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1.
Nat Commun ; 12(1): 814, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33547300

RESUMEN

On the basis of Covid-19-induced pulmonary pathological and vascular changes, we hypothesize that the anti-vascular endothelial growth factor (VEGF) drug bevacizumab might be beneficial for treating Covid-19 patients. From Feb 15 to April 5, 2020, we conducted a single-arm trial (NCT04275414) and recruited 26 patients from 2-centers (China and Italy) with severe Covid-19, with respiratory rate ≥30 times/min, oxygen saturation ≤93% with ambient air, or partial arterial oxygen pressure to fraction of inspiration O2 ratio (PaO2/FiO2) >100 mmHg and ≤300 mmHg, and diffuse pneumonia confirmed by chest imaging. Followed up for 28 days. Among these, bevacizumab plus standard care markedly improves the PaO2/FiO2 ratios at days 1 and 7. By day 28, 24 (92%) patients show improvement in oxygen-support status, 17 (65%) patients are discharged, and none show worsen oxygen-support status nor die. Significant reduction of lesion areas/ratios are shown in chest computed tomography (CT) or X-ray within 7 days. Of 14 patients with fever, body temperature normalizes within 72 h in 13 (93%) patients. Relative to comparable controls, bevacizumab shows clinical efficacy by improving oxygenation and shortening oxygen-support duration. Our findings suggest bevacizumab plus standard care is highly beneficial for patients with severe Covid-19. Randomized controlled trial is warranted.


Asunto(s)
Bevacizumab/uso terapéutico , /efectos de los fármacos , Anciano , Inhibidores de la Angiogénesis/uso terapéutico , Temperatura Corporal/efectos de los fármacos , China , Femenino , Fiebre/prevención & control , Humanos , Italia , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
2.
Cochrane Database Syst Rev ; 10: CD006811, 2020 10 31.
Artículo en Inglés | MEDLINE | ID: mdl-33126293

RESUMEN

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability, with an estimated 5.5 million people experiencing severe TBI worldwide every year. Observational clinical studies of people with TBI suggest an association between raised body temperature and unfavourable outcome, although this relationship is inconsistent. Additionally, preclinical models suggest that reducing temperature to 35 °C to 37.5 °C improves biochemical and histopathological outcomes compared to reducing temperature to a lower threshold of 33 °C to 35 °C. It is unknown whether reducing body temperature to 35 °C to 37.5 °C in people admitted to hospital with TBI is beneficial, has no effect, or causes harm. This is an update of a review last published in 2014. OBJECTIVES: To assess the effects of pharmacological interventions or physical interventions given with the intention of reducing body temperature to 35 °C to 37.5 °C in adults and children admitted to hospital after TBI. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Web of Science, and PubMed on 28 November 2019. We searched clinical trials registers, grey literature and references lists of reviews, and we carried out forward citation searches of included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with participants of any age admitted to hospital following TBI. We included interventions that aimed to reduce body temperature to 35 °C to 37.5 °C: these included pharmacological interventions (such as paracetamol, or non-steroidal anti-inflammatory drugs), or physical interventions (such as surface cooling devices, bedside fans, or cooled intravenous fluids). Eligible comparators were placebo or usual care. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of the evidence with GRADE. MAIN RESULTS: We included one RCT with 41 participants. This study recruited adult participants admitted to two intensive care units in Australia, and evaluated a pharmacological intervention. Researchers gave participants 1 g paracetamol or a placebo intravenously at four-hourly intervals for 72 hours. We could not be certain whether intravenous paracetamol influenced mortality at 28 days (risk ratio 2.86, 95% confidence interval 0.32 to 25.24). We judged the evidence for this outcome to be very low certainty, meaning we have very little confidence in this effect estimate, and the true result may be substantially different to this effect. We downgraded the certainty for imprecision (because the evidence was from a single study with very few participants), and study limitations (because we noted a high risk of selective reporting bias). This study was otherwise at low risk of bias. The included study did not report the primary outcome for this review, which was the number of people with a poor outcome at the end of follow-up (defined as death or dependency, as measured on a scale such as the Glasgow Outcome Score), or any of our secondary outcomes, which included the number of people with further intracranial haemorrhage, extracranial haemorrhage, abnormal intracranial pressure, or pneumonia or other serious infections. The only other completed trial that we found was of a physical intervention that compared advanced fever control (using a surface cooling device) versus conventional fever control in 12 participants. The trial was published as an abstract only, with insufficient details to allow inclusion, so we have added this to the 'studies awaiting classification' section, pending further information from the study authors or publication of the full study report. We identified four ongoing studies that will contribute evidence to future updates of the review if they measure relevant outcomes and, in studies with a mixed population, report data separately for participants with TBI. AUTHORS' CONCLUSIONS: One small study contributed very low-certainty evidence for mortality to this review. The uncertainty is largely driven by limited research into reduction of body temperature to 35 °C to 37.5 °C in people with TBI. Further research that evaluates pharmacological or physical interventions, or both, may increase certainty in this field. We propose that future updates of the review, and ongoing and future research in this field, incorporate outcomes that are important to the people receiving the interventions, including side effects of any pharmacological agent (e.g. nausea or vomiting), and discomfort caused by physical therapies.


