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1.
Cochrane Database Syst Rev ; 3: CD001337, 2021 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-33705565

RESUMEN

BACKGROUND: Retained placenta is a common complication of pregnancy affecting 1% to 6% of all births. If a retained placenta is left untreated, spontaneous delivery of the placenta may occur, but there is a high risk of bleeding and infection. Manual removal of the placenta (MROP) in an operating theatre under anaesthetic is the usual treatment, but is invasive and may have complications. An effective non-surgical alternative for retained placenta would potentially reduce the physical and psychological trauma of the procedure, and costs. It could also be lifesaving by providing a therapy for settings without easy access to modern operating theatres or anaesthetics. Injection of uterotonics into the uterus via the umbilical vein and placenta is an attractive low-cost option for this. This is an update of a review last published in 2011. OBJECTIVES: To assess the use of umbilical vein injection (UVI) of saline solution with or without uterotonics compared to either expectant management or with an alternative solution or other uterotonic agent for retained placenta. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (14 June 2020), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing UVI of saline or other fluids (with or without uterotonics), either with expectant management or with an alternative solution or other uterotonic agent, in the management of retained placenta. We considered quasi-randomised, cluster-randomised, and trials reported only in abstract form. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data, and checked them for accuracy. We assessed the certainty of the evidence using the GRADE approach. We calculated pooled risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs), and presented results using 'Summary of findings' tables. MAIN RESULTS: We included 24 trials (n = 2348). All included trials were RCTs, one was quasi-randomised, and none were cluster-randomised. Risk of bias was variable across the included studies. We assessed certainty of evidence for four comparisons: saline versus expectant management, oxytocin versus expectant management, oxytocin versus saline, and oxytocin versus plasma expander. Evidence was moderate to very-low certainty and downgraded for risk of bias of included studies, imprecision, and inconsistency of effect estimates. Saline solution versus expectant management There is probably little or no difference in the incidence of MROP between saline and expectant management (RR 0.93, 95% CI 0.80 to 1.10; 5 studies, n = 445; moderate-certainty evidence). Evidence for the following remaining primary outcomes was very-low certainty: severe postpartum haemorrhage 1000 mL or greater, blood transfusion, and infection. There were no events reported for maternal mortality or postpartum anaemia (24 to 48 hours postnatal). No studies reported addition of therapeutic uterotonics. Oxytocin solution versus expectant management UVI of oxytocin solution might slightly reduce in the need for manual removal compared with expectant management (mean RR 0.73, 95% CI 0.56 to 0.95; 7 studies, n = 546; low-certainty evidence). There may be little to no difference between the incidence of blood transfusion between groups (RR 0.81, 95% CI 0.47 to 1.38; 4 studies, n = 339; low-certainty evidence). There were no maternal deaths reported (2 studies, n = 93). Evidence for severe postpartum haemorrhage of 1000 mL or greater, additional uterotonics, and infection was very-low certainty. There were no events for postpartum anaemia (24 to 48 hours postnatal). Oxytocin solution versus saline solution UVI of oxytocin solution may reduce the use of MROP compared with saline solution, but there was high heterogeneity (RR 0.82, 95% CI 0.69 to 0.97; 14 studies, n = 1370; I² = 54%; low-certainty evidence). There were no differences between subgroups according to risk of bias or oxytocin dose for the outcome MROP. There may be little to no difference between groups in severe postpartum haemorrhage of 1000 mL or greater, blood transfusion, use of additional therapeutic uterotonics, and antibiotic use. There were no events for postpartum anaemia (24 to 48 hours postnatal) (very low-certainty evidence) and there was only one event for maternal mortality (low-certainty evidence). Oxytocin solution versus plasma expander One small study reported UVI of oxytocin compared with plasma expander (n = 109). The evidence was very unclear about any effect on MROP or blood transfusion between the two groups (very low-certainty evidence). No other primary outcomes were reported. For other comparisons there were little to no differences for most outcomes examined. However, there was some evidence to suggest that there may be a reduction in MROP with prostaglandins in comparison to oxytocin (4 studies, n = 173) and ergometrine (1 study, n = 52), although further large-scale studies are needed to confirm these findings. AUTHORS' CONCLUSIONS: UVI of oxytocin solution is an inexpensive and simple intervention that can be performed when placental delivery is delayed. This review identified low-certainty evidence that oxytocin solution may slightly reduce the need for manual removal. However, there are little or no differences for other outcomes. Small studies examining injection of prostaglandin (such as dissolved misoprostol) into the umbilical vein show promise and deserve to be studied further.


Asunto(s)
Oxitócicos/administración & dosificación , Oxitocina/administración & dosificación , Retención de la Placenta/terapia , Antibacterianos/uso terapéutico , Sesgo , Transfusión Sanguínea/estadística & datos numéricos , Femenino , Humanos , Inyecciones Intravenosas , Sustitutos del Plasma/administración & dosificación , Embarazo , Prostaglandinas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Cloruro de Sodio/administración & dosificación , Venas Umbilicales
2.
Undersea Hyperb Med ; 48(1): 25-31, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33648030

RESUMEN

Background: The treatment of decompression sickness (DCS) with hyperbaric oxygen (HBO2) serves to decrease intravascular bubble size, increase oxygen (O2) delivery to tissue and enhance the elimination of inert gas. Emulsified perfluorocarbons (PFC) combined with breathing O2 have been shown to have similar effects animal models. We studied an ovine model of severe DCS treated with the intravenous PFC Oxycyte™ while breathing O2 compared to saline control also breathing O2. Methods: Juvenile male sheep (N=67; weight 24.4±2.10kg) were compressed to 257 feet of sea water (fsw) in our multiple large-animal chamber where they remained under pressure for 31 minutes. Animals then were decompressed to surface pressure and randomized to receive either Oxycyte at 5mL/kg intravenously (IV) or 5mL/kg saline IV (both receiving 100% O2) 10 minutes after reaching surface pressure. Mortality was recorded at two hours, four hours, and 24 hours after receiving the study drug. Surviving animals underwent perfusion fixation and harvesting of the spinal cord at 24 hours. Spinal cord sections were assessed for volume of lesion area and compared. Results: There was no significant difference in survival at two hours (p=0.2737), four hours (p=0.2101), or 24 hours (p=0.3171). Paralysis at 24 hours was not significantly different. However, spinal cord lesion area was significantly smaller in the Oxycyte group as compared to the saline group, with median spinal cord lesion areas 0.65% vs. 0.94% (p=0.0107). Conclusion: In this ovine model of severe DCS the intravenous PFC Oxycyte did not reduce mortality but did ameliorate spinal cord injury when used after the onset of DCS.


