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1.
Nihon Yakurigaku Zasshi ; 158(1): 89-100, 2023.
Artigo em Japonês | MEDLINE | ID: mdl-36596498

RESUMO

Andexanet alfa is a modified recombinant human factor Xa (FXa) that was designed to serve as a binding target for FXa inhibitors as decoy protein. It sequesters FXa inhibitors from binding to endogenous FXa, thereby reversing anticoagulant effect of FXa inhibitors. Andexanet alfa has been approved in March 2022 in Japan for patients with life-threatening or uncontrolled bleeding while on treatment with a FXa inhibitor, apixaban, rivaroxaban, or edoxaban tosilate hydrate. It is administered via two dosing regimens, based on the type of FXa inhibitor, dose, and time since the last dose. In nonclinical studies, andexanet alfa significantly inhibited bleeding induced by FXa inhibitors in animal bleeding models. In the development for Japanese patients, the following two clinical studies have been conducted to confirm the efficacy and safety. First, safety and the reversal effect of andexanet alfa on the FXa inhibitor-mediated anticoagulant activity in healthy adults were confirmed in the overseas phase 2 study including Japanese subjects. Next, the reversal effect of andexanet alfa on the anticoagulation activity and the hemostasis were demonstrated in patients with acute major bleeding while on FXa inhibitor treatment in the global phase 3b/4 study (ANNEXA-4 study). The subgroup analysis of Japanese population showed that the efficacy and safety results were consistent with those of overall population. Andexanet alfa is the first approved reversal agent for FXa inhibitors in Japan and is expected to contribute to the improvement of prognosis in patients with fatal and/or uncontrolled bleeding by timely reversing anticoagulant effect of FXa inhibitors.


Assuntos
Inibidores do Fator Xa , Fator Xa , Hemorragia , Proteínas Recombinantes , Adulto , Animais , Humanos , Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Injeções Intravenosas , Proteínas Recombinantes/administração & dosagem , Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Fase IV como Assunto
2.
BMJ Case Rep ; 16(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36596629

RESUMO

We report the case of a previously healthy woman in her 60s who presented to the emergency department with acute confusion, vomiting and fever. She was recently diagnosed with a urinary tract infection as an outpatient and had completed the fifth day of a 7-day course of treatment with nitrofurantoin. We maintained a wide differential diagnosis including infectious, metabolic, autoimmune and medication-related causes. She developed an acute normocytic anaemia in hospital with a haemoglobin drop from 121 g/L to 89 g/L. Further investigation revealed evidence of haemolysis with an elevated bilirubin, lactate dehydrogenase, reticulocyte count and decreased haptoglobin. She was worked up for both inherited and acquired causes of haemolysis and found to have glucose-6-phosphate dehydrogenase deficiency. Her presentation was thought to be secondary to nitrofurantoin-induced haemolysis and she recovered completely with conservative management through intravenous fluids and discontinuation of nitrofurantoin.


Assuntos
Deficiência de Glucosefosfato Desidrogenase , Infecções Urinárias , Feminino , Humanos , Nitrofurantoína/efeitos adversos , Hemólise , Deficiência de Glucosefosfato Desidrogenase/complicações , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/complicações , Febre/complicações
3.
BMJ Case Rep ; 16(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36596626

RESUMO

With increasing utilisation of meshes in inguinal hernia repair, reports of mesh-related complications are emerging, particularly late visceral complications, with mesh migration and erosion into the small bowel, bladder and colon reported after laparoscopic totally extraperitoneal (TEP) inguinal hernia repair. We present a case of spontaneous mesh migration through the superficial inguinal ring with skin erosion following TEP inguinal hernia repair, the first published report in the literature to our knowledge. This case highlights the difficulty in diagnosis due to the long latent period of hernia repair and the onset of erosion. A high index of suspicion is required when diagnosing any patient who presents with an unexplained groin abscess following ipsilateral TEP repair. CT scan should be performed early for diagnosis and assessment. Removal of the migrated portion of the mesh, antibiotic therapy and secondary wound closure are strategies for the successful treatment of this complication.


Assuntos
Hérnia Inguinal , Herniorrafia , Telas Cirúrgicas , Humanos , Hérnia Inguinal/cirurgia , Herniorrafia/efeitos adversos , Herniorrafia/métodos , Laparoscopia , Telas Cirúrgicas/efeitos adversos , Resultado do Tratamento , Bexiga Urinária/cirurgia
4.
BMC Cancer ; 23(1): 6, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36597021