Asunto(s)
Acetaminofén/administración & dosificación , Antipiréticos/administración & dosificación , Temperatura Corporal , Lesiones Traumáticas del Encéfalo/terapia , Hipotermia Inducida/métodos , Adulto , Sesgo , Temperatura Corporal/efectos de los fármacos , Lesiones Traumáticas del Encéfalo/mortalidad , Humanos , Hipotermia Inducida/mortalidad , Inyecciones Intravenosas , Placebos
3.
Br J Anaesth ; 125(4): 548-559, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32807382

RESUMEN

BACKGROUND: Circadian differences in the induction, maintenance, or emergence from volatile anaesthesia have not been well studied. METHODS: The minimal alveolar concentration (MAC) for preventing movement in response to a painful stimulus, MAC for loss of righting reflex (MACLORR), and MAC for recovery of righting reflex (MACRORR) in C57BL/6J male mice with isoflurane or sevoflurane exposure were measured during either the light or dark phase. Time to onset of loss of righting reflex (TimeLORR) and recovery of righting reflex (TimeRORR) upon exposure to 1 MAC of isoflurane or sevoflurane were determined. EEG was also monitored in the light and dark phase under isoflurane or sevoflurane exposure. The noradrenergic toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) was used to deplete noradrenergic neurones in the locus coeruleus to explore the impact of norepinephrine on these measurements. RESULTS: MACLORR, TimeLORR, and MAC did not show light- or dark-phase-dependent variations for either isoflurane or sevoflurane exposure. However, MACRORR was higher and TimeRORR was shorter in the dark phase than in the light phase for both isoflurane and sevoflurane exposure. The EEG delta wave power was higher but theta wave power was lower in the light phase than that in the dark phase during the rest state and emergence of anaesthesia. These light- and dark-phase-dependent changes in emergence were abolished in DSP-4-treated mice. CONCLUSION: Our data show that circadian differences exist during emergence but not during induction or maintenance of sevoflurane or isoflurane anaesthesia. The locus coeruleus noradrenergic system may contribute to these differences.


Asunto(s)
Anestésicos por Inhalación/farmacología , Ritmo Circadiano/fisiología , Locus Coeruleus/fisiología , Norepinefrina/fisiología , Anestésicos por Inhalación/farmacocinética , Animales , Bencilaminas/farmacología , Temperatura Corporal/efectos de los fármacos , Electroencefalografía/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Reflejo de Enderezamiento/efectos de los fármacos
4.
Nature ; 583(7816): 421-424, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32641825

RESUMEN

The suprachiasmatic nucleus (SCN) serves as the body's master circadian clock that adaptively coordinates changes in physiology and behaviour in anticipation of changing requirements throughout the 24-h day-night cycle1-4. For example, the SCN opposes overnight adipsia by driving water intake before sleep5,6, and by driving the secretion of anti-diuretic hormone7,8 and lowering body temperature9,10 to reduce water loss during sleep11. These responses can also be driven by central osmo-sodium sensors to oppose an unscheduled rise in osmolality during the active phase12-16. However, it is unknown whether osmo-sodium sensors require clock-output networks to drive homeostatic responses. Here we show that a systemic salt injection (hypertonic saline) given at Zeitgeber time 19-a time at which SCNVP (vasopressin) neurons are inactive-excited SCNVP neurons and decreased non-shivering thermogenesis (NST) and body temperature. The effects of hypertonic saline on NST and body temperature were prevented by chemogenetic inhibition of SCNVP neurons and mimicked by optogenetic stimulation of SCNVP neurons in vivo. Combined anatomical and electrophysiological experiments revealed that osmo-sodium-sensing organum vasculosum lamina terminalis (OVLT) neurons expressing glutamic acid decarboxylase (OVLTGAD) relay this information to SCNVP neurons via an excitatory effect of γ-aminobutyric acid (GABA). Optogenetic activation of OVLTGAD neuron axon terminals excited SCNVP neurons in vitro and mimicked the effects of hypertonic saline on NST and body temperature in vivo. Furthermore, chemogenetic inhibition of OVLTGAD neurons blunted the effects of systemic hypertonic saline on NST and body temperature. Finally, we show that hypertonic saline significantly phase-advanced the circadian locomotor activity onset of mice. This effect was mimicked by optogenetic activation of the OVLTGAD→ SCNVP pathway and was prevented by chemogenetic inhibition of OVLTGAD neurons. Collectively, our findings provide demonstration that clock time can be regulated by non-photic physiologically relevant cues, and that such cues can drive unscheduled homeostatic responses via clock-output networks.


Asunto(s)
Relojes Circadianos/fisiología , Vías Nerviosas , Neuronas/metabolismo , Sodio/metabolismo , Núcleo Supraquiasmático/fisiología , Ácido gamma-Aminobutírico/metabolismo , Animales , Temperatura Corporal/efectos de los fármacos , Temperatura Corporal/fisiología , Relojes Circadianos/efectos de los fármacos , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/fisiología , Ingestión de Líquidos/efectos de los fármacos , Glutamato Descarboxilasa/metabolismo , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Ratones , Vías Nerviosas/efectos de los fármacos , Neuronas/efectos de los fármacos , Optogenética , Organum Vasculosum/citología , Organum Vasculosum/efectos de los fármacos , Organum Vasculosum/enzimología , Organum Vasculosum/fisiología , Concentración Osmolar , Solución Salina Hipertónica/administración & dosificación , Solución Salina Hipertónica/metabolismo , Solución Salina Hipertónica/farmacología , Sodio/administración & dosificación , Sodio/farmacología , Núcleo Supraquiasmático/citología , Núcleo Supraquiasmático/efectos de los fármacos , Vasopresinas/metabolismo
5.
Int J Nanomedicine ; 15: 4139-4149, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32606669