Asunto(s)
Enfermedad de Descompresión/terapia , Fluorocarburos/uso terapéutico , Terapia por Inhalación de Oxígeno/métodos , Traumatismos de la Médula Espinal/prevención & control , Animales , Enfermedad de Descompresión/complicaciones , Enfermedad de Descompresión/mortalidad , Modelos Animales de Enfermedad , Fluorocarburos/administración & dosificación , Inyecciones Intravenosas , Masculino , Parálisis/etiología , Distribución Aleatoria , Solución Salina/administración & dosificación , Agua de Mar , Ovinos , Traumatismos de la Médula Espinal/patología , Factores de Tiempo
3.
Medicine (Baltimore) ; 100(9): e25044, 2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33655983

RESUMEN

RATIONALE: Chronic disseminated intravascular coagulation (DIC) associated with thoracic aortic aneurysm is characterized by enhanced fibrinolysis and is thought to be stable in the compensated/asymptomatic stage, with few bleeding symptoms. However, DIC can lead to decompensated/hemorrhagic stage disseminated intravascular coagulation, resulting in severe bleeding diathesis, and there is currently no established strategy for treatment of DIC in aortic aneurysms. PATIENT CONCERNS: A 77-year-old woman underwent angiography and cardiac catheterization, before descending aortic replacement surgery. She developed DIC in postprocedure week 2 with extensive, uncontrollable massive subcutaneous hemorrhage. DIAGNOSES: Her acute-phase DIC score was 7 points, and the risk of mortality within 30 days after surgery according to the JapanSCORE was estimated to be 33.6%. INTERVENTIONS: Therapy was a combination of recombinant human soluble thrombomodulin (rhTM) and an aortic stent-graft treatment. OUTCOMES: Short-term improvements were seen in both DIC and bleeding diathesis. The thoracic aortic aneurysm with severe DIC was eventually corrected by administration of rhTM. LESSONS: We report the use of rhTM as an effective, novel anticoagulant drug with anti-inflammatory activity for treating DIC with suppressed fibrinolysis, which is typically associated with sepsis. In patients with a high hemorrhagic diathesis, in whom preoperative control of DIC cannot be achieved with conventional anticoagulation and radical surgical repair cannot be performed, a combination of rhTM and endovascular therapy may be a powerful new treatment option.


Asunto(s)
Aneurisma de la Aorta Torácica/etiología , Coagulación Intravascular Diseminada/tratamiento farmacológico , Cuidados Preoperatorios/métodos , Trombomodulina/administración & dosificación , Procedimientos Quirúrgicos Vasculares , Anciano , Angiografía , Aneurisma de la Aorta Torácica/diagnóstico , Aneurisma de la Aorta Torácica/cirugía , Coagulación Intravascular Diseminada/complicaciones , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inyecciones Intravenosas , Proteínas Recombinantes/administración & dosificación
4.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-33540815

RESUMEN

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.


Asunto(s)
Trastorno del Espectro Autista/complicaciones , Melatonina/farmacocinética , Trastornos Intrínsecos del Sueño/tratamiento farmacológico , Administración Oral , Adulto , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/psicología , Disponibilidad Biológica , Niño , Preescolar , Ritmo Circadiano , Preparaciones de Acción Retardada , Suplementos Dietéticos , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Melatonina/administración & dosificación , Melatonina/análogos & derivados , Melatonina/fisiología , Melatonina/uso terapéutico , Melatonina/orina , Receptores de Melatonina/fisiología , Saliva/química , Estaciones del Año , Serotonina/metabolismo , Trastornos Intrínsecos del Sueño/etiología , Trastornos Intrínsecos del Sueño/fisiopatología , Latencia del Sueño/efectos de los fármacos , Trastorno de la Conducta Social/tratamiento farmacológico , Trastorno de la Conducta Social/etiología , Triptófano/metabolismo
5.
Braz J Anesthesiol ; 71(1): 79-83, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33518836

RESUMEN

The management of acute hypoxemic respiratory failure and the effect of antiviral drugs in patients with severe COVID-19 have been debated. This case presents the management of a 64-year-old man COVID-19 patient admitted to the Intensive Care Unit with fever, fatigue, shortness of breath and hemophagocytic lymphohistiocytosis syndrome. Helmet mask was successfully used to treat his hypoxemic respiratory failure without any aerosol problems. Tocilizumab, an antagonist interleukin-6, was intravenously infused as an alternative drug. After administration, the high level of IL-6, CRP, ferritin, D-dimer, triglyceride, and H-scores decreased, and the patient observed good clinical and laboratory improvements. In this case report, we describe the effect of noninvasive ventilation delivered by helmet mask and antiviral drugs, and the intravenous administration of tocilizumab in a patient with hemophagocytic lymphohistiocytosis syndrome and COVID-19.


Asunto(s)
/complicaciones , Linfohistiocitosis Hemofagocítica/complicaciones , Máscaras , Ventilación no Invasiva/métodos , Insuficiencia Respiratoria/terapia , Anticuerpos Monoclonales Humanizados/administración & dosificación , Humanos , Inyecciones Intravenosas , Interleucina-6/antagonistas & inhibidores , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Insuficiencia Respiratoria/sangre
6.
J Allergy Clin Immunol ; 147(4): 1217-1225, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33556464