RESUMO

BACKGROUND: Conquering acquired resistance to osimertinib remains a major challenge in treating patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Thus, we aimed to determine the safety and efficacy of combination treatment with osimertinib and afatinib for patients with acquired resistance to osimertinib. METHODS: This open-label phase I study was a feasibility study of the combination of afatinib and osimertinib for patients with advanced EGFR-positive NSCLC who had progressive disease after receiving osimertinib. The primary endpoint was to determine the maximum tolerated dose (MTD). We enrolled patients who received afatinib at three different dose levels (level 1, 20 mg; level 2, 30 mg; level 3, 40 mg) combined with osimertinib at a standard dose of 80 mg once per day. RESULTS: Thirteen patients were enrolled in this study. The MTD was defined as 30 mg afatinib when combined with daily oral administration of osimertinib (80 mg). The most frequent adverse events were diarrhea (76.9%), anemia (76.9%), and rash (69.2%). Considering the toxicity profiles during all treatment periods, the recommended oral dose of afatinib was determined as 20 mg daily, with an osimertinib dose of 80 mg. For all evaluable patients (n = 12), the response rate was 7.7% and the disease-control rate was 46.2%. CONCLUSION: Combination therapy with osimertinib and afatinib was tolerable; however, the synergistic effect of afatinib with osimertinib may be limited in osimertinib-resistant patients. TRIAL REGISTRATION: Japan Registry of Clinical Trials ID: jRCTs051180008, registered date: 08/11/2018.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Afatinib , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação
5.
Artigo em Chinês | MEDLINE | ID: mdl-36597367

RESUMO

Objective:To investigate the safety and feasibility of transoral vestibular endoscopy in the treatment of patients with thyroid malignant tumors. Methods:120 patients with thyroid cancer admitted to Xi 'an Central Hospital from January 2019 to December 2021 were selected and randomly divided into endoscopic surgery group(60 cases) and traditional open surgery group(60 cases). The general operation conditions, postoperative complications and postoperative quality of life were compared between the two groups. Results:The intraoperative blood loss, indwelling drainage tube time and average length of hospital stay in the endoscopic surgery group were significantly lower than those in the traditional open surgery group (P<0.05), while the operation time and number of lymph nodes dissected were significantly higher than those in the traditional open surgery group (P<0.05). There was no significant differences in VAS score at 24h after surgery, white blood cell count, TgAb (+) and temporary hypothyroidism between the two groups at 24 h after operation (P >0.05). The CRP, total drainage volume, TgAb and serum calcium in the endoscopic surgery group were higher than those in the traditional open surgery group, and the PTH and Tg were lower than those in the traditional open surgery group (P<0.05).One case of hoarseness,2 cases of extremities numbness, 1 case of subcutaneous effusion and 2 cases of chin nerve injury occurred in the endoscopic surgery group, the total incidence of postoperative complications was 10.00%. Five cases of hoarseness, 11 cases of choking cough limbs numbness, 1 case of drinking water, 1 case of postoperative bleeding and 4 cases of subcutaneous effusion occurred in the traditional open surgery group, the total postoperative incidence of complications was 36.67%, the total incidence of complications in endoscopic surgery group was lower than that in traditional open surgery group (P<0.05). The total scores of physiological status, social/family status, emotional status, functional status and quality of life in endoscopic surgery group were significantly lower than those in traditional open surgery group (P<0.05). Conclusion:The application of oral vestibular endoscopy in the treatment of thyroid malignant tumors has the advantages of good surgical status and postoperative recovery, fewer postoperative complications.The patient was well tolerated,with positive safety,this technique has high clinical application value.


Assuntos
Endoscopia , Neoplasias da Glândula Tireoide , Humanos , Endoscopia/efeitos adversos , Endoscopia/métodos , Estudos de Viabilidade , Rouquidão/etiologia , Hipestesia/etiologia , Hipestesia/cirurgia , Complicações Pós-Operatórias/cirurgia , Qualidade de Vida , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia
6.
Trials ; 24(1): 5, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36597115

RESUMO

BACKGROUND: Mass drug administration (MDA) of azithromycin (AZI) has been shown to reduce under-5 mortality in some but not all sub-Saharan African settings. A large-scale cluster-randomized trial conducted in Malawi, Niger, and Tanzania suggested that the effect differs by country, may be stronger in infants, and may be concentrated within the first 3 months after treatment. Another study found no effect when azithromycin was given concomitantly with seasonal malaria chemoprevention (SMC). Given the observed heterogeneity and possible effect modification by other co-interventions, further trials are needed to determine the efficacy in additional settings and to determine the most effective treatment regimen. METHODS: LAKANA stands for Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin. The LAKANA trial is designed to address the mortality and health impacts of 4 or 2 annual rounds of azithromycin MDA delivered to 1-11-month-old (29-364 days) infants, in a high-mortality and malaria holoendemic Malian setting where there is a national SMC program. Participating villages (clusters) are randomly allocated in a ratio of 3:2:4 to three groups: placebo (control):4-dose AZI:2-dose AZI. The primary outcome measured is mortality. Antimicrobial resistance (AMR) will be monitored closely before, during, and after the intervention and both among those receiving and those not receiving MDA with the study drugs. Other outcomes, from a subset of villages, comprise efficacy outcomes related to morbidity, growth and nutritional status, outcomes related to the mechanism of azithromycin activity through measures of malaria parasitemia and inflammation, safety outcomes (AMR, adverse and serious adverse events), and outcomes related to the implementation of the intervention documenting feasibility, acceptability, and economic aspects. The enrolment commenced in October 2020 and is planned to be completed by the end of 2022. The expected date of study completion is December 2024. DISCUSSION: If LAKANA provides evidence in support of a positive mortality benefit resulting from azithromycin MDA, it will significantly contribute to the options for successfully promoting child survival in Mali, and elsewhere in sub-Saharan Africa. TRIAL REGISTRATION: ClinicalTrials.gov NCT04424511. Registered on 11 June 2020.