RESUMEN

Introduction: A correlation is established between the efficacy of Chinese herbal medicine and its charcoal drugs. Lonicerae japonicae Flos (LJF) is commonly used to treat fever, carbuncle, and tumors, among others. LJF Carbonisatas (LJFC) is preferred for detoxifying and relieving dysentery and its related symptoms. However, the mechanisms underlying the effects of LJFC remain unknown. Aim: The aim of this study was to explore the effects of LJFC-derived carbon dots (LJFC-CDs) on lipopolysaccharide (LPS)-induced fever and hypothermia rat models. Methods: LJFC-CDs were characterized using transmission electron microscopy, high-resolution transmission electron microscopy, Fourier-transform infrared, ultraviolet, fluorescence, X-ray photoelectron spectroscopy, X-ray diffraction and high-performance liquid chromatography. The anti-inflammatory effects of LJFC-CDs were evaluated and confirmed using rat models of LPS-induced fever or hypothermia. Results: The LJFC-CDs ranged from 1.0 to 10.0 nm in diameter, with a yield of 0.5%. LJFC-CDs alleviated LPS-induced inflammation, as demonstrated by the expression of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 and the recovery of normal body temperature. Conclusion: LJFC-CDs may have an anti-inflammatory effect and a potential to alleviate fever and hypothermia caused by inflammation.


Asunto(s)
Carbono/química , Fiebre/tratamiento farmacológico , Hipotermia/tratamiento farmacológico , Lonicera/química , Extractos Vegetales/uso terapéutico , Animales , Temperatura Corporal/efectos de los fármacos , Cromatografía Líquida de Alta Presión , AMP Cíclico/metabolismo , Citocinas/metabolismo , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/química , Mediadores de Inflamación/sangre , Lipopolisacáridos , Masculino , Ratones , Extractos Vegetales/toxicidad , Células RAW 264.7 , Ratas Sprague-Dawley , Espectrometría de Fluorescencia
6.
Artículo en Inglés | MEDLINE | ID: mdl-32708894

RESUMEN

The aim of this study is to evaluate the effect of ingesting ibuprofen on post-workout recovery of muscle damage, body temperature and muscle power indicators in Paralympic powerlifting athletes. The study was carried out with eight Paralympic powerlifting athletes (aged 27.0 ± 5.3 years and 79.9 ± 25.5 kg of body mass) competing at the national level, with a minimum training experience of 12 months, who all submitted to two experimental conditions: Ibuprofen (2 × 00 mg) and control. The maximal isometric force of the upper limbs and rate of force development, thermography, and serum biochemical analyzes of creatine kinase, lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase were measured before, after, 24 h after and 48 h after the intervention. Maximal isometric force only decreased in the placebo condition, which increased back to baseline levels, while no substantial decline in baseline force was seen in the ibuprofen condition, although no effect for exercise condition was detected. After the exercise, the rate of force development decreased significantly for both conditions and did not exceed baseline levels again after 48 h. Muscle temperature decreased significantly at 48-h post-exercise in the placebo condition, when compared with the previous day of measurement; and deltoid muscle temperature at 48-h post-exercise was higher with the ibuprofen condition. Although the results indicate some positive effects of ibuprofen use, they do not enable a clear statement regarding its positive effects on muscle function and muscle damage. Ibuprofen seems to have caused a delay in the anti-inflammatory response following exercise.


Asunto(s)
Antiinflamatorios no Esteroideos , Temperatura Corporal , Ibuprofeno , Músculo Esquelético , Levantamiento de Peso , Adulto , Antiinflamatorios no Esteroideos/farmacología , Atletas , Temperatura Corporal/efectos de los fármacos , Creatina Quinasa , Ejercicio Físico , Humanos , Ibuprofeno/farmacología , Músculo Esquelético/efectos de los fármacos , Adulto Joven
7.
J Pharmacol Sci ; 144(2): 61-68, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32684333

RESUMEN

The effects of adipokine administration to the hypothalamic preoptic area (POA), which is one of the body temperature (BT) regulation centers in the central nervous system, on BT were investigated in male Wistar rats. BT was measured in conscious rats using telemetry. Insulin-like growth factor-1 (IGF-1), interleukin-1ß (IL-1ß), monocyte chemoattractant protein-1 and lipocalin-2 produced hyperthermia, and the effects induced by IL-1ß (25 ng) and IGF-1 (5 µg) were sustainable and remarkable. IL-6 did not show any significant effect. The IGF-1-induced effect was inhibited by pretreatment with IGF binding protein 3 (IGFBP3) or NVP-AEW541 (NVP, a selective inhibitor of type 1 IGF receptor tyrosine kinase, IGF1R TK). NVP-induced inhibition was observed only in the early phase of IGF-1-induced hyperthermia. In addition, IGF-1 increased the IL-1ß concentration in the microdialysate of POA perfusion, but did not increase the IL-1ß concentration in the plasma or the PGE2 concentration in the microdialysate. These findings suggested that IGF-1 produced hyperthermia, which was mediated, at least a part, through an increased IL-1ß concentration after activation of IGF1R TK in the POA, and the IGF-IGFBP system possibly participates in BT homeostasis in the POA.


