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1.
Cochrane Database Syst Rev ; 10: CD006811, 2020 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-33126293

RESUMO

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.


Assuntos
Acetaminofen/administração & dosagem , Antipiréticos/administração & dosagem , Temperatura Corporal , Lesões Encefálicas Traumáticas/terapia , Hipotermia Induzida/métodos , Adulto , Viés , Temperatura Corporal/efeitos dos fármacos , Lesões Encefálicas Traumáticas/mortalidade , Humanos , Hipotermia Induzida/mortalidade , Injeções Intravenosas , Placebos
2.
Nat Commun ; 11(1): 4907, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32999289

RESUMO

Global alterations in the metabolic network provide substances and energy to support tumor progression. To fuel these metabolic processes, extracellular matrix (ECM) plays a dominant role in supporting the mass transport and providing essential nutrients. Here, we report a fibrinogen and thrombin based coagulation system to construct an artificial ECM (aECM) for selectively cutting-off the tumor metabolic flux. Once a micro-wound is induced, a cascaded gelation of aECM can be triggered to besiege the tumor. Studies on cell behaviors and metabolomics reveal that aECM cuts off the mass transport and leads to a tumor specific starvation to inhibit tumor growth. In orthotopic and spontaneous murine tumor models, this physical barrier also hinders cancer cells from distant metastasis. The in vivo gelation provides an efficient approach to selectively alter the tumor mass transport. This strategy results in a 77% suppression of tumor growth. Most importantly, the gelation of aECM can be induced by clinical operations such as ultrasonic treatment, surgery or radiotherapy, implying this strategy is potential to be translated into a clinical combination regimen.


Assuntos
Materiais Biomiméticos/administração & dosagem , Matriz Extracelular/química , Neoplasias/terapia , Animais , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/efeitos da radiação , Materiais Biomiméticos/química , Materiais Biomiméticos/efeitos da radiação , Linhagem Celular Tumoral/transplante , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Quimiorradioterapia/métodos , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Matriz Extracelular/efeitos da radiação , Feminino , Fibrinogênio/administração & dosagem , Fibrinogênio/química , Fibrinogênio/efeitos da radiação , Géis , Humanos , Injeções Intravenosas , Metabolômica , Camundongos , Neoplasias/metabolismo , Trombina/administração & dosagem , Trombina/química , Trombina/efeitos da radiação , Terapia por Ultrassom/métodos , Ondas Ultrassônicas
3.
Lancet Haematol ; 7(11): e808-e815, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33010817