RESUMEN

BACKGROUND: IL-1 plays a pivotal role in the inflammatory response during cytokine storm syndromes. OBJECTIVE: Our aim was to analyze the efficacy and safety of early anti-inflammatory treatment (AIT) with intravenous anakinra with or without glucocorticoids in coronavirus disease 2019 (COVID-19) pneumonia. METHODS: We performed a retrospective single-center cohort study of patients admitted for COVID-19 pneumonia from February 26 to April 29, 2020, to assess the efficacy of early AIT with intravenous anakinra (100 mg every 8 hours for 3 days, with tapering) alone or in combination with a glucocorticoid (intravenous methylprednisolone, 1-2 mg/kg daily, with tapering). The standard of care (SOC) treatment was hydroxychloroquine and/or azithromycin with or without antivirals and anticoagulants. Late rescue AIT with anakinra or tocilizumab was also evaluated. Treatment effect on overall survival was assessed by a propensity score-adjusted Cox model. RESULTS: A total of 128 patients were analyzed; 63 patients received early AIT (30 received anakinra alone and 33 received anakinra plus a glucocorticoid) at admission, and 65 patients did not receive early AIT and were used as controls; of the latter 65 patients, 44 received the SOC treatment alone and 21 received the SOC treatment plus late rescue AIT. After adjustment for all the unbalanced baseline covariates, early AIT reduced the hazard of mortality by 74% (adjusted hazard ratio [HR] = 0.26; P < .001). The effect was similar in patients receiving anakinra alone (adjusted HR = 0.28; P = .04) and anakinra plus a glucocorticoid (adjusted HR = 0.33; P = .07). Late rescue treatment did not show a significant advantage over SOC treatment alone (adjusted HR = 0.82; P = .70). CONCLUSIONS: This study suggests, on a larger series of patients with COVID-19 pneumonia, the potential efficacy and safety of the early use of high doses of intravenous anakinra with or without glucocorticoids.


Asunto(s)
Antiinflamatorios/administración & dosificación , Glucocorticoides/administración & dosificación , Proteína Antagonista del Receptor de Interleucina 1/administración & dosificación , Anciano , Anciano de 80 o más Años , Proteína C-Reactiva/metabolismo , /fisiopatología , Estudios de Cohortes , Progresión de la Enfermedad , Esquema de Medicación , Femenino , Humanos , Inyecciones Intravenosas , Italia/epidemiología , Estimación de Kaplan-Meier , Masculino , Metilprednisolona/administración & dosificación , Persona de Mediana Edad , Pandemias , Respiración Artificial , Estudios Retrospectivos , Resultado del Tratamiento
7.
J Vis Exp ; (168)2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33616115

RESUMEN

Metastatic spread to the brain is a common and devastating manifestation of many types of cancer. In the United States alone, about 200,000 patients are diagnosed with brain metastases each year. Significant progress has been made in improving survival outcomes for patients with primary breast cancer and systemic malignancies; however, the dismal prognosis for patients with clinical brain metastases highlights the urgent need to develop novel therapeutic agents and strategies against this deadly disease. The lack of suitable experimental models has been one of the major hurdles impeding advancement of our understanding of brain metastasis biology and treatment. Herein, we describe a xenograft mouse model of brain metastasis generated via tail-vein injection of an endogenously HER2-amplified cell line derived from inflammatory breast cancer (IBC), a rare and aggressive form of breast cancer. Cells were labeled with firefly luciferase and green fluorescence protein to monitor brain metastasis, and quantified metastatic burden by bioluminescence imaging, fluorescent stereomicroscopy, and histologic evaluation. Mice robustly and consistently develop brain metastases, allowing investigation of key mediators in the metastatic process and the development of preclinical testing of new treatment strategies.


Asunto(s)
Neoplasias Encefálicas/secundario , Rastreo Celular/métodos , Neoplasias Inflamatorias de la Mama/patología , Inyecciones Intravenosas/métodos , Luciferasas de Luciérnaga/metabolismo , Animales , Femenino , Humanos , Luciferasas de Luciérnaga/genética , Ratones , Cola (estructura animal) , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
8.
J Zoo Wildl Med ; 51(4): 889-895, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33480569

RESUMEN

Koi carp (Cyprinus carpio), a variety of common carp, has gained popularity as an ornamental fish worldwide. Their high monetary and sentimental value has necessitated the development of antemortem diagnostic options. Contrast-enhanced computed tomography (CT) scanning with intravenous iopamidol has been shown to be safe and diagnostically effective at a minimum dose of 480 mg iodine (I)/kg in koi. The purpose of this study was to evaluate the pharmacokinetic parameters of this dose of iopamidol, as well as excretory mechanisms specific to fish, using common carp as a model. Blood, posterior kidney, gill, and bile were collected, necessitating sacrificial sampling. Thirty-five adult fish were randomly divided into six sampling groups. Five sampling groups (n = 6/group) received 480 mg I/kg; the control group (n = 5) received an equivalent volume of saline. The iopamidol groups were sampled at the following time points postinjection: 5 min, 1 hr, 6 hr, 24 hr, and 48 hr. The control group was sampled at 48 hr. Concentrations of iopamidol were determined using liquid chromatography tandem mass spectrometry; noncompartmental analysis was used to calculate pharmacokinetic parameters. Total clearance (3.04 ml/hr per kilogram) was slower, the volume of distribution smaller (79.92 ml/ kg), and the elimination half-life (20.39 hr) prolonged compared to similar studies in mammals. The time-concentration profiles of kidney and gill were similar; these organs appear to be responsible for the majority of iopamidol excretion. However, that of bile was much different, showing slower, low-level accumulation with time, suggesting that in fish, multiple organ systems play a role in elimination beyond just the kidney. In particular, they may rely more heavily upon biliary excretion, which thus far has been noted only in mammals with renal impairment. Further research is warranted to investigate if the slower elimination allows diagnostic CT images to be acquired at different time points postinjection.