Asunto(s)
Adipoquinas/administración & dosificación , Adipoquinas/farmacología , Temperatura Corporal/efectos de los fármacos , Temperatura Corporal/genética , Área Preóptica/metabolismo , Área Preóptica/fisiología , Animales , Quimiocina CCL2/administración & dosificación , Quimiocina CCL2/farmacología , Fiebre/inducido químicamente , Fiebre/genética , Factor I del Crecimiento Similar a la Insulina/administración & dosificación , Factor I del Crecimiento Similar a la Insulina/farmacología , Interleucina-1beta/administración & dosificación , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacología , Lipocalina 2/administración & dosificación , Lipocalina 2/farmacología , Masculino , Proteínas Tirosina Quinasas/metabolismo , Ratas Wistar , Receptor IGF Tipo 1/metabolismo
8.
BMC Psychiatry ; 20(1): 290, 2020 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-32517724

RESUMEN

BACKGROUND: Here we describe a unique case of clozapine-associated hypothermia during initial titration of this medication in an acute inpatient psychiatry setting. Only a handful of cases on this topic have been published. We discuss possible pharmacologic mechanisms supporting or refuting the propensity of clozapine to induce hypothermia, as well as risk factors for clozapine-induced hypothermia, and a comparison to clozapine-induced hyperthermia. CASE PRESENTATION: A 70 year-old African American female with treatment-refractory schizoaffective disorder developed hypothermia with a nadir temperature of 89 °F (31.7 °C) after 7 days on clozapine, on a total dose of 50 mg twice daily. Accompanying symptoms included bradycardia, hypotension, QTc prolongation, tachypnea, hypoxemia, and an absence of shivering. The patient was transferred to the ICU, and rewarmed within 10 h with the discontinuation of her clozapine, ziprasidone, and carvedilol. Broad spectrum antibiotics were initiated, but discontinued shortly after, as the patient had no leukocytosis, and blood cultures were negative. DISCUSSION: While hypoglycemia, hypothyroidism, sepsis, and stroke were effectively ruled out, alternative drug-disease (including chronic kidney disease), and drug-drug interactions were considered possible contributing features. Benzodiazepines, valproic acid, ziprasidone, and the numerous antihypertensive agents the patient was taking were considered as either primary or compounding factors for hypothermia. After exclusion or inclusion of these alternative causes, we calculated a score of 4 (possible) for clozapine-induced hypothermia on the Naranjo Scale. CONCLUSIONS: Clozapine-induced hypothermia may occur more commonly than clinicians believe. Practitioners should be cognizant of this potentially fatal phenomenon, and monitor for temperature dysregulations while on clozapine, especially during initial titration, in those with multiple comorbid factors, and on additional medications that may contribute to hypothermia.


Asunto(s)
Antipsicóticos/efectos adversos , Regulación de la Temperatura Corporal/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Clozapina/administración & dosificación , Clozapina/efectos adversos , Hipotermia/inducido químicamente , Anciano , Antipsicóticos/administración & dosificación , Antipsicóticos/uso terapéutico , Clozapina/uso terapéutico , Femenino , Humanos , Pacientes Internos
9.
Nat Commun ; 11(1): 2397, 2020 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-32409697

RESUMEN

Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity. BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.


Asunto(s)
Diaminas/administración & dosificación , Resistencia a la Insulina , Mitocondrias/efectos de los fármacos , Obesidad/tratamiento farmacológico , Oxadiazoles/administración & dosificación , Pirazinas/administración & dosificación , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Administración Oral , Animales , Glucemia/análisis , Temperatura Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Diaminas/efectos adversos , Dieta Occidental/efectos adversos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Técnica de Clampeo de la Glucosa , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/metabolismo , Obesidad/sangre , Obesidad/etiología , Obesidad/metabolismo , Oxadiazoles/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Pirazinas/efectos adversos
10.
PLoS One ; 15(5): e0233558, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32469977

RESUMEN

Eye temperature measured using infrared thermography (IRT) can be used as a non-invasive measure of autonomic nervous system (ANS) activity in cattle. The objective of this study was to evaluate if changes in eye temperature (measured using IRT) can be used to non-invasively measure ANS activity in sheep. Twenty, 2 to 4-year-old, Romney ewes were randomly assigned to receive either epinephrine (EPI) or physiological saline (SAL) for 5 min administered via jugular catheter (n = 10 ewes/treatment). Eye temperature (°C) was recorded continuously using IRT for approximately 25 min before and 20 min after the start of infusion. Heart rate and heart rate variability, measured using the root mean square of successive differences (RMSSD) and the standard deviation of all inter-beat intervals (SDNN), were recorded for 5 min before and up to 10 min after the start of infusion. Blood samples were taken before and after the infusion period to measure plasma epinephrine, norepinephrine, cortisol and packed cell volume (PCV) concentrations. During the infusion period, maximum eye temperature was on average higher (P<0.05) in sheep that received epinephrine than those that received saline. On average, heart rate was higher (SAL: 87.5 beats/min, EPI: 123.2 beats/min, SED = 7.07 beats/min; P<0.05), and RMSSD (SAL: 55.3 ms, EPI: 17.3 ms, SED = 14.18 ms) and SDNN (SAL: 54.3 ms, EPI: 21.5 ms, SED = 10.00 ms) lower (P<0.05) in ewes during the 5 min post-infusion period compared with ewes that received saline. An infusion of epinephrine resulted in higher geometric mean epinephrine (P<0.05) and cortisol (P<0.05) but not norepinephrine (P>0.05) concentrations in ewes compared to an infusion of saline. PCV concentrations were higher (P<0.001) by 7 ± 1.0% (mean±SED) in ewes after an epinephrine infusion. These results suggest that heart rate variability is a sensitive, non-invasive method that can be used to measure ANS activity in sheep, whereas change in eye temperature measured using IRT is a less sensitive method.


