , Recuperación de la Función , Porcinos , Porcinos Enanos , Factores de TiempoRESUMEN
Drug-drug interactions can substantially change pharmacological effects of the individual substances involved. For the use of sedatives or anaesthetics, having knowledge of the extent and characteristics of such interactions is crucial for ensuring the proper protection of patients undergoing any kind of sedation. Remimazolam is a new ultra-short acting benzodiazepine that is currently under development for intravenous use in procedural sedation and general anaesthesia. It exhibits a fast onset and fast offset which enables a more rapid recovery than currently available drugs in that class, such as midazolam. The purpose of this study was to more closely investigate the sedative properties and pharmacodynamic drug-drug interaction potential of remimazolam with the opioid analgesic remifentanil and compare it with other commonly used sedatives - midazolam and propofol. For this purpose, six Cynomolgus monkeys received escalating doses of remimazolam, propofol, and midazolam intravenously without or with concurrent remifentanil. Sedation was evaluated using a general sedation scale that included monitoring exploratory and avoidance behaviour, responses to sensory stimuli, posture and gait, and eyelid position as endpoints. Based on the results, sedative doses were calculated to allow evaluation of pharmacological drug-drug interaction with remifentanil. Remimazolam induced dose-dependent and consistent sedative effects in each endpoint tested and showed a high degree of synergism with remifentanil. Midazolam showed a comparable synergism while the interaction between propofol and remifentanil was less pronounced.
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Analgésicos Opioides/farmacología , Benzodiazepinas/farmacología , Hipnóticos y Sedantes/farmacología , Midazolam/farmacología , Propofol/farmacología , Remifentanilo/farmacología , Administración Intravenosa , Analgésicos Opioides/administración & dosificación , Animales , Benzodiazepinas/administración & dosificación , Estudios Cruzados , Interacciones Farmacológicas , Hipnóticos y Sedantes/administración & dosificación , Macaca fascicularis , Masculino , Midazolam/administración & dosificación , Propofol/administración & dosificación , Remifentanilo/administración & dosificaciónRESUMEN
STUDY OBJECTIVE: To evaluate factors affecting variability in response to remimazolam in general anesthesia. DESIGN: Plasma concentration-time data from 11 Phase 1-3 clinical trials were pooled for the population pharmacokinetic (popPK) analysis and concentration-bispectral index (BIS) data were pooled from 8 trials for popPK-PD analysis. A 3-compartment model with allometric exponents on clearance and volume described remimazolam concentrations over time. An effect compartment model with an inhibitory sigmoid Emax model was fit to the concentration-BIS data. Simulations were performed to assess sedation in general anesthesia and post-surgical sedation in healthy and sensitive populations. SETTING: General anesthesia and post-surgical sedation. PATIENTS: 689 subjects included in popPK and 604 subjects included in popPK-PD. Most subjects (>85%) were ASA Class 1 or 2, with the remaining subjects being ASA Class 3. INTERVENTIONS: Serial plasma concentrations and BIS scores. MEASUREMENTS: Standard intra-operative monitoring. MAIN RESULTS: PopPK model included an effect of extracorporeal circulation, ASA class, and sex on PK and a time-dependent clearance (~30% lower at 24 h) that was not related to cumulative dose. Co-administered remifentanil had a synergistic decrease in BIS with remimazolam. Remimazolam IC50 increased with cumulative dose. Onset was faster in overweight subjects and slower in Asian subjects. If using a weight-based regimen, simulations showed that remimazolam 6 mg/kg/h until loss of consciousness followed by 1 mg/kg/h during general anesthesia and 0.25 mg/kg/h for post-surgical sedation for up to 24 h is optimal, regardless of ASA class or sensitivity of subjects. CONCLUSIONS: If using a weight-based regimen, results illustrated an appropriate regimen of remimazolam for general anesthesia and post-surgical sedation in general and sensitive populations, although lower doses can be considered in elderly patients with a significant disease burden or in ASA Class 3 patients. The time-dependent change in clearance is not clinically relevant for up to 24 h.