Assuntos
Azitromicina , Administração Massiva de Medicamentos , Humanos , Lactente , Antibacterianos/efeitos adversos , Azitromicina/efeitos adversos , Mortalidade Infantil , Malária/prevenção & controle , Mali/epidemiologia , Administração Massiva de Medicamentos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
7.
Trials ; 24(1): 4, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36597128

RESUMO

BACKGROUND: The prognosis for patients with relapsed and/or refractory (R/R) non-Hodgkin's lymphoma (NHL) or acute lymphoblastic leukaemia (ALL) remains poor, with existing treatments having significant side effects. Developed for the treatment of these cancers, AFM11 is a tetravalent, bispecific humanised recombinant antibody construct (TandAb®) designed to bind to human CD19 and CD3 and lead to the activation of T cells inducing apoptosis and killing of malignant B cells. METHODS: Two open-label, multicentre, dose-escalation phase 1 studies evaluated the safety, pharmacokinetics and activity of AFM11 in patients with R/R CD19-positive B cell NHL (AFM11-101) and in patients with CD19 + B-precursor Philadelphia-chromosome negative ALL (AFM11-102). Adverse events (AEs) were assessed and recorded; imaging (NHL) or bone marrow assessment (ALL) were used to evaluate response. Additional pharmacodynamic assays undertaken included cytokine release analysis and B-cell and T-cell depletion. RESULTS: In AFM11-101, 16 patients with R/R NHL received AFM11 in five different dose cohorts. Of which, 14 experienced drug-related treatment-emergent AEs (TEAEs) [including five serious AEs (SAEs)], five patients experienced dose-limiting toxicity (DLT) and ten patients discontinued the study. The high number of neurological events led to a decrease in infusion frequency during the study. No objective response to treatment was observed. In AFM11-102, 17 patients with R/R ALL received AFM11 in six different dose cohorts. Thirteen patients experienced drug-related TEAEs (including four SAEs), DLTs occurred in two patients and five patients discontinued the study. An objective response was recorded in three patients. The maximum tolerated dose could not be determined in either study due to early termination. CONCLUSIONS: AFM11 treatment was associated with frequent neurological adverse reactions that were severe in some patients. In ALL, some signs of activity, albeit short-lived, were observed whereas no activity was observed in patients with NHL; therefore, further clinical development was terminated. TRIAL REGISTRATION: NCT02106091 . Safety Study to Assess AFM11 in Patients With Relapsed and/or Refractory CD19 Positive B-cell NHL. Registered April 2014. NCT02848911 . Safety Study to Assess AFM11 in Patients With Relapsed or Refractory Adult B-precursor ALL. Registered July 2016.


Assuntos
Anticorpos Biespecíficos , Antineoplásicos , Linfoma não Hodgkin , Adulto , Humanos , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos/efeitos adversos , Citocinas , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Linfócitos T
8.
J Coll Physicians Surg Pak ; 33(1): 5-9, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36597226

RESUMO

OBJECTIVE: To compare intravenous lidocaine infusion adjunct to NSAID and Acetaminophen with regular analgesics for postoperative mean pain score and mean ambulation time after laparoscopic cholecystectomy. STUDY DESIGN: Randomised controlled trial. PLACE AND DURATION OF STUDY: Department of General Surgery, Islamabad Medical Complex, (IMC), from March 2020 to December 2021. METHODOLOGY: Sixty (n=60) adult patients, both males and females between the ages of 18-60 years planned for laparoscopic cholecystectomy, were selected and randomly allocated to two groups of treatment (Lidocaine and Ringer Lactate). The control group did not receive any other placebo other than Ringer Lactate infusion. Both groups received Intramuscular Diclofenac 12 hourly and intravenous acetaminophen infusion 8 hourly. Postoperative pain 2, 6, 12 and 24 hours (h) and mean ambulation time were compared in both groups. RESULTS: Mean VAS (Visual Analogue Scale) of group 1 versus group 2 at 2 h, 6 h, 12 h and 24 h were 3.47 ± 0.82 vs. 6.27 ± 0.52 (p=<0.001), 2.7 ± 0.75 vs. 4.8 ± 0.8 (p<0.001), 2.0 ± 0.49 vs. 3.93 ± 0.94 (p<0.001), 0.73 ± 0.82 vs. 2.2 ± 0.61 (p<0.001). Time for spontaneous ambulation after surgery was 5.57 ± 1.55 hours for Group 1 versus 7.3 ± 1.9 hours for Group 2 (p<0.001). CONCLUSION: Pain scores at all-time intervals were lower, and ambulation time was shorter in patients who received intravenous infusion of lidocaine as compared to patients who received only regular analgesics for laparoscopic cholecystectomy. KEY WORDS: Ambulation time, Laparoscopic cholecystectomy, Postoperative pain.