Asunto(s)
Carpas/metabolismo , Medios de Contraste/farmacocinética , Yopamidol/farmacocinética , Animales , Área Bajo la Curva , Medios de Contraste/administración & dosificación , Semivida , Inyecciones Intravenosas/veterinaria , Yopamidol/administración & dosificación , Distribución Tisular
9.
Trials ; 22(1): 1, 2021 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397449

RESUMEN

OBJECTIVES: Conestat alfa, a recombinant human C1 esterase inhibitor, is a multi-target inhibitor of inflammatory cascades including the complement, the kinin-kallikrein and the contact activation system. The study objective is to investigate the efficacy and safety of conestat alfa in improving disease severity and short-term outcome in COVID-19 patients with pulmonary disease. TRIAL DESIGN: This study is an investigator-initiated, randomized (2:1 ratio), open-label, parallel-group, controlled, multi-center, phase 2a clinical trial. PARTICIPANTS: This trial is conducted in 3 hospitals in Switzerland, 1 hospital in Brazil and 1 hospital in Mexico (academic and non-academic). All patients with confirmed SARS-CoV-2 infection requiring hospitalization for at least 3 calendar days for severe COVID-19 will be screened for study eligibility. INCLUSION CRITERIA: - Signed informed consent - Age 18-85 years - Evidence of pulmonary involvement on CT scan or X-ray of the chest - Duration of symptoms associated with COVID-19 ≤ 10 days - At least one of the following risk factors for progression to mechanical ventilation on the day of enrolment: 1) Arterial hypertension 2) ≥ 50 years 3) Obesity (BMI ≥ 30 kg/m2) 4) History of cardiovascular disease 5) Chronic pulmonary disease 6) Chronic renal disease 7) C-reactive protein > 35mg/L 8) Oxygen saturation at rest of ≤ 94% when breathing ambient air Exclusion criteria: - Incapacity or inability to provide informed consent - Contraindications to the class of drugs under investigation (C1 esterase inhibitor) - Treatment with tocilizumab or another IL-6R or IL-6 inhibitor before enrolment - History or suspicion of allergy to rabbits - Pregnancy or breast feeding - Active or anticipated treatment with any other complement inhibitor - Liver cirrhosis (any Child-Pugh score) - Admission to an ICU on the day or anticipated within the next 24 hours of enrolment - Invasive or non-invasive ventilation - Participation in another study with any investigational drug within the 30 days prior to enrolment - Enrolment of the study investigators, their family members, employees and other closely related or dependent persons INTERVENTION AND COMPARATOR: Patients randomized to the experimental arm will receive conestat alfa in addition to standard of care (SOC). Conestat alfa (8400 U followed by 4200 U every 8 hours) will be administered as a slow intravenous injection (5-10 minutes) over a 72-hour period (i.e. 9 administrations in total). The first conestat alfa treatment will be administered on the day of enrolment. The control group will receive SOC only. SOC treatment will be administered according to local institutional guidelines, including supplemental oxygen, antibiotics, corticosteroids, remdesivir, and anticoagulation. MAIN OUTCOMES: The primary endpoint of this trial is disease severity on day 7 after enrolment assessed by an adapted WHO Ordinal Scale for Clinical Improvement (score 0 will be omitted and score 6 and 7 will be combined) from 1 (no limitation of activities) to 7 (death). Secondary outcomes include (i) the time to clinical improvement (time from randomization to an improvement of two points on the WHO ordinal scale or discharge from hospital) within 14 days after enrolment, (ii) the proportion of participants alive and not having required invasive or non-invasive ventilation at 14 days after enrolment and (iii) the proportion of subjects without an acute lung injury (defined by PaO2/FiO2 ratio of ≤300mmHg) within 14 days after enrolment. Exploratory outcomes include virological clearance, C1 esterase inhibitor pharmacokinetics and changes in routine laboratory parameters and inflammatory proteins. RANDOMISATION: Subjects will be randomised in a 2:1 ratio to treatment with conestat alfa in addition to SOC or SOC only. Randomization is performed via an interactive web response system (SecuTrial®). BLINDING (MASKING): In this open-label trial, participants, caregivers and outcome assessors are not blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): We will randomise approximately 120 individuals (80 in the active treatment arm, 40 in the SOC group). Two interim analyses after 40 and 80 patients are planned according to the Pocock adjusted levels αp = 0.0221. The results of the interim analysis will allow adjustment of the sample size (Lehmacher, Wassmer, 1999). TRIAL STATUS: PROTECT-COVID-19 protocol version 3.0 (July 07 2020). Participant recruitment started on July 30 2020 in one center (Basel, Switzerland, first participant included on August 06 2020). In four of five study centers patients are actively recruited. Participation of the fifth study center (Mexico) is anticipated by mid December 2020. Completion of trial recruitment depends on the development of the SARS-CoV-2 pandemic. TRIAL REGISTRATION: Clinicaltrials.gov, number: NCT04414631 , registered on 4 June 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Asunto(s)
/tratamiento farmacológico , Proteína Inhibidora del Complemento C1/administración & dosificación , /aislamiento & purificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Brasil , /diagnóstico , Ensayos Clínicos Fase II como Asunto , Proteína Inhibidora del Complemento C1/efectos adversos , Proteína Inhibidora del Complemento C1/farmacocinética , Esquema de Medicación , Femenino , Humanos , Inyecciones Intravenosas/métodos , Masculino , México , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Proyectos Piloto , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/farmacocinética , Índice de Severidad de la Enfermedad , Suiza , Resultado del Tratamiento , Adulto Joven
10.
Nutrients ; 13(1)2021 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-33466642

RESUMEN

Little information is available on the beneficial effects of cholecalciferol treatment in comorbid patients hospitalized for COVID-19. The aim of this study was to retrospectively examine the clinical outcome of patients receiving in-hospital high-dose bolus cholecalciferol. Patients with a positive diagnosis of SARS-CoV-2 and overt COVID-19, hospitalized from 15 March to 20 April 2020, were considered. Based on clinical characteristics, they were supplemented (or not) with 400,000 IU bolus oral cholecalciferol (200,000 IU administered in two consecutive days) and the composite outcome (transfer to intensive care unit; ICU and/or death) was recorded. Ninety-one patients (aged 74 ± 13 years) with COVID-19 were included in this retrospective study. Fifty (54.9%) patients presented with two or more comorbid diseases. Based on the decision of the referring physician, 36 (39.6%) patients were treated with vitamin D. Receiver operating characteristic curve analysis revealed a significant predictive power of the four variables: (a) low (<50 nmol/L) 25(OH) vitamin D levels, (b) current cigarette smoking, (c) elevated D-dimer levels (d) and the presence of comorbid diseases, to explain the decision to administer vitamin D (area under the curve = 0.77, 95% CI: 0.67-0.87, p < 0.0001). Over the follow-up period (14 ± 10 days), 27 (29.7%) patients were transferred to the ICU and 22 (24.2%) died (16 prior to ICU and six in ICU). Overall, 43 (47.3%) patients experienced the combined endpoint of transfer to ICU and/or death. Logistic regression analyses revealed that the comorbidity burden significantly modified the effect of vitamin D treatment on the study outcome, both in crude (p = 0.033) and propensity score-adjusted analyses (p = 0.039), so the positive effect of high-dose cholecalciferol on the combined endpoint was significantly amplified with increasing comorbidity burden. This hypothesis-generating study warrants the formal evaluation (i.e., clinical trial) of the potential benefit that cholecalciferol can offer in these comorbid COVID-19 patients.