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Anestesia General , Hipnóticos y Sedantes , Anciano , Anestesia General/efectos adversos , Benzodiazepinas , Relación Dosis-Respuesta a Droga , Voluntarios Sanos , HumanosRESUMEN
Remimazolam is an ultra-short-acting benzodiazepine being investigated for induction and maintenance of general anesthesia and for procedural sedation. This dose-response analysis of 4 phase 2-3 studies evaluated covariates that may impact the pharmacodynamic profile (based on theoretical pharmacokinetic principles) and require dose adjustments in subpopulations, particularly elderly, and if remimazolam has cumulative properties. Covariates affecting the time to loss of consciousness and time to extubation were evaluated using Cox proportional hazards models. Factors affecting steady-state infusion rate required to produce adequate sedation were evaluated using linear regression. Variability in time to loss of consciousness was explained by induction dose, age, body mass index, and time from initiation of opioids to initiation of remimazolam. The steady-state infusion rate producing adequate sedation was higher in European than Japanese subjects due to differences in study design. American Society of Anesthesiologists physical status class 3 subjects had a 28% lower maintenance infusion rate than class 1 subjects. Other statistically significant covariates (American Society of Anesthesiologists class 2, estimated glomerular filtration rate, and sex) resulted in small (≤14%), non-clinically relevant differences. Factors affecting time to extubation included the last infusion rate (ie, tapering), the bispectral index score at the end of infusion, and sex. The time to extubation after remimazolam did not increase with increased cumulative dose of remimazolam or duration of surgery. This evaluation of remimazolam's pharmacodynamic profile, in the absence of pharmacokinetic data, informed dosing recommendations and showed that remimazolam does not have cumulative properties in the general anesthesia setting.
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Benzodiazepinas/farmacocinética , Hipnóticos y Sedantes/farmacocinética , Adulto , Anciano , Anestesia General/métodos , Benzodiazepinas/administración & dosificación , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Humanos , Hipnóticos y Sedantes/administración & dosificación , Estimación de Kaplan-Meier , Modelos Lineales , Persona de Mediana Edad , Modelos Biológicos , Probabilidad , TiempoRESUMEN
BACKGROUND: Remimazolam is an ultra-short acting benzodiazepine under development for procedural sedation and general anesthesia. It is hydrolyzed by CES1 to an inactive metabolite (CNS7054). PURPOSE: In this study, the effect of continuous remimazolam exposure on its metabolism and on CES1 expression was investigated in a dynamic 3-D bioreactor culture model inoculated with primary human hepatocytes. METHODS: Remimazolam was continuously infused into bioreactors for 5 days at a final concentration of 3,000 ng/ml (6.8 µM). In parallel, 2-D cultures were run with cells from the same donors, but with discontinuous exposure to remimazolam. RESULTS: Daily measurement of clinical chemistry parameters (glucose, lactate, urea, ammonia, and liver enzymes) in culture supernatants indicated no noxious effect of remimazolam on hepatocyte integrity as compared to untreated controls. Concentrations of remimazolam reached steady-state values of around 250 ng/ml within 8 hours in 3-D bioreactors whereas in 2-D cultures remimazolam concentrations declined to almost zero within the same time frame. Levels of CNS7054 showed an inverse time-course reaching average values of 1,350 ng/ml in perfused 3-D bioreactors resp. 2,800 ng/ml in static 2-D cultures. Analysis of mRNA expression levels of CES1 indicated no changes in gene expression over the culture period. CONCLUSION: The results indicated a stable metabolism of remimazolam during 5 days of continuous exposure to clinically relevant concentrations of the drug. Moreover, there was no evidence for a harmful effect of remimazolam exposure on the integrity and metabolic activity of in vitro cultivated primary human hepatocytes.