Assuntos
Anestésicos Locais , Colecistectomia Laparoscópica , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Acetaminofen/uso terapêutico , Analgésicos/uso terapêutico , Analgésicos Opioides , Colecistectomia , Colecistectomia Laparoscópica/efeitos adversos , Método Duplo-Cego , Infusões Intravenosas , Lactatos , Lidocaína , Dor Pós-Operatória/tratamento farmacológico
9.
PLoS One ; 18(1): e0279893, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36598904

RESUMO

Arsenic is a potent environmental toxicant and human carcinogen. Skin lesions are the most common manifestations of chronic exposure to arsenic. Advanced-stage skin lesions, particularly hyperkeratosis have been recognized as precancerous diseases. However, the underlying mechanism of arsenic-induced skin lesions remains unknown. Periostin, a matricellular protein, is implicated in the pathogenesis of many forms of skin lesions. The objective of this study was to examine whether periostin is associated with arsenic-induced skin lesions. A total of 442 individuals from low- (n = 123) and high-arsenic exposure areas (n = 319) in rural Bangladesh were evaluated for the presence of arsenic-induced skin lesions (Yes/No). Participants with skin lesions were further categorized into two groups: early-stage skin lesions (melanosis and keratosis) and advanced-stage skin lesions (hyperkeratosis). Drinking water, hair, and nail arsenic concentrations were considered as the participants' exposure levels. The higher levels of arsenic and serum periostin were significantly associated with skin lesions. Causal mediation analysis revealed the significant effect of arsenic on skin lesions through the mediator, periostin, suggesting that periostin contributes to the development of skin lesions. When skin lesion was used as a three-category outcome (none, early-stage, and advanced-stage skin lesions), higher serum periostin levels were significantly associated with both early-stage and advanced-stage skin lesions. Median (IQR) periostin levels were progressively increased with the increasing severity of skin lesions. Furthermore, there were general trends in increasing serum type 2 cytokines (IL-4, IL-5, IL-13, and eotaxin) and immunoglobulin E (IgE) levels with the progression of the disease. The median (IQR) of IL-4, IL-5, IL-13, eotaxin, and IgE levels were significantly higher in the early-and advanced-stage skin lesions compared to the group of participants without skin lesions. The results of this study suggest that periostin is implicated in the pathogenesis and progression of arsenic-induced skin lesions through the dysregulation of type 2 immune response.


Assuntos
Arsênio , Ceratose Actínica , Dermatopatias , Humanos , Arsênio/toxicidade , Arsênio/análise , Interleucina-13 , Interleucina-4 , Interleucina-5 , Exposição Ambiental , Abastecimento de Água , Dermatopatias/induzido quimicamente , Imunoglobulina E/efeitos adversos
10.
Nutrients ; 15(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36678340

RESUMO

We studied the activities of Siraitia grosvenorii extracts (SGE) on airway inflammation in a mouse model of chronic obstructive pulmonary disease (COPD) stimulated by cigarette smoke extract (CSE) and lipopolysaccharide (LPS), as well as in LPS-treated human bronchial epithelial cell line (BEAS-2B). SGE improved the viability of LPS-incubated BEAS-2B cells and inhibited the expression and production of inflammatory cytokines. SGE also attenuated the mitogen-activated protein kinase (MAPK)-nuclear factor-kappa B (NF-κB) signaling activated by LPS stimulation in BEAS-2B cells. In mice stimulated by CSE and LPS, we observed the infiltration of immune cells into the airway after COPD induction. SGE reduced the number of activated T cells, B cells, and neutrophils in bronchoalveolar fluid (BALF), lung tissue, mesenteric lymph node, and peripheral blood mononuclear cells, as well as inhibited infiltration into organs and mucus production. The secretion of cytokines in BALF and the expression level of pro-inflammatory cytokines, mucin 5AC, Transient receptor potential vanilloid 1, and Transient receptor potential ankyrin 1 in lung tissue were alleviated by SGE. In addition, to investigate the activity of SGE on expectoration, we evaluated phenol red secretions in the trachea of mice. SGE administration showed the effect of improving expectoration through an increase in phenol red secretion. Consequently, SGE attenuates the airway inflammatory response in CSE/LPS-stimulated COPD. These findings indicate that SGE may be a potential herbal candidate for the therapy of COPD.