Asunto(s)
/tratamiento farmacológico , Colecalciferol/uso terapéutico , Vitaminas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , /mortalidad , Colecalciferol/administración & dosificación , Femenino , Hospitalización , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Curva ROC , Estudios Retrospectivos , Resultado del Tratamiento , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/tratamiento farmacológico , Vitaminas/administración & dosificación
11.
Life Sci ; 268: 119014, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33412216

RESUMEN

AIMS: Hepatocyte growth factor (HGF) is a multifunctional cytokine that plays important roles in pancreatic physiology. Approvals of gene therapy drugs have highlighted gene therapy as an innovative new drug modality, but the very recent reports of deaths in clinical trials have provided a warning that high-dose gene therapy can cause dangerous liver toxicity. The present study aimed to develop a safe and low-dose but therapeutically effective adenovirus-mediated HGF gene therapy for streptozotocin (STZ)-induced type 1 diabetes (T1D) in mice. MAIN METHODS: A single intravenous injection of a low dose (3 × 108 plaque forming units) of adenoviral vector expressing the HGF gene under the transcriptional control of a strong promoter, i.e., the cytomegalovirus immediate-early enhancer and a modified chicken ß-actin promoter (Ad.CA-HGF), was given to T1D mice. KEY FINDINGS: Low-dose HGF gene therapy significantly attenuated the elevation of blood glucose concentrations at the acute phase of T1D, and this effect persisted for several weeks. Temporal upregulation of plasma insulin at the acute phase was maintained at a normal level in Ad.CA-HGF-treated mice, suggesting that the therapeutic mechanism may involve protection of the remaining ß-cells by HGF. Liver enzymes in plasma were not elevated in any of the mice, including the Ad.CA-HGF-treated animals, all of which looked healthy, suggesting the absence of lethal adverse effects observed in patients receiving high intravenous doses of viral vectors. SIGNIFICANCE: A low dose of intravenous Ad-mediated HGF gene therapy is clinically feasible and safe, and thus represents a new therapeutic strategy for treating T1D.


Asunto(s)
Adenoviridae/genética , Diabetes Mellitus Tipo 1/terapia , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Factor de Crecimiento de Hepatocito/genética , Animales , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/genética , Vectores Genéticos/genética , Vectores Genéticos/farmacología , Factor de Crecimiento de Hepatocito/administración & dosificación , Hiperglucemia/genética , Hiperglucemia/terapia , Inyecciones Intravenosas , Insulina/sangre , Hígado/enzimología , Masculino , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas
12.
Trials ; 22(1): 71, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33472675

RESUMEN

BACKGROUND: SARS-CoV-2, the virus that causes COVID-19, enters the cells through a mechanism dependent on its binding to angiotensin-converting enzyme 2 (ACE2), a protein highly expressed in the lungs. The putative viral-induced inhibition of ACE2 could result in the defective degradation of bradykinin, a potent inflammatory substance. We hypothesize that increased bradykinin in the lungs is an important mechanism driving the development of pneumonia and respiratory failure in COVID-19. METHODS: This is a phase II, single-center, three-armed parallel-group, open-label, active control superiority randomized clinical trial. One hundred eighty eligible patients will be randomly assigned in a 1:1:1 ratio to receive either the inhibitor of C1e/kallikrein 20 U/kg intravenously on day 1 and day 4 plus standard care; or icatibant 30 mg subcutaneously, three doses/day for 4 days plus standard care; or standard care alone, as recommended in the clinical trials published to date, which includes supplemental oxygen, non-invasive and invasive ventilation, antibiotic agents, anti-inflammatory agents, prophylactic antithrombotic therapy, vasopressor support, and renal replacement therapy. DISCUSSION: Accumulation of bradykinin in the lungs is a common side effect of ACE inhibitors leading to cough. In animal models, the inactivation of ACE2 leads to severe acute pneumonitis in response to lipopolysaccharide (LPS), and the inhibition of bradykinin almost completely restores the lung structure. We believe that inhibition of bradykinin in severe COVID-19 patients could reduce the lung inflammatory response, impacting positively on the severity of disease and mortality rates. TRIAL REGISTRATION: Brazilian Clinical Trials Registry Universal Trial Number (UTN) U1111-1250-1843. Registered on May/5/2020.


Asunto(s)
Bradiquinina/análogos & derivados , Proteína Inhibidora del Complemento C1/administración & dosificación , Insuficiencia Respiratoria/tratamiento farmacológico , Adulto , Bradiquinina/administración & dosificación , Bradiquinina/efectos adversos , Bradiquinina/antagonistas & inhibidores , Bradiquinina/inmunología , Bradiquinina/metabolismo , Antagonistas del Receptor de Bradiquinina B2/administración & dosificación , Antagonistas del Receptor de Bradiquinina B2/efectos adversos , Brasil , /inmunología , Ensayos Clínicos Fase II como Asunto , Proteína Inhibidora del Complemento C1/efectos adversos , Esquema de Medicación , Quimioterapia Combinada/efectos adversos , Quimioterapia Combinada/métodos , Humanos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Calicreínas/antagonistas & inhibidores , Calicreínas/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Insuficiencia Respiratoria/inmunología , Insuficiencia Respiratoria/virología , /patogenicidad , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
13.
Int J Pharm Compd ; 25(1): 52-61, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33503010