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Benzodiazepinas/metabolismo , Reactores Biológicos , Hepatocitos/metabolismo , Benzodiazepinas/administración & dosificación , Benzodiazepinas/farmacología , Hidrolasas de Éster Carboxílico/biosíntesis , Hepatocitos/efectos de los fármacos , HumanosRESUMEN
BACKGROUND: Functional dyspepsia is a heterogeneous disorder lacking an established therapeutic strategy. Historical treatment attempts with pepsin products were shrugged off, as a simple calculation shows that quantitative substitution is pointless. However, such attempts might have been right for the wrong reason. SUMMARY: Today, the role of pepsins is primarily seen in the provision of signalling amino acids (especially phenylalanine and tryptophan) and peptides, which initiate processes promoting digestion. Proteolysis benefits from pepsin variants showing, contrary to common belief, activities of up to a pH value of 5.0. Non-clinical and clinical studies support the view that liberated amino acids produce a variety of direct and indirect effects. Signal chains stimulated by (mostly aromatic) amino acids lead to secretion of gastrin and cholecystokinin (CCK), mediated, respectively, by CCK2 (gastrin) and Ca2+-sensing receptors in the parietal cell, and Ca2+-sensing receptors in the antral and duodenal mucosa. Thus, CCK effects such as secretion of pancreatic enzymes and promotion of gastric accommodation are (also) consequential to peptic liberation of amino acids. Key Message: As functional dyspepsia represents a heterogeneous disorder, it may be intriguing to view pepsin as a potential (although still to be proven) treatment modality, distinguished by a diversity of pro-digestive effects.
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Dispepsia/enzimología , Pepsina A/metabolismo , Aminoácidos/metabolismo , Animales , Digestión , Dispepsia/fisiopatología , Humanos , Proteolisis , Estómago/enzimologíaRESUMEN
BACKGROUND AND AIMS: Chronic constipation is a serious medical condition that affects 30%-40% of people over 60 years old. Although not normally life threatening, constipation reduces quality of life by the same extent as diabetes and osteoarthritis. There are currently no Europe-wide guidelines for treating constipation in older people, although there is some country-level guidance for the general population. We have evaluated the existing guidance and best clinical practice to improve the care of older people with constipation. METHOD: European healthcare professionals working in gastroenterology, geriatrics, nursing and pharmacology discussed the treatment of constipation in older people and reviewed existing guidance on the treatment of constipation in the general population. This manuscript represents the consensus of all authors. DISCUSSION: Most general guidance for constipation treatment recommends increased dietary fibre, fluid intake and exercise; however, this is not always possible in older patients. Although a common first-line treatment, bulk-forming laxatives are unsuitable for older people because of an associated need to increase fluid intake, osmotic laxatives are likely to be the most suitable laxative type for older patients. Treatment is often hampered by reluctance to talk about bowel problems so healthcare providers should proactively identify older constipated patients who are self-medicating or not receiving treatment. CONCLUSIONS: With certain modifications, general treatment guidelines can be applied to older people with constipation, although specific guidelines are still required for this age group. Awareness of constipation, its complications and treatment options need to be increased among healthcare providers, patients and carers.
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Estreñimiento/terapia , Laxativos/uso terapéutico , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Consenso , Estreñimiento/diagnóstico , Fibras de la Dieta/administración & dosificación , Europa (Continente) , Humanos , Laxativos/clasificación , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , Calidad de VidaRESUMEN
N-methyl-d-aspartate receptors (NMDARs) are ion channels whose synaptic versus extrasynaptic localization critically influences their functions. This distribution of NMDARs is highly dependent on their lateral diffusion at the cell membrane. Each obligatory subunit of NMDARs (GluN1 and GluN2) contains two extracellular clamshell-like domains with an agonist-binding domain and a distal N-terminal domain (NTD). To date, the roles and dynamics of the NTD of the GluN1 subunit in NMDAR allosteric signaling remain poorly understood. Using single nanoparticle tracking in mouse neurons, we demonstrate that the extracellular neuronal protease tissue-type plasminogen activator (tPA), well known to have a role in the synaptic plasticity and neuronal survival, leads to a selective increase of the surface dynamics and subsequent diffusion of extrasynaptic NMDARs. This process explains the previously reported ability of tPA to promote NMDAR-mediated calcium influx. In parallel, we developed a monoclonal antibody capable of specifically blocking the interaction of tPA with the NTD of the GluN1 subunit of NMDAR. Using this original approach, we demonstrate that the tPA binds the NTD of the GluN1 subunit at a lysine in position 178. Accordingly, when applied to mouse neurons, our selected antibody (named Glunomab) leads to a selective reduction of the tPA-mediated surface dynamics of extrasynaptic NMDARs, subsequent signaling and neurotoxicity, both in vitro and in vivo. Altogether, we demonstrate that the tPA is a ligand of the NTD of the obligatory GluN1 subunit of NMDAR acting as a modulator of their dynamic distribution at the neuronal surface and subsequent signaling.