RESUMO

BACKGROUND: Hodgkin lymphoma is potentially curable. However, 15-35% of older patients (ie, >60 years) have a lower response rate, worse survival outcomes, and greater toxicity than younger patients. Brentuximab vedotin and nivolumab exhibit activity in patients with relapsed or refractory Hodgkin lymphoma. We therefore aimed to evaluate the safety and efficacy of brentuximab vedotin and nivolumab in untreated older patients with Hodgkin lymphoma or in younger patients considered unsuitable for standard ABVD (ie, doxorubicin, bleomycin, vinblastine, and dacarbazine) therapy. METHODS: We did a multicentre, single-arm, phase 2 trial at eight cancer centres in the USA. Previously untreated patients with classic Hodgkin lymphoma were eligible for study enrolment if they were 60 years or older, or younger than 60 years but considered unsuitable for standard chemotherapy because of a cardiac ejection fraction of less than 50%, pulmonary diffusion capacity of less than 80%, or a creatinine clearance of 30 mL/min or more but less than 60 mL/min, or those who refused chemotherapy. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients received brentuximab vedotin at 1·8 mg/kg (dose cap at 180 mg) and nivolumab at 3 mg/kg both intravenously every 21 days for 8 cycles. The primary endpoint was the overall response, defined as a partial metabolic response or complete metabolic response at the end of 8 cycles of treatment. A per protocol analysis was done including all patients who received treatment in the activity and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02758717. FINDINGS: Between May 13, 2016, and Jan 30, 2019, the study accrued 46 patients. The median age was 71·5 years (IQR 64-77), with two (4%) of 46 patients younger than 60 years. Median follow-up was 21·2 months (IQR 15·6-29·9), and 35 (76%) of 46 patients completed all 8 cycles of therapy. At the interim analysis on Oct 11, 2019, the first 25 evaluable patients had an overall response rate of 64% ([95% CI 43-82] 16 of 25 patients; 13 [52%] had a complete metabolic response and three [12%] had a partial metabolic response). The trial was closed to accrual on Oct 14, 2019, after the interim analysis failed to meet the predefined criteria. In all 46 evaluable patients, 22 (48%) patients achieved a complete metabolic response and six (13%) achieved a partial metabolic response (overall response rate 61% [95% CI 45-75]). 14 (30%) of 46 patients had 16 dose adjustments, primarily due to neurotoxicity. 22 (48%) of 46 patients had peripheral neuropathy (five [11%] patients had grade 3 peripheral neuropathy). Grade 4 adverse events included increased aminotranferases (one [2%] of 46), increased lipase or amylase (two [4%]), and pancreatitis (one [2%]). One (2%) patient died from cardiac arrest, possibly treatment related. INTERPRETATION: Although the trial did not meet the prespecified activity criteria, brentuximab vedotin plus nivolumab is active in older patients with previously untreated Hodgkin lymphoma with comorbidities. The regimen was also well tolerated in the majority of patients in this older population. Future trials should be based on optimising the dose and schedule, perhaps combined with other targeted agents that might permit chemotherapy-free strategies in older patients with Hodgkin lymphoma. FUNDING: Seattle Genetics and Bristol Myers Squibb.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Brentuximab Vedotin/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Nivolumabe/uso terapêutico , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Brentuximab Vedotin/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/etiologia , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/etiologia , Intervalo Livre de Progressão , Indução de Remissão , Resultado do Tratamento
4.
Am J Vet Res ; 81(11): 837-877, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33107745

RESUMO

OBJECTIVE: To compare the pharmacokinetics of cefquinome sulfate in ducklings and goslings after IV or IM administration of a single dose. ANIMALS: 216 healthy Muscovy ducklings (Cairina moschata) and 216 healthy Sichuan white goslings (Anser cygnoides). PROCEDURES: Ducklings and goslings were each randomly assigned to 3 groups (n = 72/group) that received a single dose (2 mg/kg) of injectable cefquinome sulfate administered IV or IM or of injectable cefquinome sulfate suspension administered IM. Blood samples were collected at various points after drug administration (n = 6 birds/time point). Plasma cefquinome concentrations were measured by high-performance liquid chromatography with UV detection, and pharmacokinetic parameters were calculated with a 2-compartment model method. RESULTS: After IV injection, mean distribution half-life of cefquinome was longer in goslings (0.446 hours) than in ducklings (0.019 hours), whereas volume of distribution at steady state was greater (0.432 vs 0.042 L/kg) and elimination half-life was slower (1.737 vs 0.972 hours). After IM administration of injectable cefquinome sulfate, bioavailability of the drug was higher in goslings (113.9%) than in ducklings (67.5%). After IM administration of injectable cefquinome sulfate suspension, bioavailability was also higher in goslings (123.1%) than in ducklings (96.8%), whereas elimination half-life was slower (6.917 vs 1.895 hours, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: In goslings, IV administration of cefquinome resulted in slower distribution and metabolism of the drug than in ducklings and IM administration resulted in higher bioavailability. The delayed-release effect of the injectable cefquinome sulfate suspension when administered IM was observed only in goslings.


Assuntos
Patos , Gansos , Animais , Antibacterianos , Área Sob a Curva , Disponibilidade Biológica , Cefalosporinas , Meia-Vida , Injeções Intramusculares/veterinária , Injeções Intravenosas/veterinária , Sulfatos
5.
Am J Vet Res ; 81(11): 894-898, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33107746