Asunto(s)
Sistema Nervioso Autónomo/fisiología , Temperatura Corporal/efectos de los fármacos , Ovinos/fisiología , Termografía/métodos , Animales , Sistema Nervioso Autónomo/efectos de los fármacos , Epinefrina/farmacología , Ojo , Femenino , Frecuencia Cardíaca , Rayos Infrarrojos
11.
J Pharmacol Exp Ther ; 374(2): 273-282, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32385092

RESUMEN

Methylenedioxypyrovalerone (MDPV) is an abused synthetic cathinone, commonly referred to as a "bath salt." Because the dopamine (DA) transporter (DAT) and vesicular monoamine transporter-2 (VMAT-2) are key regulators of both the abuse and neurotoxic potential of structurally and behaviorally related agents, the impact of MDPV on these transporters was investigated. Results revealed that a single in vivo MDPV administration rapidly (within 1 hour) and reversibly increased both rat striatal DAT and VMAT-2 activity, as assessed via [3H]DA uptake in synaptosomes and synaptic vesicles, respectively, prepared from treated rats. There was no evidence of an MDPV-induced increase in plasmalemmal membrane DAT surface expression. Plasma concentrations of MDPV increased dose-dependently as assessed 1 hour after 2.5 and 5.0 mg/kg (s.c.) administration and returned to levels less than 10 ng/ml by 18 hours after 2.5 mg/kg (s.c.). Neither pretreatment with a D1 receptor (SCH23390), a D2 receptor (eticlopride), nor a nicotinic receptor (mecamylamine) antagonist attenuated the MDPV-induced increase in DAT activity. In contrast, eticlopride pretreatment attenuated both the MDPV-induced increase in VMAT-2-mediated DA uptake and an associated increase in cytoplasmic-associated vesicle VMAT-2 immunoreactivity. SCH23390 did not attenuate the MDPV-induced increase in VMAT-2 activity. Repeated MDPV injections did not cause persistent DAergic deficits, as assessed 7 to 8 days later. The impact of MDPV on striatal and hippocampal serotonergic assessments was minimal. Taken together, these data contribute to a growing pharmacological rubric for evaluating the ever-growing list of designer cathinone-related stimulants. The profile of MDPV compared with related psychostimulants is discussed. SIGNIFICANCE STATEMENT: Pharmacological characterization of the synthetic cathinone, 3,4-methylenedioxypyrovalerone (MDPV; commonly referred to as a "bath salt"), is critical for understanding the abuse liability and neurotoxic potential of this and related agents. Accordingly, the impact of MDPV on monoaminergic neurons is described and compared with that of related psychostimulants.


Asunto(s)
Benzodioxoles/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Drogas de Diseño/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Pirrolidinas/farmacología , Trastornos Relacionados con Sustancias/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Animales , Benzodioxoles/farmacocinética , Temperatura Corporal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacocinética , Drogas de Diseño/farmacocinética , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Femenino , Masculino , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Pirrolidinas/farmacocinética , Ratas , Ratas Sprague-Dawley
12.
Sci Rep ; 10(1): 5724, 2020 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-32235895

RESUMEN

Communication technologies based on radiofrequency (RF) propagation bring great benefits to our daily life. However, their rapid expansion raises concerns about possible impacts on public health. At intensity levels below the threshold to produce thermal effects, RF exposure has also recently been reported to elicit biological effects, resembling reactions to cold. The objective of the present study was to investigate the effects of non-thermal RF on body temperature in mice and the related mechanisms. 3-months-old C57BL/6 J mice were exposed to a continuous RF signal at 900 MHz, 20 ± 5 V.m-1 for 7 consecutive days, twice per day during the light phase, for one hour each time. The SAR was 0.16 ± 0.10 W.kg-1. We showed that body temperature patterns in mice change synchronously with the RF exposure periods. Average body temperature in the light phase in the exposed group was higher than in the control group. The expression of the TRPM8 gene was not affected by RF in trigeminal ganglia. Furthermore, the injection of a TRPM8 antagonist did not induce a temperature decrease in exposed mice, as this was the case for sham-controls. These findings indicate that 900 MHz RF exposure at non-thermal level produce a physiological effect on body temperature in mice. However, the involvement of TRPM8 receptors in the mechanism by which RF induced changes in body temperature of mice which remains to be further explored. It must then be assessed if this effect is extrapolable to man, and if this could lead to consequences on health.


Asunto(s)
Temperatura Corporal/efectos de la radiación , Peso Corporal/efectos de la radiación , Ondas de Radio , Animales , Temperatura Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Ratones , Naftiridinas/farmacología , Canales Catiónicos TRPM/antagonistas & inhibidores , Canales Catiónicos TRPM/metabolismo , Ganglio del Trigémino/metabolismo , Ganglio del Trigémino/efectos de la radiación
13.
Brasilia; s.n; 19 abr. , 2020. 39 p.
No convencional en Portugués | LILACS, BRISA/RedTESA, PIE | ID: biblio-1095204

RESUMEN

Na comparação 1: hidroxicloroquina (HCQ) versus grupo controle/terapia padrão: quanto a cura clínica, normalização da temperatura corporal e número de dias de tosse, o grupo da HCQ sugere benefício quando comparado ao grupo controle. Em termos de cura virológica e morte/progressão da doença após o início do tratamento com HCQ, não houve diferença significativa em relação ao grupo controle. Ainda nessa mesma comparação entre os grupos, quando realizado tratamento com HCQ, observou-se menos casos com progressão radiológica quando comparado ao grupo controle. Quando se avaliou a segurança, não houve diferença significativa entre os grupos. Na metanálise, foi verificado um benefício no grupo controle/tratamento padrão quanto à progressão radiológica. Na comparação 2: HCQ associado à azitromicina (AZT) ou outras drogas versus controle/terapia padrão: em um dos estudos, 100% dos pacientes estava com cura virológica ao usar HCQ/AZT no dia 6, comparado a 57,1% em monoterapia com HCQ. Em um dos estudos, o teste de PCR positivou novamente em um paciente que ficou negativo para a PCR por tratamento com HCQ + Azitromicina. Em um dos estudos, 11% da população em terapia combinada teve prolongamento significativo do QTc (> 500 ms) e o desenvolvimento de insuficiência renal aguda foi um importante preditor de prolongamento extremo do QTc. Ainda não se pode admitir o benefício da associação do tratamento da HCQ com a AZT, pois são necessários mais estudos clínicos para uma conclusão definitiva sobre essa associação.1