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Membrana Celular/metabolismo , Neuronas/citología , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo , Activador de Tejido Plasminógeno/farmacología , Animales , Anticuerpos Monoclonales/farmacología , Calcio/metabolismo , Muerte Celular/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Difusión , Fibrinolisina/farmacología , Células HEK293 , Humanos , Lisina/metabolismo , Masculino , Ratones Endogámicos BALB C , Neuronas/efectos de los fármacos , Neurotoxinas/toxicidad , Dominios Proteicos , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/química , Transducción de Señal/efectos de los fármacos , Sinapsis/efectos de los fármacosRESUMEN
Intestinal radiation toxicity occurs during and after abdominopelvic radiotherapy. Endothelial cells play a significant role in modulating radiation-induced intestinal damage. We demonstrated that the endothelial cell surface receptor thrombomodulin (TM), a protein with anticoagulant, anti-inflammatory and antioxidant properties, mitigates radiation-induced lethality in mice. The goal of this study was to determine whether recombinant TM (Solulin) can protect the intestine from toxicity in a clinically relevant rat model. A 4 cm loop of rat small bowel was exposed to fractionated 5 Gy X radiation for 9 consecutive days. The animals were randomly assigned to receive daily subcutaneous injections of vehicle or Solulin (3 mg/kg/day or 10 mg/kg/day) for 27 days starting 4 days before irradiation. Early intestinal injury was assessed two weeks after irradiation by quantitative histology, morphometry, immunohistochemistry and luminol bioluminescence imaging. Solulin treatment significantly ameliorated intestinal radiation injury, made evident by a decrease in myeloperoxidase (MPO) activity, transforming growth factor beta (TGF-ß) immunoreactivity, collagen-I deposition, radiation injury score (RIS) and intestinal serosal thickening. These findings indicate the need for further development of Solulin as a prophylactic and/or therapeutic agent to mitigate radiation-induced intestinal damage.
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Intestinos/efectos de los fármacos , Intestinos/efectos de la radiación , Proteínas Recombinantes/farmacología , Trombomodulina/metabolismo , Animales , Colágeno/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de la radiación , Humanos , Mucosa Intestinal/metabolismo , Intestinos/inmunología , Masculino , Infiltración Neutrófila/efectos de los fármacos , Infiltración Neutrófila/efectos de la radiación , Peroxidasa/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Hepatic encephalopathy is a result of insufficient liver function, with grave consequences for the patients. It is primarily caused by disturbed hepatic elimination of the neurotoxin, ammonia (NH3). Aside from dietetic measures, treatment rests on drugs designed to reduce the NH3 burden. The primary options, lactulose and the practically unabsorbable antibiotic rifaximin are suitable to decrease the bacterial NH3 generation in the intestine. Other antibiotics like neomycin at best have a place in acute treatment. L-ornithine-L-aspartate (LOLA) and branched-chain amino acids (valine, leucine, isoleucine) aim at supporting the scavenge of NH3 in glutamine; however, the final balance of this pathway is unfavourable. In addition, the constituents of LOLA enhance the capacity of the urea cycle and, ultimately, the elimination of NH3. As the evidence from available studies--is not unequivocal in each case, the current place of LOLA in treatment is that of an option for patients, who do not respond to standard therapy.