RESUMO

OBJECTIVE: To evaluate the pharmacokinetics of hydromorphone hydrochloride after IM and IV administration to orange-winged Amazon parrots (Amazona amazonica). ANIMALS: 8 orange-winged Amazon parrots (4 males and 4 females). PROCEDURES: Hydromorphone (1 mg/kg) was administered once IM. Blood samples were collected 5 minutes and 0.5, 1.5, 2, 3, 6, and 9 hours after drug administration. Plasma hydromorphone concentrations were determined with liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were calculated with a compartmental model. The experiment was repeated 1 month later with the same dose of hydromorphone administered IV. RESULTS: Plasma hydromorphone concentrations were > 1 ng/mL for 6 hours in 8 of 8 and 6 of 7 parrots after IM and IV injection, respectively. After IM administration, mean bioavailability was 97.6%, and mean maximum plasma concentration was 179.1 ng/mL 17 minutes after injection. Mean volume of distribution and plasma drug clearance were 4.24 L/kg and 64.2 mL/min/kg, respectively, after IV administration. Mean elimination half-lives were 1.74 and 1.45 hours after IM and IV administration, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Hydromorphone hydrochloride had high bioavailability and rapid elimination after IM administration, with rapid plasma clearance and a large volume of distribution after IV administration in orange-winged Amazon parrots. Drug elimination half-lives were short. Further pharmacokinetic studies of hydromorphone and its metabolites, including investigation of multiple doses, different routes of administration, and sustained-release formulations, are recommended.


Assuntos
Amazona , Hidromorfona , Administração Intravenosa/veterinária , Analgésicos Opioides , Animais , Área Sob a Curva , Estudos Cross-Over , Feminino , Meia-Vida , Injeções Intramusculares/veterinária , Injeções Intravenosas/veterinária , Masculino
6.
J Toxicol Sci ; 45(10): 625-637, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33012731

RESUMO

NOD-like receptor protein 3 (NLRP3) is involved in acute lung injury (ALI), but its exact role in phosgene-induced ALI is not clearly understood. The aim of the study is to explore the potential therapeutic effect of NLRP3 inflammasome modulation in the management of phosgene-induced ALI. ALI was induced in rats by phosgene exposure at 8.33 g/m3 for 5 min, 30 hr before intravenous injection of adenovirus-NLRP3 shRNA (Ad/NLRP3-shRNA). The histological changes in the lung were evaluated. Bronchoalveolar lavage fluid (BALF) neutrophils were counted (smear), and protein content was measured using the BCA assay. The wet/dry ratio of lung tissue (W/D) was measured. TUNEL staining for DNA damage was used to indirectly assess pyroptosis. NLRP3 inflammasome was assessed by immunohistochemistry, RT-PCR, western blotting. Cytokines were measured by ELISA. Histological analyses revealed reduced severity in phosgene-induced ALI with Ad/NLRP3-shRNA pretreatment. TUNEL staining indicated decreased pyroptosis in Psg-Ad/NLRP3-shRNA rats. Decreased mRNA and protein levels of NLRP3 and caspase-1 (all P < 0.05), but not ASC (P > 0.05), were found in Psg-Ad/NLRP3-shRNA rats. Immunohistochemistry revealed that Ad/NLRP3-shRNA pretreatment inhibited NLRP3 inflammasome activation. Reduced level of pro-inflammatory interleukin (IL)-1ß, IL-18, IL-33, and tumor necrosis factor (TNF)-α (all P < 0.05), but not of anti-inflammatory IL-4 and IL-10 (all P > 0.05), were found in serum and BALF from Ad/NLRP3-shRNA rats. NLRP3 gene silencing exerts beneficial effects on phosgene-induced lung injury by inhibiting NLRP3 inflammasome activation and pro-inflammatory factors, but not anti-inflammatory factors. Disruption of NLRP3 inflammasome activation might be used as a therapeutic modality for the treatment of phosgene-induced ALI.