RESUMEN

The physical compatibility of cefiderocol for injection (prepared as a diluted 2% cefiderocol solution) with potential co-administration drug products is presented. The compatibility of cefiderocol with a selection of 91 intravenous drugs was tested at clinically relevant concentrations using the admixed volume ratio 1:1. Compatibility of the mixtures was determined by visual observations, turbidity, and particulate-matter measurements. The mixtures were examined immediately after mixing, and then at 1 hour and 4 hours thereafter at room temperature. When using 0.9% sodium chloride or 5% dextrose injection for diluents, solutions of dobutamine hydrochloride, esomeprazole sodium, methylprednisolone acetate, propofol, rocuronium bromide, amiodarone hydrochloride, famotidine, labetalol hydrochloride, mycophenolate mofetil, acyclovir sodium, amphotericin B, caspofungin acetate, doxycycline, posaconazole, diphenhydramine hydrochloride, and phenytoin sodium were found to cause visible cloudiness upon mixing with 2% cefiderocol in both diluents. Solutions of lorazepam, tobramycin sulfate, and vancomycin hydrochloride were determined incompatible by examining the mixtures with the aid of a Tyndall light. These 19 drugs were clearly incompatible with cefiderocol for injection by visual examination. In addition, solutions of iron sucrose and albumin were incompatible with 2% cefiderocol based on sub-visual tests for turbidity and/or particulate matter. Based on sub-visual data, the 0.9% sodium chloride admixture of aminophylline and 2% cefiderocol was incompatible, while inconclusive results were obtained for the 0.9% sodium chloride admixtures of 2% cefiderocol with amikacin sulfate. Similarly, the 5% dextrose admixtures of either ciprofloxacin or polymyxin B sulfate with 2% cefiderocol were incompatible, whereas data for phenylephrine hydrochloride morphine sulfate, or undiluted sodium bicarbonate were inconclusive. Overall, the 2% cefiderocol solution was physically compatible with 63 of 91 drugs challenged at 1:1 volume ratio in both 0.9% sodium chloride and 5% dextrose diluents for at least 4 hours at the concentrations tested in this study.


Asunto(s)
Cefalosporinas , Preparaciones Farmacéuticas , Incompatibilidad de Medicamentos , Estabilidad de Medicamentos , Inyecciones Intravenosas
14.
J Stroke Cerebrovasc Dis ; 30(3): 105595, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33450605

RESUMEN

BACKGROUND: Endovascular thrombectomy (EVT) is highly effective but may also lead to hemorrhagic transformation (HT) and edema, which may be more pronounced in severe ischemia. We sought to determine whether glibenclamide can attenuate HT and edema in a severe ischemia-reperfusion model that reflects EVT. METHODS: Using a transient middle cerebral artery occlusion (tMCAo) rodent model of stroke, we studied two rat cohorts, one without rt-PA and a second cohort treated with rt-PA. Glibenclamide or vehicle control was administered as an intravenous bolus at reperfusion, followed by continuous subcutaneous administration with an osmotic pump. RESULTS: Compared to vehicle control, glibenclamide improved neurological outcome (median 7, interquartile range [IQR 6-8] vs. control median 6 [IQR 0-6], p = 0.025), reduced stroke volume (323 ± 42 vs. 484 ± 60 mm3, p < 0.01), swelling volume (10 ± 4 vs. 28 ± 7%, p < 0.01) and water content (84 ± 1 vs. 85 ± 1%, p < 0.05). Glibenclamide administration also reduced HT based on ECASS criteria, densitometry (0.94 ± 0.1 vs. 1.15 ± 0.2, p < 0.01), and quantitative hemoglobin concentration (2.7 ± 1.5 vs. 6.2 ± 4.6 uL, p = 0.011). In the second cohort with rt-PA coadministration, concordant effects on HT were observed with glibenclamide. CONCLUSIONS: Taken together, these studies demonstrated that glibenclamide reduced the amount of edema and HT after severe ischemia. This study suggests that co-administration of glibenclamide may be worth further study in severe stroke patients treated with EVT with or without IV rt-PA.


Asunto(s)
Edema Encefálico/prevención & control , Gliburida/administración & dosificación , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Hemorragias Intracraneales/prevención & control , Fármacos Neuroprotectores/administración & dosificación , Daño por Reperfusión/tratamiento farmacológico , Animales , Edema Encefálico/diagnóstico por imagen , Edema Encefálico/patología , Modelos Animales de Enfermedad , Fibrinolíticos/farmacología , Infarto de la Arteria Cerebral Media/diagnóstico por imagen , Infarto de la Arteria Cerebral Media/patología , Infusiones Subcutáneas , Inyecciones Intravenosas , Hemorragias Intracraneales/diagnóstico por imagen , Hemorragias Intracraneales/patología , Masculino , Ratas Wistar , Daño por Reperfusión/diagnóstico por imagen , Daño por Reperfusión/patología , Terapia Trombolítica , Activador de Tejido Plasminógeno/farmacología
15.
Neurology ; 96(9): e1301-e1311, 2021 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-33472921

RESUMEN

OBJECTIVE: To determine the IV tissue plasminogen activator (tPA) treatment rate of patients with minor acute ischemic stroke (mAIS) at our centers and compare the frequency of MRI targets by treatment stratification and clinical severity, we evaluated clinical characteristics and baseline MRIs for tPA-treated and untreated patients. METHODS: Patients with ischemic stroke from 2015 to 2017 with admit NIH Stroke Scale (NIHSS) <6 were considered. The treated cohort received standard IV tPA and was screened with baseline MRI. The untreated cohort received no acute intervention and baseline MRI was <4 hours from onset. Patients were stratified into "clearly" and "not clearly" disabling deficits by NIHSS elements. Baseline MRI was evaluated by independent raters for AIS targets, with frequencies compared between groups. RESULTS: Of 255 patients with mAIS ≤4.5 hours from onset, 140 (55%) received IV tPA, accounting for 46% of all IV tPA patients (n = 305). Eighty-five percent (n = 119) were screened with baseline MRI and had significantly more frequent imaging targets compared to those untreated (n = 90). Of this treated cohort, 75% (n = 89) were not clearly disabling. Except for perfusion-diffusion mismatch (81% clearly disabling vs 56% not clearly disabling [p = 0.036]), there were no significant differences in the frequency of imaging targets across the treated cohort stratified by clinical severity. CONCLUSIONS: In MRI-screened mAIS, imaging targets were more frequently seen in patients treated with IV tPA, with similar frequencies even in those without clearly disabling deficits. MRI targets could be used to guide thrombolytic therapy in patients with mAIS; however, a randomized trial is needed to demonstrate efficacy.