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Encefalopatía Hepática/terapia , Aminoácidos de Cadena Ramificada/uso terapéutico , Amoníaco/metabolismo , Antibacterianos/uso terapéutico , Dipéptidos/uso terapéutico , Encefalopatía Hepática/metabolismo , Humanos , Rifamicinas/uso terapéutico , RifaximinaAsunto(s)
Adyuvantes Farmacéuticos/administración & dosificación , Analgésicos/administración & dosificación , Cafeína/administración & dosificación , Mitología , Adyuvantes Farmacéuticos/efectos adversos , Analgésicos/efectos adversos , Cafeína/efectos adversos , Relación Dosis-Respuesta a Droga , Humanos , Dimensión del Dolor , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
AIM: The rising prevalence of bronchial asthma has led to world-wide efforts to understand and stem this development. Cross-sectional studies appear to show that early childhood use of antibiotics may be an important contributory factor, with paracetamol as an additional suspected cause. However, mounting evidence, which is reviewed here, points to various confounding factors as the major reasons for these reported associations. METHODS: PubMed and EMBASE were systematically searched for studies on associations between antibiotics and/or paracetamol with asthma and/or wheezing, published up to November 2012. A total of 64 pertinent studies were identified, 35 focusing on antibiotics, 19 on paracetamol, and ten addressing both antibiotics and paracetamol, bringing the number of relevant datasets to 74. RESULTS: Numerous studies were cross-sectional and made no adjustment for the indication of antibiotics or paracetamol; consequently, they were unable to dismiss possible confounding by indication. Where such adjustments could be performed (mostly in longitudinal studies), they substantially weakened or entirely eliminated the association with asthma or asthma surrogates present in the unadjusted data. CONCLUSION: The weight of evidence of the collected studies in our review strongly suggests that the association of antibiotics with childhood asthma reflects various forms of bias, the most prominent of which is confounding by indication. Recent studies and meta-analyses support the same conclusion for paracetamol. Truly indicated antibiotics should not be withheld from infants or young children for fears they might develop asthma. Likewise, there is no sound reason to replace paracetamol as the preferred pain relief and fever medication in this age group.
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Acetaminofén/efectos adversos , Analgésicos no Narcóticos/efectos adversos , Antibacterianos/efectos adversos , Asma/inducido químicamente , Edad de Inicio , Asma/diagnóstico , Asma/epidemiología , Niño , Preescolar , Humanos , Oportunidad Relativa , Medición de Riesgo , Factores de RiesgoRESUMEN
Ischemic and hemorrhagic strokes have different etiologies, but share some pathogenic mechanisms, including a pro-neurotoxic effect of endogenous tissue plasminogen activator (tPA) via N-methyl-d-Aspartate (NMDA) receptors. Thus, in a model of intracerebral hemorrhage in rats, we investigated the therapeutic value of a strategy of immunotherapy (αATD-GluN1 antibody) preventing the interaction of tPA with NMDA receptors. We found that a single intravenous injection of αATD-GluN1 reduced brain edema, neuronal death, microglial activation and functional deficits following intracerebral hemorrhage, without affecting the hematoma volume.
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Inmunoterapia/métodos , Hemorragias Intracraneales/inmunología , Hemorragias Intracraneales/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/metabolismo , Activador de Tejido Plasminógeno/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Hemorragias Intracraneales/terapia , Masculino , Ratones , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Accidente Cerebrovascular/terapia , Activador de Tejido Plasminógeno/fisiología , Resultado del TratamientoRESUMEN
Tissue damage induced by ionizing radiation in the hematopoietic and gastrointestinal systems is the major cause of lethality in radiological emergency scenarios and underlies some deleterious side effects in patients undergoing radiation therapy. The identification of target-specific interventions that confer radiomitigating activity is an unmet challenge. Here we identify the thrombomodulin (Thbd)-activated protein C (aPC) pathway as a new mechanism for the mitigation of total body irradiation (TBI)-induced mortality. Although the effects of the endogenous Thbd-aPC pathway were largely confined to the local microenvironment of Thbd-expressing cells, systemic administration of soluble Thbd or aPC could reproduce and augment the radioprotective effect of the endogenous Thbd-aPC pathway. Therapeutic administration of recombinant, soluble Thbd or aPC to lethally irradiated wild-type mice resulted in an accelerated recovery of hematopoietic progenitor activity in bone marrow and a mitigation of lethal TBI. Starting infusion of aPC as late as 24 h after exposure to radiation was sufficient to mitigate radiation-induced mortality in these mice. These findings suggest that pharmacologic augmentation of the activity of the Thbd-aPC pathway by recombinant Thbd or aPC might offer a rational approach to the mitigation of tissue injury and lethality caused by ionizing radiation.