Assuntos
Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/terapia , Inativação Gênica , Terapia Genética/métodos , Inflamassomos/genética , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fosgênio/envenenamento , RNA Interferente Pequeno/administração & dosagem , Lesão Pulmonar Aguda/diagnóstico , Animais , Biomarcadores/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Injeções Intravenosas , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Masculino , Ratos Sprague-Dawley
8.
J Investig Med High Impact Case Rep ; 8: 2324709620963635, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33019829

RESUMO

As COVID-19 (coronavirus disease 2019) spreads across the world multiple therapeutic interventions have been tried to reduce morbidity and mortality. We describe a case of collapsing focal sclerosing glomerulosclerosis (FSGS) and acute oxalate nephropathy in a patient treated with high-dose intravenous vitamin C for severe COVID-19 infection. Collapsing FSGS has been described in patients with COVID-19 infection associated with APOL-1; however, this case had collapsing FSGS developing in low-risk heterozygous APOL-1 variant, and we postulate that the intensity of the COVID-19 cytokine storm overwhelmed the protective state of APOL-1 heterozygosity. This case illustrates the importance of assessing the risk and benefit of planned therapeutic interventions on a case-by-case basis especially when there are still so many unknowns in the management of COVID-19 infection. Strong consideration should be given for performing a renal biopsy in patients who develop multifactorial acute kidney injury.


Assuntos
Ácido Ascórbico/efeitos adversos , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Glomerulosclerose Segmentar e Focal/induzido quimicamente , Hiperoxalúria/induzido quimicamente , Glomérulos Renais/patologia , Oxalatos/metabolismo , Pneumonia Viral/tratamento farmacológico , Doença Aguda , Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/etiologia , Ácido Ascórbico/administração & dosagem , Biópsia , Infecções por Coronavirus/epidemiologia , Progressão da Doença , Glomerulosclerose Segmentar e Focal/diagnóstico , Humanos , Hiperoxalúria/diagnóstico , Hiperoxalúria/metabolismo , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Vitaminas/administração & dosagem , Vitaminas/efeitos adversos
9.
Medicine (Baltimore) ; 99(42): e22751, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33080740

RESUMO

BACKGROUND: The use of hysteroscopy for the diagnosis and treatment of uterine and endometrial abnormalities is often associated with postoperative pain. This randomized controlled trial aimed to assess the efficacy of preoperative intravenous (IV) lidocaine in reducing pain after hysteroscopy. METHODS: In total, 138 patients undergoing elective hysteroscopy at the CHA Bundang Medical Center, Seongnam, Korea were randomly assigned to a control group (n = 69) or a lidocaine group (n = 69), which received normal saline or IV lidocaine at 1.5 mg/kg, respectively. The primary outcome was the incidence of postoperative pain. RESULTS: The incidence of pain was significantly lower in the IV lidocaine group than in the control group at the post-anesthesia care unit (27.3% vs 68.2%, P < .001). The visual analog scale (0-10) score (median [interquartile range]) was lower in the IV lidocaine group than in the control group (0 [0-2]) vs 2 [0-4]), P < .001). The use of rescue analgesics and postoperative nausea and vomiting were similar between the 2 groups. This study demonstrated that administering 1.5 mg/kg of preoperative IV lidocaine can be a simple method to reduce incidence of pain after hysteroscopy. CONCLUSION: Preoperative bolus administration of 1.5 mg/kg of IV lidocaine may be used to decrease incidence of pain after hysteroscopy under general anesthesia.


Assuntos
Anestésicos Locais/administração & dosagem , Histeroscopia , Lidocaína/administração & dosagem , Dor Pós-Operatória/prevenção & controle , Adulto , Feminino , Humanos , Injeções Intravenosas , Cuidados Pré-Operatórios , Escala Visual Analógica
10.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 4016-4019, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018880

RESUMO

Intravenous needle insertion is typically conducted manually, with needles guided into vessels by feel while looking for a brief flash of blood. This process is imprecise and leads to mispositioned needles, multiple reinsertion attempts, increased procedure time and higher costs for the hospital. We present a method for indicating that the needle has reached the vein by measuring the change in mechanical impedance of the needle as it passes through different tissue layers. Testing in a phantom indicated that this has the potential to identify transitions through tissue boundaries.