Assuntos
Fumar Cigarros , Doença Pulmonar Obstrutiva Crônica , Camundongos , Humanos , Animais , Lipopolissacarídeos/farmacologia , Fumar Cigarros/efeitos adversos , Modelos Animais de Doenças , Leucócitos Mononucleares/metabolismo , Fenolsulfonaftaleína/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Pulmão/patologia , Inflamação/metabolismo , Citocinas/metabolismo , Tabaco
11.
Nutrients ; 15(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36678345

RESUMO

The food supplement market is growing as many consumers wish to complement their nutrient intake. Despite all the regulations in place to ensure food supplements safety, there are still many cases of irregularities reported especially connected to internet sales. Twenty resveratrol food supplement products sold on the Slovenian market were evaluated on their compliance of declared vs. determined resveratrol content, as well as the compliance of labels with the European Union (EU) and Slovenian regulatory requirements. Both the ingredient contents and food information are important parts of food safety. Analyses of 20 food supplements performed using high-performance thin-layer chromatography (HPTLC) coupled with densitometry showed that 95% of products had contents different from what was declared and 55% of products contained higher contents than declared. In 25% of the products the determined content per unit exceeded the maximum level (150 mg/day) specified in EU novel food conditions for food supplement with trans-resveratrol. Evaluation of the 20 food supplement labels included mandatory and voluntary food information, food supplement information, novel food information, health claims and nutrition claims. Most labels contained the necessary information, but multiple errors were observed ranging from typos to misleading practices. From a food safety perspective there is still a lot of improvement needed in the field of food supplements.


Assuntos
Rotulagem de Alimentos , Inocuidade dos Alimentos , Resveratrol , Suplementos Nutricionais/efeitos adversos , Suplementos Nutricionais/análise , União Europeia
12.
Nutrients ; 15(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36678346

RESUMO

BACKGROUND: The enhanced consumption of fructose as added sugar represents a major health concern. Due to the complexity and multiplicity of hypothalamic functions, we aim to point out early molecular alterations triggered by a sugar-rich diet throughout adolescence, and to verify their persistence until the young adulthood phase. METHODS: Thirty days old rats received a high-fructose or control diet for 3 weeks. At the end of the experimental period, treated animals were switched to the control diet for further 3 weeks, and then analyzed in comparison with those that were fed the control diet for the entire experimental period. RESULTS: Quantitative proteomics identified 19 differentially represented proteins, between control and fructose-fed groups, belonging to intermediate filament cytoskeleton, neurofilament, pore complex and mitochondrial respiratory chain complexes. Western blotting analysis confirmed proteomic data, evidencing a decreased abundance of mitochondrial respiratory complexes and voltage-dependent anion channel 1, the coregulator of mitochondrial biogenesis PGC-1α, and the protein subunit of neurofilaments α-internexin in fructose-fed rats. Diet-associated hypothalamic inflammation was also detected. Finally, the amount of brain-derived neurotrophic factor and its high-affinity receptor TrkB, as well as of synaptophysin, synaptotagmin, and post-synaptic protein PSD-95 was reduced in sugar-fed rats. Notably, deregulated levels of all proteins were fully rescued after switching to the control diet. CONCLUSIONS: A short-term fructose-rich diet in adolescent rats induces hypothalamic inflammation and highly affects mitochondrial and cytoskeletal compartments, as well as the level of specific markers of brain function; above-reported effects are reverted after switching animals to the control diet.


Assuntos
Frutose , Proteômica , Ratos , Animais , Frutose/efeitos adversos , Frutose/metabolismo , Dieta , Hipotálamo/metabolismo , Inflamação/metabolismo
13.
Stroke ; 54(2): 457-467, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36647921

RESUMO

BACKGROUND: There is uncertainty whether elderly patients with symptomatic carotid stenosis have higher rates of adverse events following carotid endarterectomy. In trials, recurrent stroke risk on medical therapy alone increased with age, whereas operative stroke risk was not related. Few octogenarians were included in trials and there has been no systematic analysis of all study types. We aimed to evaluate the safety of carotid endarterectomy in symptomatic elderly patients, particularly in octogenarians. METHODS: We did a systematic review and meta-analysis of studies (from January 1, 1980 through March 1, 2022) reporting post carotid endarterectomy risk of stroke, myocardial infarction, and death in patients with symptomatic carotid stenosis. We included observational studies and interventional arms of randomized trials if the outcome rates (or the raw data to calculate these) were provided. Individual patient data from 4 prospective cohorts enabled multivariate analysis. RESULTS: Of 47 studies (107 587 patients), risk of perioperative stroke was 2.04% (1.94-2.14) in octogenarians (390 strokes/19 101 patients) and 1.85% (1.75-1.95) in nonoctogenarians (1395/75 537); P=0.046. Perioperative death was 1.09% (0.94-1.25) in octogenarians (203/18 702) and 0.53% (0.48-0.59) in nonoctogenarians (392/73 327); P<0.001. Per 5-year age increment, a linear increase in perioperative stroke, myocardial infarction, and death were observed; P=0.04 to 0.002. However, during the last 3 decades, perioperative stroke±death has declined significantly in octogenarians (7.78% [5.58-10.55] before year 2000 to 2.80% [2.56-3.04] after 2010); P<0.001. In Individual patient data multivariate-analysis (5111 patients), age ≥85 years was independently associated with perioperative stroke (P<0.001) and death (P=0.005). Yet, survival was similar for octogenarians versus nonoctogenarians at 1-year (95.0% [93.2-96.5] versus 97.5% [96.4-98.6]; P=0.08), as was 5-year stroke risk (11.93% [9.98-14.16]) versus 12.78% [11.65-13.61]; P=0.24). CONCLUSIONS: We found a modest increase in perioperative risk with age in symptomatic patients undergoing carotid endarterectomy. As stroke risk increases with age when on medical therapy alone, our findings support selective urgent intervention in symptomatic elderly patients.