Asunto(s)
Humanos , Neumonía Viral/tratamiento farmacológico , Temperatura Corporal/efectos de los fármacos , Cloroquina/administración & dosificación , Cloroquina/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Azitromicina/administración & dosificación , Azitromicina/uso terapéutico , Evaluación de la Tecnología Biomédica , Progresión de la Enfermedad , Terapias en Investigación/instrumentación , Betacoronavirus/efectos de los fármacos
14.
J Zoo Wildl Med ; 51(1): 96-101, 2020 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-32212551

RESUMEN

Alfaxalone is a neurosteroid anesthetic agent that has been extensively used in both human and veterinary medicine for more than 50 yr. Previous studies involving avian species demonstrated various dose ranges and multiple routes of administration. The aim of this study was to evaluate the short-term sedative, cardiorespiratory, and thermoregulatory effects of an intramuscular injection of alfaxalone on budgerigars (Melopsittacus undulatus). A crossover study was performed with a sample size of 10 male budgerigars, previously determined to be healthy based on physical examination. Alfaxalone was administered intramuscularly at two doses: 15 and 20 mg/kg. The lower dose resulted in mild to moderate sedation for 29 ± 5 min, whereas the higher dose resulted in moderate to profound sedation for 29 ± 7 min. A statistically significant decrease in heart rate was observed 2 min after administration of alfaxalone at 15 mg/kg; however, this finding was noted to be transient. A statistically significant decrease in respiratory rate was observed at 6 and 10 min after injection in both groups. Cloacal temperature measurement with a digital thermometer and eye temperature calculated from thermographic images demonstrated a decrease in body temperature over time but was not found to be statistically significant. Intramuscular use of alfaxalone proved to provide short-term sedation in budgerigars, with statistically significant but clinically mild cardiorespiratory effects. Due to a significant decrease in body temperature, active warming is recommended when using alfaxalone in budgerigars.


Asunto(s)
Anestésicos/administración & dosificación , Temperatura Corporal/efectos de los fármacos , Sedación Consciente/veterinaria , Melopsittacus/fisiología , Pregnanodionas/administración & dosificación , Frecuencia Respiratoria/efectos de los fármacos , Animales , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Inyecciones Intramusculares/veterinaria , Masculino , Distribución Aleatoria
15.
Med Sci Monit ; 26: e919213, 2020 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-32034118

RESUMEN

BACKGROUND This study aimed to investigate the effects of dexmedetomidine in a rat model of sepsis-induced lung injury and the role of the adenosine monophosphate-activated protein kinase (AMPK) gene and silent information regulator 1 (SIRT1) gene signaling pathway. MATERIAL AND METHODS Sixty 28-week-old healthy male Sprague-Dawley rats were randomly divided into three groups, the sham group, the model group, and the dexmedetomidine-treated group. The rat model of sepsis-induced lung injury was developed by surgical cecal ligation and puncture. Lung tissues examined histologically in the three study groups. Cell apoptosis was measured using the TUNEL assay, and the expression of inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-1ß (IL-1ß), and IL-10 were measured in rat lung tissue by enzyme-linked immunosorbent assay (ELISA). Apoptosis-associated proteins and AMPK/SIRT1 pathway-associated protein expression levels were detected using Western blot. RESULTS Dexmedetomidine significantly increased the survival rate and reduced the body temperature of rats in the model group with sepsis-induced lung injury, reduced lung injury, significantly reduced apoptosis in lung tissues, and reduced the expression levels of TNF-alpha, and IL-1ß, and increased the levels of IL-10. Dexmedetomidine significantly reduced the expression of caspase-3 in the rat lung tissue (P<0.01), and significantly increased the expression of Bcl-2/Bax and the phosphorylation levels of AMPK, SIRT1, nuclear factor-kappaB (NF-kappaB), and forkhead box class O 3a (FOXO3a). CONCLUSIONS In a rat model of sepsis-induced lung injury, dexmedetomidine reduced lung damage by activating the AMPK/SIRT1 signaling pathway and reduced the expression of inflammatory cytokines and cell apoptosis.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Dexmedetomidina/uso terapéutico , Lesión Pulmonar/tratamiento farmacológico , Lesión Pulmonar/etiología , Sepsis/complicaciones , Transducción de Señal , Sirtuina 1/metabolismo , Animales , Apoptosis/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Citocinas/metabolismo , Dexmedetomidina/farmacología , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Pulmón/enzimología , Pulmón/patología , Lesión Pulmonar/enzimología , Masculino , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia
16.
Eur J Pharmacol ; 871: 172934, 2020 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-31954706