Asunto(s)
/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Activadores Plasminogénicos/uso terapéutico , Activador de Tejido Plasminógeno/uso terapéutico , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Evaluación de la Discapacidad , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Activadores Plasminogénicos/administración & dosificación , Recuperación de la Función , Tiempo de Tratamiento , Activador de Tejido Plasminógeno/administración & dosificación , Resultado del Tratamiento
16.
Carbohydr Polym ; 254: 117476, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33357929

RESUMEN

Herein the nucleic acid aptamers were attached to the polydeoxyadenylic acid (poly(dA)) tail for improving the tumor-targetability and cellular internalization of s-LNT/poly(dA) composite composed of two single chains of triple helical ß-glucan lentinan (s-LNT) and one poly(dA) chain. The in vitro results demonstrate that the cellular uptake of s-LNT/poly(dA) composites in MCF-7 cancer cells was enhanced effectively after attaching the aptamer. The as-prepared fluorescin isothiocyanate (FITC)-labelled LNT (LNT-FITC) through grafting was used for tracing the enhanced tumor-targetability of the composites. As a result, the cellular internalization of the LNT-FITC into MCF-7 and 4T1 cancer cells was further increased by the aptamer conjugated to poly(dA). Meanwhile, the in vivo experiments further demonstrate more s-LNT/poly(dA)-aptamer composites were effectively accumulated at the tumor site compared with s-LNT alone. This work provides a novel strategy for fabricating triplex ß-glucan as delivery vectors with active tumor-targetability.


Asunto(s)
Antineoplásicos/farmacología , Aptámeros de Nucleótidos/administración & dosificación , Lentinano/farmacología , Neoplasias Mamarias Experimentales/terapia , Terapia Molecular Dirigida/métodos , Poli A/administración & dosificación , Animales , Antineoplásicos/química , Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/genética , Línea Celular Tumoral , Portadores de Fármacos , Femenino , Fluoresceína-5-Isotiocianato/química , Colorantes Fluorescentes/química , Humanos , Inyecciones Intravenosas , Lentinano/química , Células MCF-7 , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Poli A/química , Poli A/genética , Coloración y Etiquetado/métodos
17.
Anal Chem ; 93(3): 1433-1442, 2021 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-33369405

RESUMEN

Glycosaminoglycans (GAGs) contribute to the treatment of many human diseases, especially in the field of thrombosis, because of their anticoagulant activity. GAGs interrupt the coagulation process by interacting with multiple coagulation factors through defined sequences within their linear and negatively charged chains, which are not fully elucidated. Numerous methods have been developed to characterize the structure of pharmaceutical GAGs, including intravenously or subcutaneously administered heparin and orally administered sulodexide. However, most currently available methods only focus on the oligosaccharide portion or analyze the whole mixture because longer-chain polysaccharides are extremely difficult to resolve by chromatographic separation. We have established two novel electrophoresis-mass spectrometry methods to provide a panoramic view of the structures of pharmaceutical GAGs. In the first method, an in-gel digestion procedure was developed to recover GAGs from the polyacrylamide gels, while in the second method, a strong anion exchange ultrafiltration procedure was developed to extract multiple GAG species from the agarose gels. Both procedures are compatible with liquid chromatography-tandem mass spectrometry, and structural information, such as disaccharide composition and chain length, can be revealed for each GAG fraction. The applications of these two methods on analysis of two different GAG drugs, heparin and sulodexide, were demonstrated. The current study offers the first robust tool to directly elucidate the structure of larger GAG chains with more biological importance rather than obtaining a vague picture of all chains as a mixture, which is fundamental for better understanding the structure-activity relationship and quality control of the GAG drugs.


Asunto(s)
Glicosaminoglicanos/análisis , Heparina/análisis , Administración Oral , Cromatografía Liquida , Electroforesis , Glicosaminoglicanos/administración & dosificación , Heparina/administración & dosificación , Humanos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Espectrometría de Masas en Tándem
18.
Methods Mol Biol ; 2223: 151-157, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33226593

RESUMEN

The regulation of vascular permeability is critical in inflammation. It controls the distribution of water and plasma contents such as immunoglobulins in peripheral tissues. To regulate allergic diseases, it is important to study vascular biology especially in inflammation. Since the vascular permeability changes in minutes upon the exposure to proinflammatory mediators, intravital imaging system is a powerful technique to capture such dynamic responses. We here describe how to evaluate vascular permeability in vivo using multiphoton microscopy. We use various sizes of fluorescence-labeled dextran to visualize how leaky the blood vessels are in the steady state and in inflammation. Using this assay system, we can illustrate the dynamic kinetics of vascular permeability in vivo in real-time. This assay system provides a novel convenient way to study vascular biology that is beneficial in the assessment of various animal models of allergic disease.


Asunto(s)
Permeabilidad Capilar/efectos de los fármacos , Dextranos/metabolismo , Fluoresceína-5-Isotiocianato/análogos & derivados , Histamina/farmacología , Hipersensibilidad Inmediata/diagnóstico por imagen , Microscopía Intravital/métodos , Microscopía de Fluorescencia por Excitación Multifotónica/métodos , Animales , Oído/irrigación sanguínea , Oído/diagnóstico por imagen , Fluoresceína-5-Isotiocianato/metabolismo , Colorantes Fluorescentes/metabolismo , Hipersensibilidad Inmediata/inducido químicamente , Inyecciones Intravenosas , Microscopía Intravital/instrumentación , Ratones Endogámicos BALB C , Microscopía de Fluorescencia por Excitación Multifotónica/instrumentación , Peso Molecular , Imagen de Lapso de Tiempo
19.
Med Hypotheses ; 146: 110421, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33308935