Assuntos
Agulhas , Veias , Impedância Elétrica , Injeções Intravenosas , Imagens de Fantasmas
12.
N Engl J Med ; 383(11): 1018-1027, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32905674

RESUMO

BACKGROUND: Factor VIII replacement products have improved the care of patients with hemophilia A, but the short half-life of these products affects the patients' quality of life. The half-life of recombinant factor VIII ranges from 15 to 19 hours because of the von Willebrand factor chaperone effect. BIVV001 (rFVIIIFc-VWF-XTEN) is a novel fusion protein designed to overcome this half-life ceiling and maintain high sustained factor VIII activity levels. Data are lacking on the safety and pharmacokinetics of single-dose BIVV001. METHODS: In this phase 1-2a open-label trial, we consecutively assigned 16 previously treated men (18 to 65 years of age) with severe hemophilia A (factor VIII activity, <1%) to receive a single intravenous injection of recombinant factor VIII at a dose of 25 IU per kilogram of body weight (lower-dose group) or 65 IU per kilogram (higher-dose group). This injection was followed by a washout period of at least 3 days. The patients then received a single intravenous injection of BIVV001 at the same corresponding dose of either 25 IU or 65 IU per kilogram. Adverse events and pharmacokinetic measurements were assessed. RESULTS: No inhibitors to factor VIII were detected and no hypersensitivity or anaphylaxis events were reported up to 28 days after the injection of single-dose BIVV001. The geometric mean half-life of BIVV001 was three to four times as long as that of recombinant factor VIII (37.6 hours vs. 9.1 hours in the lower-dose group and 42.5 vs. 13.2 hours in the higher-dose group); the area under the curve (AUC) for product exposure was six to seven times as great in the two dose groups (4470 hours vs. 638 hours × IU per deciliter in the lower-dose group and 12,800 hours vs. 1960 hours × IU per deciliter in the higher-dose group). After the injection of BIVV001 in the higher-dose group, the mean factor VIII level was in the normal range (≥51%) for 4 days and 17% at day 7, which suggested the possibility of a weekly interval between treatments. CONCLUSIONS: In a small, early-phase study involving men with severe hemophilia A, a single intravenous injection of BIVV001 resulted in high sustained factor VIII activity levels, with a half-life that was up to four times the half-life associated with recombinant factor VIII, an increase that could signal a new class of factor VIII replacement therapy with a weekly treatment interval. No safety concerns were reported during the 28-day period after administration. (Funded by Sanofi and Sobi; ClinicalTrials.gov number, NCT03205163.).


Assuntos
Fator VIII/metabolismo , Hemofilia A/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Adulto , Relação Dose-Resposta a Droga , Fator VIII/antagonistas & inibidores , Meia-Vida , Hemofilia A/metabolismo , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacocinética , Adulto Jovem
13.
PLoS One ; 15(9): e0238524, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915806

RESUMO

BACKGROUND: Markers of lung inflammation measured directly in expectorated sputum have the potential of improving the timing of antibiotic treatment in cystic fibrosis (CF). L-Lactate might be a marker of inflammation, as it is produced from glucose by polymorphonuclear neutrophils (PMNs) in CF lungs. We aimed to investigate changes in and associations between PMNs, glucose and L-lactate in sputum during antibiotic treatment. In addition, the effect of hemoglobin A1c and plasma glucose on these biomarkers were investigated. METHODS: We sampled non-induced sputum at day 0, 7, 14 and 42 in 27 chronically infected CF patients electively treated with 14 days of intravenous antibiotic. To analyze sputum samples, we used flowcytometry to count PMNs and colorimetric assays to estimate lactate and glucose. RESULTS: No changes in levels of PMNs, glucose and lactate were detected in sputum during the antibiotic treatment. Sputum PMNs were positively associated with both glucose (log coefficient = 0.20, p = 0.01) and L-lactate (log coefficient = 0.34, p<0.001). In multivariate analyses, hemoglobin A1c was negatively associated with sputum PMNs (log coefficient = -1.68, p<0.001) and plasma glucose was negatively associated with sputum glucose (log coefficient = -0.09, p = 0.02). CONCLUSIONS: In CF sputum PMNs, glucose and lactate were unchanged during elective antibiotic treatment. However, sputum PMNs were associated with both sputum glucose and sputum lactate. Surprisingly, hyperglycemia seemed to be associated with less PMNs infiltration and less glucose in CF sputum.