RESUMEN

The TRPV1 ion channel is a neuronal sensor that plays an important role in nociception and neuropathic as well as inflammatory pain. In clinical trials, hyperthermia and thermo-hypoaesthesia turned out as major side effects of TRPV1 antagonists, preventing successful development of such molecules as analgesics. In vitro studies demonstrated that the TRPV1 ion channel is a polymodal sensor integrating stimuli from molecular modulators with temperature, pH and transmembrane potential. Temperature dependent gating is suggested to constitute the molecular basis for its role in heat sensation and body temperature regulation. Drug discovery scientists since many years seek to obtain "thermoneutral" TRPV1 inhibitors, blocking the channels sensitivity for painful stimuli while keeping its temperature mode of activation unaffected. Aiming for a screening rational for the identification of thermoneutral TRPV1 antagonists, we broadly characterized the prototypic small molecule TRPV1 inhibitors GRT12360V and GRTE16523. In vitro, GRT12360V demonstrated pan-modality inhibition on human, cynomolgus and rodent TRPV1, whereas GRTE16523 selectively bypassed the channels temperature mode on human and cynomolgus TRPV1 and revealed partial agonism on rodent channels. Strikingly, in vivo, GRT12360V induced hyperthermia in all species tested whereas GRTE16523 proved thermoneutral in cynomolgus monkeys and induced hypothermia in rodents. Hence, working out the different in vitro to in vivo correlations of two compounds, we suggest temperature dependent voltage gating as key parameter when screening for thermoneutral TRPV1 inhibitors. We highlight a species difference of molecular TRPV1 pharmacology between primates and rodents and provide a methodological breakthrough to engineer thermoneutral TRPV1 antagonists with improved therapeutic safety.


Asunto(s)
Canales Catiónicos TRPV/antagonistas & inhibidores , Temperatura , Animales , Temperatura Corporal/efectos de los fármacos , Células CHO , Cricetulus , Células HEK293 , Humanos , Activación del Canal Iónico/efectos de los fármacos , Macaca fascicularis , Canales Catiónicos TRPV/metabolismo
17.
Anesth Analg ; 130(4): 983-990, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31274602

RESUMEN

BACKGROUND: In this randomized, triple-blind, placebo-controlled trial, we tested the hypothesis that perioperative acetaminophen administration has a prophylactic effect on postoperative shivering. METHODS: Forty-five women scheduled for gynecological laparotomy were randomized to either the acetaminophen or the placebo groups. After induction of general anesthesia, the test drug (acetaminophen 15 mg/kg) or placebo (0.9% saline) was intravenously administered over 15 minutes. The primary outcome measure was the incidence of severe postoperative shivering (ie, shivering score >2) in the postanesthesia care unit, where patients stayed for 30 minutes after their emergence from anesthesia. For the secondary outcomes, core body temperature (BT) was recorded at the forehead just before anesthesia induction (time 0 [T0]), at the start of surgery (time 1 [T1]), at the end of surgery (time 2 [T2]), at the initiation of postoperative observation in the postanesthesia care unit (time 3 [T3]), and 30 minutes after T3 (time 4 [T4]). At 1 hour after T4 (ie, time 5 [T5]), the BT was recorded from the axilla (BTA). Primary outcome was analyzed using a χ test. BT recorded at the forehead (BTF) and BTA were analyzed using a 2-way repeated-measures analysis of variance (ANOVA) and a 2-sample t test, respectively. For all comparisons, a P value <.05 was considered statistically significant. RESULTS: The study duration was 2 years. Of the 45 patients initially enrolled, 8 patients were excluded. The acetaminophen and placebo groups included 18 and 19 patients, respectively. The incidence of severe postoperative shivering in the postanesthesia care unit was significantly lower in the acetaminophen group (22.2%) than in the placebo group (73.7%) (relative risk, 0.302; 95% confidence interval, 0.122-0.746; P = .005). Two-way repeated-measures ANOVA showed a significant effect of time (F4,140 = 54.8; P < .001) and a significant time by treatment interaction (F4,140 = 9.61; P < .001) but did not show a main effect of the treatment (F1,35 = 1.83; P = .185) in BTF. Moreover, BTA at T5 was significantly lower in the acetaminophen group (mean [standard deviation {SD}], 37.2°C [0.48°C]) than in the placebo group (37.9°C [0.63°C]; P < .001). CONCLUSIONS: Our findings in patients undergoing gynecological laparotomy suggest that perioperative acetaminophen administration can prevent postoperative severe shivering. This prophylactic effect might be due to suppressing the postoperative increase in the BT set point, rather than lowering the threshold for shivering, as observed with clonidine.


Asunto(s)
Acetaminofén/uso terapéutico , Analgésicos no Narcóticos/uso terapéutico , Complicaciones Posoperatorias/prevención & control , Tiritona/efectos de los fármacos , Adulto , Anciano , Temperatura Corporal/efectos de los fármacos , Femenino , Procedimientos Quirúrgicos Ginecológicos , Humanos , Incidencia , Laparotomía , Persona de Mediana Edad , Cuidados Posoperatorios , Resultado del Tratamiento
18.
J Ethnopharmacol ; 248: 112271, 2020 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-31586693