RESUMEN

BACKGROUND: Infection with SARS-CoV-2 is responsible for the COVID-19 crisis affecting the whole world. This virus can provoke acute respiratory distress syndrome (ARDS) leading to overcrowed the intensive care unit (ICU). Over the last months, worldwide experience demonstrated that the ARDS in COVID-19 patients are in many ways "atypical". The mortality rate in ventilated patients is high despite the application of the gold standard treatment (protective ventilation, curare, prone position, inhaled NO). Several studies suggested that the SARS-CoV-2 could interact negatively on red blood cell homeostasis. Furthermore, SarsCov2 creates Reactive Oxygen Species (ROS), which are toxic and generate endothelial dysfunction. Hypothesis/objective(s) We hypothesis that HEMO2Life® administrated intravenously is safe and could help symptomatically the patient condition. It would increase arterial oxygen content despite lung failure and allow better tissue oxygenation control. The use of HEMO2Life® is also interesting due to its anti-oxidative effect preventing cytokine storm induced by the SARS-CoV-2. Evaluation of the hypothesis: Hemarina is based on the properties of the hemoglobin of the Arenicola marina sea-worm (HEMO2Life®). This extracellular hemoglobin has an oxygen capacity 40 times greater than the hemoglobin of vertebrates. Furthermore, the size of this molecule is 250 times smaller than a human red blood cell, allowing it to diffuse in all areas of the microcirculation, without diffusing outside the vascular sector. It possesses an antioxidative property du a Superoxide Dismutase Activity. This technology has been the subject of numerous publications and HEMO2Life® was found to be well-tolerated and did not induce toxicity. It was administered intravenously to hamsters and rats, and showed no acute effect on heart rate and blood pressure and did not cause microvascular vasoconstriction. In preclinical in vivo models (mice, rats, and dogs), HEMO2Life® has enabled better tissue oxygenation, especially in the brain. This molecule has already been used in humans in organ preservation solutions and the patients showed no abnormal clinical signs. CONSEQUENCES OF THE HYPOTHESIS: The expected benefits of HEMO2Life® for COVID-19 patients are improved survival, avoidance of tracheal intubation, shorter oxygen supplementation, and the possibility of treating a larger number of patients as molecular respirator without to use an invasive machine.


Asunto(s)
/complicaciones , Hemoglobinas/uso terapéutico , Hipoxia/etiología , Hipoxia/terapia , Modelos Biológicos , Oxígeno/administración & dosificación , Animales , Cricetinae , Perros , Hemoglobinas/administración & dosificación , Hemoglobinas/metabolismo , Humanos , Hipoxia/fisiopatología , Inyecciones Intravenosas , Ratones , Estrés Oxidativo/efectos de los fármacos , Oxígeno/metabolismo , Pandemias , Ratas , Investigación en Medicina Traslacional
20.
J Dairy Sci ; 104(2): 2040-2055, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33309349

RESUMEN

Both the economic loss and welfare implications of lameness affect the dairy industry. Currently no analgesic drugs are approved to alleviate lameness-associated pain in lactating dairy cattle in the United States. In this randomized controlled trial, 48 lactating Holsteins were enrolled to evaluate the effect of oral meloxicam and i.v. flunixin meglumine on induced lameness. Cows were allocated to 1 of 4 treatment groups (n = 12 per group): lameness and flunixin meglumine (LAME + FLU); lameness and meloxicam (LAME + MEL); lameness and placebo (LAME + PLBO); or sham induction and placebo (SHAM + PLBO). Six hours before treatment, arthritis-synovitis was induced in the distal interphalangeal joint with 20 mg of amphotericin B, whereas SHAM cows were given an intra-articular injection of an equal volume (4 mL) of isotonic saline. Cows in LAME + FLU received 2.2 mg/kg flunixin meglumine i.v. and whey protein placebo orally; LAME + MEL were administered 1 mg/kg meloxicam orally and 2 mL/45 kg sterile saline placebo i.v.; LAME + PLBO were administered 2 mL/45 kg sterile saline placebo i.v. and whey protein placebo orally; and SHAM + PLBO received 2 mL/45 kg sterile saline placebo i.v. and whey protein placebo orally. The initial treatment of MEL, FLU, or PLBO was identified as time 0 h and followed by a second dose 24 h later with data collection for 120 h. The methods used to assess analgesic efficacy were electronic pressure mat, visual lameness assessment, visual analog score, plasma cortisol concentration, plasma substance P concentration, mechanical nociception threshold, and infrared thermography imaging. Linear mixed effect modeling was the primary method of statistical analysis. Visual lameness scoring indicated a lower proportion of the FLU + LAME group was lame at the T2 h and T8 h time points in comparison to the positive controls, whereas MEL therapy resulted in a lower proportion of lame cows at the T8 h time point. Cortisol area under the effect curve was lower following FLU therapy compared with LAME + PBLO for the 0-2 h (LSM difference = 35.1 ng·h/mL, 95% CI: 6.8, 63.3 ng·h/mL), 2-8 h (LSM difference = 120.6 ng·h/mL, 95% CI: 77.2, 164.0 ng·h/mL), and 0-24 h (LSM difference = 226.0 ng·h/mL, 95% CI: 103.3, 348.8 ng·h/mL) time intervals. Following MEL therapy, cortisol area under the effect curve was lower than LAME + PLBO for both the 2 to 8 h (LSM difference = 93.6 ng·h/mL, 95% CI: 50.2, 137.0 ng·h/mL) and 0 to 24 h time intervals (LSM difference = 187.6 ng·h/mL, 95% CI: 64.9, 310.4 ng·h/mL). Analysis of data from other assessment modalities failed to discern biologically relevant differences between treatment groups. We conclude that meaningful differences were evident for visual lameness assessment and cortisol from MEL and FLU treatment versus the positive control. Further clinical research is needed toward development of a model that will create reproducible events that are more pronounced in severity and duration of lameness which can be validated as a substitute for naturally occurring lameness cases.


Asunto(s)
Analgésicos/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Enfermedades de los Bovinos/tratamiento farmacológico , Clonixina/análogos & derivados , Cojera Animal/tratamiento farmacológico , Meloxicam/uso terapéutico , Dolor/veterinaria , Administración Oral , Analgésicos/administración & dosificación , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Bovinos , Clonixina/administración & dosificación , Clonixina/uso terapéutico , Industria Lechera , Femenino , Inyecciones Intravenosas/veterinaria , Lactancia/efectos de los fármacos , Cojera Animal/etiología , Meloxicam/administración & dosificación , Dolor/tratamiento farmacológico
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