Assuntos
Fibrose Cística/sangue , Glucose/metabolismo , Ácido Láctico/metabolismo , Neutrófilos/metabolismo , Escarro/metabolismo , Adulto , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Biomarcadores/metabolismo , Glicemia/metabolismo , Fibrose Cística/fisiopatologia , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Injeções Intravenosas , Contagem de Leucócitos , Masculino , Análise Multivariada , Testes de Função Respiratória , Adulto Jovem
14.
PLoS One ; 15(9): e0224414, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32931488

RESUMO

PROCEDURES: To preliminary assess the relationship between Manganese Enhanced Magnetic Resonance Imaging (MEMRI) and the expression of calcium receptors in human prostate and breast cancer animal models. METHODS: NOD/SCID mice were inoculated with MDA-MB-231 breast cancer cells and prostate PC3 cancer cells to develop orthotopic or pseudometastatic cancer animal models. Mice were studied on a clinical 3T scanner by using a prototype birdcage coil before and after intravenous injection of MnCl2. Assessment of receptor's status was carried out after the MR images acquisition by immunohistochemistry on excised tumours. RESULTS: Manganese contrast enhancement in breast or prostate cancer animal models well correlated with CaSR expression (p<0.01), whereas TRPV6 expression levels appeared not relevant to the Mn uptake. CONCLUSION: Our preliminary results suggest that MEMRI appears an efficient tool to characterize human breast and prostate cancer animal models in the presence of different expression level of calcium receptors.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Cloretos/administração & dosagem , Meios de Contraste/administração & dosagem , Imagem por Ressonância Magnética/métodos , Compostos de Manganês/administração & dosagem , Neoplasias da Próstata/diagnóstico por imagem , Animais , Neoplasias da Mama/patologia , Cálcio/metabolismo , Linhagem Celular Tumoral , Cloretos/farmacocinética , Meios de Contraste/farmacocinética , Estudos de Viabilidade , Feminino , Humanos , Imuno-Histoquímica , Injeções Intravenosas , Masculino , Compostos de Manganês/farmacocinética , Camundongos , Projetos Piloto , Neoplasias da Próstata/patologia , Receptores de Detecção de Cálcio/metabolismo , Canais de Cátion TRPV/metabolismo , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Med Klin Intensivmed Notfmed ; 115(7): 550-556, 2020 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-32880673

RESUMO

Peripheral intravenous lines are indispensable for emergency and intensive medical care. They have a high importance, especially in the context of primary care as well as in the early stages of treatment initiation. This requires in-depth knowledge of the persons being treated. This article describes the most important aspects of the indications, puncture and fixation techniques as well as special features in terms of management and hygiene.


Assuntos
Emergências , Serviço Hospitalar de Emergência , Humanos , Infusões Intravenosas , Injeções Intravenosas
16.
Nat Commun ; 11(1): 4387, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873795

RESUMO

The role of neutrophils in solid tumor metastasis remains largely controversial. In preclinical models of solid tumors, both pro-metastatic and anti-metastatic effects of neutrophils have been reported. In this study, using mouse models of breast cancer, we demonstrate that the metastasis-modulating effects of neutrophils are dictated by the status of host natural killer (NK) cells. In NK cell-deficient mice, granulocyte colony-stimulating factor-expanded neutrophils show an inhibitory effect on the metastatic colonization of breast tumor cells in the lung. In contrast, in NK cell-competent mice, neutrophils facilitate metastatic colonization in the same tumor models. In an ex vivo neutrophil-NK cell-tumor cell tri-cell co-culture system, neutrophils are shown to potentially suppress the tumoricidal activity of NK cells, while neutrophils themselves are tumoricidal. Intriguingly, these two modulatory effects by neutrophils are both mediated by reactive oxygen species. Collectively, the absence or presence of NK cells, governs the net tumor-modulatory effects of neutrophils.