Assuntos
Estenose das Carótidas , Endarterectomia das Carótidas , Infarto do Miocárdio , Acidente Vascular Cerebral , Idoso de 80 Anos ou mais , Humanos , Idoso , Endarterectomia das Carótidas/efeitos adversos , Estenose das Carótidas/cirurgia , Constrição Patológica/complicações , Estudos Prospectivos , Fatores de Risco , Resultado do Tratamento , Acidente Vascular Cerebral/etiologia , Infarto do Miocárdio/etiologia
14.
J Clin Psychiatry ; 84(1)2023 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-36652686

RESUMO

Objective: Most research on safety of attention-deficit/hyperactivity disorder (ADHD) medications during pregnancy concerns central nervous system stimulants, while little is known about the safety of atomoxetine, a primary treatment alternative. We assessed the prevalence of major congenital malformations overall, and cardiac malformations and limb malformations specifically, after first-trimester exposure.Methods: In this cohort study, we included all approximately 2.4 million pregnancies ending in live births recorded in the population-based nationwide health registers of Denmark, Iceland, Norway, and Sweden (2003-2017) and approximately 1.8 million publicly insured pregnancies ending in live births recorded in the US Medicaid Analytic eXtract (MAX, 2001-2013) health care claims database. We compared the prevalence of major congenital malformations in the newborn among pregnancies exposed and unexposed to atomoxetine. For each country, we calculated prevalence ratios (PRs), crude and stratified by propensity scores (PSs). We pooled the country-specific PS strata to obtain a PR adjusted for potential confounding factors.Results: We identified 368 pregnancies exposed to atomoxetine during the first trimester in the 4 Nordic countries and 622 in the US. The pooled crude PR for any major congenital malformation was 1.18 (95% CI, 0.88-1.60), and the adjusted PR was 0.99 (95% CI, 0.74-1.34). For cardiac malformations, the adjusted PR was 1.34 (95% CI, 0.86-2.09). For limb malformations, the adjusted PR was 0.90 (95% CI, 0.38-2.16).Conclusions: After atomoxetine exposure in early pregnancy, we observed no increase in major congenital malformations overall and, although with some uncertainty due to sample size, no statistically increased risk estimates for cardiac malformations and limb malformations.


Assuntos
Anormalidades Induzidas por Medicamentos , Cardiopatias Congênitas , Gravidez , Recém-Nascido , Feminino , Humanos , Cloridrato de Atomoxetina/efeitos adversos , Estudos de Coortes , Prevalência , Anormalidades Induzidas por Medicamentos/epidemiologia , Anormalidades Induzidas por Medicamentos/etiologia , Primeiro Trimestre da Gravidez , Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/epidemiologia
15.
Int J Mol Sci ; 24(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36674448

RESUMO

High-fat/sucrose diet feeding in mice causes loss of corneal nerve function and impairs corneal wound healing. While changing to a diet with a low fat/sugar composition and enrichments in complex carbohydrates mitigates the reduction in nerve function, it remains to be determined if it has an effect on corneal wound healing. In this study, 6-week-old C57BL/6 male mice were fed either a normal diet or a high-fat/sucrose diet for 20 weeks. A third group (diet reversal) was placed on a high-fat/sucrose diet for 10 weeks followed by a normal diet for an additional 10 weeks. A central corneal epithelial abrasion wound was created, and wound closure was monitored. Neutrophil and platelet recruitment was assessed by immunofluorescence microscopy. Mice fed the high-fat/sucrose diet-only had greater adiposity (p < 0.005) than normal diet-only fed mice; diet reversal markedly reduced adiposity. Following corneal abrasion, wound closure was delayed by ~6 h (p ≤ 0.01) and, at 30 h post-wounding, fewer neutrophils reached the wound center and fewer extravascular platelets were present at the limbus (p < 0.05). Diet restored normal wound closure and neutrophil and platelet influx in the injured cornea. These data suggest compositional changes to the diet may be an effective diet-based therapeutic strategy for maintaining or restoring corneal health.