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Gui Zhi Tang, a well-known Chinese herbal formula recorded in the Eastern Han Dynasty, has been widely used to treat exogenous cold for thousands of years. Recent studies have shown that Gui Zhi Tang has the effect of regulating the body temperature. Because of its effect on heat production, protecting vital organs of the body and avoiding damage from the cold environment, Jiang Gui Fang (JG) was obtained from the Department of Traditional Chinese Medicine at the General Hospital of Northern Theatre Command where it has been used clinically for many years and has exhibited favourable efficacy. Based on research on Gui Zhi Tang, the principles of traditional Chinese medicine and survey of a large number of studies, this empirical formula was developed. The composition of JG included Dried ginger, Cassia twig, and Liquorice in Gui Zhi Tang, which play a major role in the treatment of exogenous cold, and combined these components with other Chinese medicines, such as Pueraria, Spatholobus, Acanthopanacis cortex, Evodiae fructus, and Codonopsis pilosula. AIM OF THE STUDY: To promote the core body temperature and prevent invasion of the major organs from the cold environment, we studied the effect of JG on the core body temperature of mice and then explored its regulation of interscapular brown adipose tissue (iBAT) and epididymal white adipose tissue (eWAT) and the possible mechanism. Finally, we determined the phytochemical composition of JG that plays a role in heat production. MATERIALS AND METHODS: In vivo study, we performed a 4-week treatment of JG in acute cold environment at -20 °C and chronic cold exposure at 4 °C. The core temperature, adipose tissue weight, serum parameters, and morphological observation of adipocytes, liver and kidney were measured. Then we investigated the expression levels of adipogenic factors, thermogenic factors and lipoprotein. In vitro, we determined the lipid droplet content, ATP content, and the maximum oxygen consumption of mitochondria. RESULTS: JG treatment promoted core temperature, inhibited eWAT weight, protected liver, and reduced glucose and lipids in Kunming (KM) mice. JG also increased the expression of BAT-associated thermogenic factors, including uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α). The levels of the lipogenic factor peroxisome proliferate-activator receptor gamma (PPARγ) and the lipolytic protein hormone-sensitive triglyceride lipase (HSL) in eWAT were elevated. The results of H&E and immunohistochemistry showed that JG significantly reduced the size of iBAT and eWAT and increased the content of UCP1. In vitro, JG reduced the content of lipid droplets and ATP in brown fat cells. The maximum oxygen consumption capacity of mitochondria and the expression levels of UCP1, PGC1α and silent mating type information regulation 2 homologue 1 (SIRT1) were enhanced after JG treatment. CONCLUSIONS: In vivo and in vitro studies, the results demonstrated that JG obviously increased the core temperature of mice by activating iBAT and inducing eWAT browning, which proved the mechanism is closely related to the PPARγ/SIRT1- PGC1α pathway. In this paper, we will provide a reference for further study of iBAT activation and eWAT browning.


Asunto(s)
Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , PPAR gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Sirtuina 1/metabolismo , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Masculino , Ratones
19.
Phytomedicine ; 74: 152815, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-30833146

RESUMEN

BACKGROUND: According to traditional Chinese medicine (TCM) theory, the herbal property is the most important guiding principle of ancient medication in China. The classification of warm- and cold-stimulating TCM is defined mainly based on the effects of herbs in regulating body temperature; however, the underlying mechanism of such distinction has not been fully identified. METHODS: Here, four commonly used spleen-meridian herbs, Ginseng Radix and Astragali Radix as typical warm-stimulating herbs, and Nelumbinis Semen and Coicis Semen as typical cold-stimulating herbs, were selected to test their effects in regulating body temperature, as well as its triggered thermo-regulatory factors and energy related metabolites, in yeast-induced fever rats. RESULTS: The intake of Astragali Radix increased body temperature in yeast-induced fever rats; while Coicis Semen showed cooling effects in such rats. In parallel, the levels of cAMP, PGE2 and thermo-related metabolites, including choline, creatine, alanine, lactate and leucine, in the blood of yeast-induced rats were increased significantly by the intake of Astragali Radix. Oppositely, the cold-stimulating herbs, Nelumbinis Semen and Coicis Semen, showed cooling effects by increasing certain metabolites, e.g. histidine, tyrosine, lipid, myo-inositol, as well as AVP level. CONCLUSION: Here, we compared different effects of warm and cooling spleen-meridian herbs in the regulation of body temperature. By providing an intuitive comparison of thermo-regulatory factors and related metabolites after intake of selected herbs, the mechanism behind the warm and cooling effects of specific herbs were revealed.


Asunto(s)
Regulación de la Temperatura Corporal/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Animales , Coix/química , Medicamentos Herbarios Chinos/química , Fiebre/tratamiento farmacológico , Fiebre/etiología , Masculino , Medicina China Tradicional/métodos , Meridianos , Panax/química , Plantas Medicinales/química , Ratas Endogámicas , Bazo , Levaduras/patogenicidad
20.
J Pineal Res ; 68(1): e12619, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31677295

RESUMEN

Modern 24-h society lifestyle is associated with experiencing frequent shifts in the lighting conditions which can negatively impact human health. Here, we use the degus, a species exhibiting diurnal and nocturnal chronotypes, to: (a) assess the impact of chronic shifts of the light:dark (LD) cycle in the animal's physiology and behaviour and (b) test the therapeutic potential of melatonin in enhancing rhythmicity under these conditions. Degus were subjected to a "5d + 2d" LD-shifting schedule for 19 weeks. This protocol aims to mimic lighting conditions experienced by humans during shift work: LD cycle was weekly delayed by 8h during 5 "working" days (Morning, Afternoon and Night schedule); during weekends (2 days), animals were kept under Morning schedule. After 9 weeks, melatonin was provided daily for 6h in the drinking water. The "5d + 2d" shifting LD schedule led to a disruption in wheel-running activity (WRA) and body temperature (Tb) rhythms which manifested up to three separate periods in the circadian range. This chronodisruption was more evident in nocturnal than in diurnal degus, particularly during the Afternoon schedule when a phase misalignment between WRA and Tb rhythms appeared. Melatonin treatment and, to a lesser extent, water restriction enhanced the 24-h component, suggesting a potential role in ameliorating the disruptive effects of shift work.


Asunto(s)
Ritmo Circadiano , Melatonina/farmacología , Octodon/fisiología , Animales , Temperatura Corporal/efectos de los fármacos , Temperatura Corporal/efectos de la radiación , Trastornos Cronobiológicos/fisiopatología , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/efectos de la radiación , Masculino , Modelos Animales , Fotoperiodo
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