Assuntos
Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Mamárias Animais/imunologia , Neutropenia/prevenção & controle , Neutrófilos/imunologia , Animais , Linhagem Celular Tumoral/transplante , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Injeções Intravenosas , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/secundário , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/imunologia , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Animais/sangue , Neoplasias Mamárias Animais/complicações , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos NOD , Neutropenia/sangue , Neutropenia/etiologia , Neutropenia/imunologia , Neutrófilos/efeitos dos fármacos , Cultura Primária de Células
17.
Br J Anaesth ; 125(5): 750-761, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32838982

RESUMO

BACKGROUND: Recent studies show activity of ketamine metabolites, such as hydroxynorketamine, in producing rapid relief of depression-related symptoms and analgesia. To improve our understanding of the pharmacokinetics of ketamine and metabolites norketamine, dehydronorketamine, and hydroxynorketamine, we developed a population pharmacokinetic model of ketamine and metabolites after i.v. administration of racemic ketamine and the S-isomer (esketamine). Pharmacokinetic data were derived from an RCT on the efficacy of sodium nitroprusside (SNP) in reducing the psychotomimetic side-effects of ketamine in human volunteers. METHODS: Three increasing i.v. doses of esketamine and racemic ketamine were administered to 20 healthy volunteers, and arterial plasma samples were obtained for measurement of ketamine and metabolites. Subjects were randomised to receive esketamine/SNP, esketamine/placebo, racemic ketamine/SNP, and racemic ketamine/placebo on four separate occasions. The time-plasma concentration data of ketamine and metabolites were analysed using a population compartmental model approach. RESULTS: The pharmacokinetics of ketamine and metabolites were adequately described by a seven-compartment model with two ketamine, norketamine, and hydroxynorketamine compartments and one dehydronorketamine compartment with metabolic compartments in-between ketamine and norketamine, and norketamine and dehydronorketamine main compartments. Significant differences were found between S- and R-ketamine enantiomer pharmacokinetics, with up to 50% lower clearances for the R-enantiomers, irrespective of formulation. Whilst SNP had a significant effect on ketamine clearances, simulations showed only minor effects of SNP on total ketamine pharmacokinetics. CONCLUSIONS: The model is of adequate quality for use in future pharmacokinetic and pharmacodynamic studies into the efficacy and side-effects of ketamine and metabolites. CLINICAL TRIAL REGISTRATION: Dutch Cochrane Center 5359.


Assuntos
Anestésicos Dissociativos/farmacocinética , Ketamina/farmacocinética , Adulto , Anestésicos Dissociativos/administração & dosagem , Biotransformação , Simulação por Computador , Estudos Cross-Over , Método Duplo-Cego , Composição de Medicamentos , Feminino , Humanos , Injeções Intravenosas , Ketamina/administração & dosagem , Ketamina/análogos & derivados , Ketamina/sangue , Ketamina/química , Masculino , Modelos Teóricos , Nitroprussiato/uso terapêutico , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/psicologia , Estereoisomerismo , Adulto Jovem
18.
Leg Med (Tokyo) ; 47: 101777, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32858459

RESUMO

The present study evaluates the postmortem redistribution of ketamine in ocular matrices, such as vitreous humor, aqueous humor, and ocular tissues in an animal model. To understand the redistribution of ketamine and its metabolite (norketamine) in the ocular matrices, an in vivo study was performed in rabbits. The rabbits were divided into two groups: perimortem and postmortem. The postmortem samples were collected at 17 h after the administration of ketamine (40 mg/kg) intravenously. For a better understanding of the metabolism of ketamine in eyes, an ex vivo study was conducted in goat eyes after administration of ketamine intravitreally. The samples were analyzed by LC-MS/MS and the levels of ketamine and norketamine in these matrices were compared with that of whole blood and plasma. The results of the in vivo study showed a decrease in ketamine levels in whole blood and plasma while an increase in ocular matrices at postmortem. Though, in most cases, this increase/decrease was statistically insignificant. Moreover, there was an increase of norketamine level in ocular matrices. Ex vivo study also shows the presence of norketamine in ocular matrices of goat eyes. The presence of norketamine in goat eyes may be indicative of the metabolism of ketamine in the eyes.