Assuntos
Lesões da Córnea , Sacarose , Masculino , Animais , Camundongos , Sacarose/farmacologia , Camundongos Endogâmicos C57BL , Córnea , Lesões da Córnea/etiologia , Obesidade/etiologia , Dieta Hiperlipídica/efeitos adversos
16.
Clinics (Sao Paulo) ; 78: 100152, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36681071

RESUMO

This study aimed to perform a meta­analysis comparing the efficacy and safety of gefitinib in combination with chemotherapy versus gefitinib alone in patients with advanced Non­Small Cell Lung Cancer (NSCLC). We searched databases for clinical studies that reported the efficacy or safety of gefitinib plus chemotherapy in comparison with gefitinib alone. Raw data from included studies were extracted and pooled to calculate the Odds Ratio (OR) for Objective Response Rate (ORR) and Disease Control Rate (DCR), the Hazard Ratio (HR) for Progression-Free Survival (PFS) and Overall Survival (OS), and OR for complication ≥ Grade 3. A total of 10 studies containing 1,528 patients with NSCLC were identified and included in the analysis. Gefitinib plus chemotherapy showed significantly better efficacy in improving ORR (OR = 1.54; 95% CI [Confidence Interval], 1.13‒2.1; p = 0.006), DCR (OR = 1.62; 95% CI 1.14‒2.29; p = 0.007), PFS (HR=1.67; 95% CI 1.45‒1.94; p < 0.001) and OS (HR = 1.49; 95% CI 1.2‒1.87; p < 0.001) as compared with gefitinib alone. Consistent results were observed in the sub-population with positive EGFR mutation. The combination of gefitinib with chemotherapy had a significantly higher risk of complication (≥ Grade 3) with an OR of 3.29 (95% CI 2.57‒4.21; p < 0.001). The findings in the present study suggest that the combination of gefitinib with chemotherapy can provide better disease response and survival outcomes for patients with advanced NSCLC.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Gefitinibe/efeitos adversos , Antineoplásicos/efeitos adversos , Intervalo Livre de Progressão , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Mutação , Inibidores de Proteínas Quinases/uso terapêutico
17.
Stroke ; 54(2): 476-487, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36689584

RESUMO

BACKGROUND: Symptomatic intracranial hemorrhage (sICH) is a severe complication of reperfusion therapy for ischemic stroke. Multiple models have been developed to predict sICH or intracranial hemorrhage (ICH) after reperfusion therapy. We provide an overview of published models and validate their ability to predict sICH in patients treated with endovascular treatment in daily clinical practice. METHODS: We conducted a systematic search to identify models either developed or validated to predict sICH or ICH after reperfusion therapy (intravenous thrombolysis and/or endovascular treatment) for ischemic stroke. Models were externally validated in the MR CLEAN Registry (n=3180; Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). The primary outcome was sICH according to the Heidelberg Bleeding Classification. Model performance was evaluated with discrimination (c-statistic, ideally 1; a c-statistic below 0.7 is considered poor in discrimination) and calibration (slope, ideally 1, and intercept, ideally 0). RESULTS: We included 39 studies describing 40 models. The most frequently used predictors were baseline National Institutes of Health Stroke Scale (NIHSS; n=35), age (n=22), and glucose level (n=22). In the MR CLEAN Registry, sICH occurred in 188/3180 (5.9%) patients. Discrimination ranged from 0.51 (SPAN-100 [Stroke Prognostication Using Age and National Institutes of Health Stroke Scale]) to 0.61 (SITS-SICH [Safe Implementation of Treatments in Stroke Symptomatic Intracerebral Hemorrhage] and STARTING-SICH [STARTING Symptomatic Intracerebral Hemorrhage]). Best calibrated models were IST-3 (intercept, -0.15 [95% CI, -0.01 to -0.31]; slope, 0.80 [95% CI, 0.50-1.09]), SITS-SICH (intercept, 0.15 [95% CI, -0.01 to 0.30]; slope, 0.62 [95% CI, 0.38-0.87]), and STARTING-SICH (intercept, -0.03 [95% CI, -0.19 to 0.12]; slope, 0.56 [95% CI, 0.35-0.76]). CONCLUSIONS: The investigated models to predict sICH or ICH discriminate poorly between patients with a low and high risk of sICH after endovascular treatment in daily clinical practice and are, therefore, not clinically useful for this patient population.


Assuntos
Isquemia Encefálica , Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Ativador de Plasminogênio Tecidual/uso terapêutico , Fibrinolíticos/uso terapêutico , AVC Isquêmico/tratamento farmacológico , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Hemorragias Intracranianas/epidemiologia , Hemorragia Cerebral/complicações , Resultado do Tratamento , Isquemia Encefálica/tratamento farmacológico , Procedimentos Endovasculares/efeitos adversos
18.
Ren Fail ; 45(1): 2167661, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36692196

RESUMO

BACKGROUND: This retrospective study aimed to determine the incidence, risk factors, and outcomes of acute kidney injury (AKI) in neonates following the arterial switch operation (ASO) for transposition of great arteries (TGA). METHODS: Retrospective review of medical data of children who underwent ASO in 2019-2020 in the Ukrainian Children's Cardiac Center. RESULTS: 76 consecutive neonatal patients were included, 48 developed AKI after ASO (51.7%), and 24 - had severe AKI (25.8%). Severe AKI development was associated with longer cross-clamp time: 82 (61-127) versus 73.5 (53-136) in the non-severe AKI group (p = 0.02). 76 min of cross-clamp time were defined as a threshold value for increased severe AKI risk, OR 4.4 (95% CI: 1.5 - 13, p = 0.01). Higher lactate levels during cardiopulmonary bypass (CPB) increased severe AKI development risk, OR 1.5 (95% CI: 1.0 - 2.0, p = 0.03). Children with severe AKI had prolonged mechanical ventilation, longer time to negative fluid balance, and higher postoperative day 3 (POD3) Inotropic Score (IS). Only one patient required peritoneal dialysis. CONCLUSIONS: In our study, 51.7% of patients developed AKI after ASO, 25.8%-severe AKI. Prolonged cross-clamp time and higher lactate levels during cardiopulmonary bypass increased the risk for severe AKI development. The development of AKI was associated with prolonged mechanical ventilation, longer time to negative fluid balance, higher POD 3 Inotropic Score.


Assuntos
Injúria Renal Aguda , Transposição das Grandes Artérias , Recém-Nascido , Criança , Humanos , Estudos Retrospectivos , Transposição das Grandes Artérias/efeitos adversos , Incidência , Complicações Pós-Operatórias/etiologia , Injúria Renal Aguda/etiologia , Ponte Cardiopulmonar/efeitos adversos , Fatores de Risco , Lactatos
19.
Cancer J ; 29(1): 28-33, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36693155

RESUMO

ABSTRACT: Genetically engineered chimeric antigen receptor (CAR) T-cell therapy leverages the ability of the immune system to eliminate tumors and redirects cytotoxic functions toward cells expressing specified tumor-restricted antigens. Although 6 CAR T-cell therapies have received Food and Drug Administration (FDA) approval for the treatment of many hematological malignancies, limitations involving T cell-intrinsic, T cell-extrinsic, and therapeutic factors remain in the treatment of both liquid and solid tumors. Chimeric antigen receptor design, signals from the tumor microenvironment, tumor antigen escape mechanisms, and systemic inflammatory consequences of CAR T-cell infusion all influence the efficacy and feasibility of CAR T-cell therapy in different malignancies. Here, we review the core structure of the CAR, the evolution of different CAR generations, CAR T-cell therapy limitations, and current strategies being investigated to overcome the T cell-intrinsic, T cell-independent, and therapeutic barriers to successful CAR T-cell therapy.


Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfócitos T , Receptores de Antígenos Quiméricos/genética , Neoplasias/terapia , Antígenos de Neoplasias , Microambiente Tumoral , Terapia Baseada em Transplante de Células e Tecidos , Receptores de Antígenos de Linfócitos T/genética
20.
Pharm Biol ; 61(1): 324-336, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36694954

RESUMO

CONTEXT: Tripterygium glycosides (TG), a traditional Chinese medicine, has been used to treat chronic urticaria (CU) in China, and the evidence of TG for CU needs to be updated thoroughly. OBJECTIVE: To systematically evaluate the efficacy and safety of TG combined with H1-antihistamine (H1-AH) in adults with CU. METHODS: Eligible randomized controlled trials were searched in eight databases until May 31, 2022, including CNKI, WanFang, VIP, SinoMed, PubMed, Cochrane Library, Embase, and Web of Science. The search terms included urticaria, Tripterygium, Lei Gong Teng, and Leigongteng. Rev Man 5.3 and Stata 12.0 were used for statistical analysis. RESULTS: A total of 27 studies with 2788 patients were included. The pooled results showed that TG plus H1-AH was superior to H1-AH alone in cure rate (RR = 1.37, 95% CI = 1.15 to 1.63, p = 0.0003), total efficacy rate (RR = 1.40, 95% CI = 1.30 to 1.50, p < 0.00001), pruritus (MD = -0.32, 95% CI = -0.54 to -0.11, p = 0.003), wheal number (MD = -0.31, 95% CI = -0.55 to -0.07, p = 0.01), wheal size (MD = -0.32, 95% CI = -0.46 to -0.19, p < 0.00001), and the serum level of immunoglobulin E (SMD = -1.39, 95% CI = -2.42 to -0.36, p = 0.008). Moreover, adverse events between two groups were mild, and their incidences were not significantly different. CONCLUSIONS: The combination of TG and H1-AH is a promising and safe treatment for adults with refractory CU. Further high-quality studies are needed to confirm the evidence.


Assuntos
Urticária Crônica , Medicamentos de Ervas Chinesas , Humanos , Adulto , Tripterygium , Glicosídeos/efeitos adversos , Cobre , Medicina Tradicional Chinesa , Medicamentos de Ervas Chinesas/efeitos adversos
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