Assuntos
Humor Aquoso/metabolismo , Medicina Legal , Ketamina/metabolismo , Mudanças Depois da Morte , Corpo Vítreo/metabolismo , Animais , Cromatografia Líquida , Feminino , Cabras , Injeções Intravenosas , Injeções Intravítreas , Ketamina/administração & dosagem , Ketamina/análogos & derivados , Ketamina/sangue , Masculino , Modelos Animais , Coelhos , Espectrometria de Massas em Tandem
19.
AAPS PharmSciTech ; 21(6): 234, 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32794077

RESUMO

We investigated the pharmacokinetics of nimodipine (NMD) in rats plasma and tissues following intraocular (io), intragastric (ig), and intravenous (iv) administration at doses of 5.0 mg/kg io and iv and 10.0 mg/kg ig. After a single dose of NMD, plasma, heart, liver, spleen, lung, kidney, and brain samples were collected at the scheduled time points. The concentration of NMD in rat plasma and tissues was determined by high-performance liquid chromatography, and the main pharmacokinetic parameters were calculated and compared. NMD was rapidly absorbed and reached the maximum plasma concentration in approximately 5 min after io administration. The absolute bioavailability after io administration was higher than that after ig administration (40.05% vs. 5.67%). There were significant differences in the tissue distribution of NMD with different administration routes. After io administration, NMD was distributed more in the lung, spleen, and brain tissues, and less in the kidney. The maximum drug concentration after io administration in the heart, liver, spleen, lung, kidney, and brain was 1.00, 0.47, 2.02, 1.47, 0.22, and 5.79 times higher than that after via ig administration, and the area under the curve value was 0.59, 0.78, 1.71, 1.84, 0.25, and 4.59 times greater, respectively. Nimodipine appears to achieve systemic effects via io administration. Compared with ig, io administration could significantly increase NMD distribution in the brain tissue, indicating that NMD could be delivered to the brain via io administration.


Assuntos
Encéfalo/metabolismo , Injeções Intraoculares/métodos , Nimodipina/administração & dosagem , Nimodipina/sangue , Administração Intravenosa , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/sangue , Anti-Hipertensivos/farmacocinética , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Injeções Intraperitoneais , Injeções Intravenosas , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Nimodipina/farmacocinética , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia
20.
Mayo Clin Proc ; 95(8): 1604-1612, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32753135

RESUMO

OBJECTIVE: To present our center's experience with a maintenance treatment algorithm for intravenous bevacizumab that allows for personalized therapy decisions. PATIENTS AND METHODS: We reviewed all patients treated with intravenous bevacizumab for hereditary hemorrhagic telangiectasia-related bleeding and/or high-output cardiac failure (HOCF) from January 1, 2013, to July 1, 2019, at the Mayo Clinic, Rochester, Minnesota. Data regarding subsequent bevacizumab dosing were abstracted. RESULTS: A total of 57 patients (n=40, 70.2% females) were identified with a median age of 65 (55 to 74; range, 37 to 89) years. High-cardiac output state was present in 21 patients (36.8%) and 10 (17.5%) were treated with intravenous bevacizumab primarily for HOCF. The median duration of follow-up after completion of the initial intravenous bevacizumab treatment was 25 (12.3 to 40.8; range, 0.1 to 65.4) months. A total of 20 (35.1%) patients with a median follow-up of 13.5 (range, 0 to 48.4) months required no maintenance dosing throughout the duration of follow-up. Among those who required subsequent maintenance doses, only a small fraction (8 patients; 14.0%) required regular maintenance doses every 4 to 8 weeks during follow-up whereas the majority of patients required intermittent "as-needed" doses at varying intervals. CONCLUSION: There is significant inter-individual variability in the need for maintenance intravenous bevacizumab when patients are followed using a predefined bevacizumab maintenance dosing treatment algorithm. The use of "as-needed" maintenance bevacizumab appears to be an effective strategy for management of hereditary hemorrhagic telangiectasia-related bleeding and HOCF.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Hemorragia/tratamento farmacológico , Telangiectasia Hemorrágica Hereditária/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Bevacizumab/administração & dosagem , Feminino , Insuficiência Cardíaca/etiologia , Hemorragia/etiologia , Humanos , Individualidade , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Medicina de Precisão/métodos , Estudos Retrospectivos , Telangiectasia Hemorrágica Hereditária/complicações
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