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1.
Zhonghua Jie He He Hu Xi Za Zhi ; 43(11): 970-974, 2020 Nov 12.
Artículo en Chino | MEDLINE | ID: mdl-33137863

RESUMEN

The novel coronavirus pneumonia (COVID-19) is still in a serious situation. There is no specific therapeutic drug for COVID-19. At present, drugs, including lopinavir/ritonavir, chloroquine phosphate, abidol, IFN-α atomization and ribavirin, are commonly used in clinical practice. However, further clinical trials are needed to evaluate the efficacy and safety of these drugs. Other potential drugs that may be effective for COVID-19, are worthy of attention, including IL-6 monoclonal antibody, tyrosine protein kinase 1/2 inhibitor, cell therapy drugs, etc. This paper reviews these potential therapeutic drugs for COVID-19.


Asunto(s)
Antivirales/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Betacoronavirus , Combinación de Medicamentos , Humanos , Pandemias
2.
Medicina (Kaunas) ; 56(11)2020 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-33138045

RESUMEN

BACKGROUND AND OBJECTIVES: Streptococcus pneumoniae urinary antigen (u-Ag) testing has recently gained attention in the early diagnosis of severe and critical acute respiratory syndrome coronavirus-2/pneumococcal co-infection. The aim of this study is to assess the effectiveness of Streptococcus pneumoniae u-Ag testing in coronavirus disease 2019 (COVID-19) patients, in order to assess whether pneumococcal co-infection is associated with different mortality rate and hospital stay in these patients. MATERIALS AND METHODS: Charts, protocols, mortality, and hospitalization data of a consecutive series of COVID-19 patients admitted to a tertiary hospital in northern Italy during COVID-19 outbreak were retrospectively reviewed. All patients underwent Streptococcus pneumoniae u-Ag testing to detect an underlying pneumococcal co-infection. Covid19+/u-Ag+ and Covid19+/u-Ag- patients were compared in terms of overall survival and length of hospital stay using chi-square test and survival analysis. RESULTS: Out of 575 patients with documented pneumonia, 13% screened positive for the u-Ag test. All u-Ag+ patients underwent treatment with Ceftriaxone and Azithromycin or Levofloxacin. Lopinavir/Ritonavir or Darunavir/Cobicistat were added in 44 patients, and hydroxychloroquine and low-molecular-weight heparin (LMWH) in 47 and 33 patients, respectively. All u-Ag+ patients were hospitalized. Mortality was 15.4% and 25.9% in u-Ag+ and u-Ag- patients, respectively (p = 0.09). Survival analysis showed a better prognosis, albeit not significant, in u-Ag+ patients. Median hospital stay did not differ among groups (10 vs. 9 days, p = 0.71). CONCLUSIONS: The routine use of Streptococcus pneumoniae u-Ag testing helped to better target antibiotic therapy with a final trend of reduction in mortality of u-Ag+ COVID-19 patients having a concomitant pneumococcal infection. Randomized trials on larger cohorts are necessary in order to draw definitive conclusion.


Asunto(s)
Antibacterianos/uso terapéutico , Antivirales/uso terapéutico , Coinfección/diagnóstico , Infecciones por Coronavirus/tratamiento farmacológico , Mortalidad Hospitalaria , Neumonía Neumocócica/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticoagulantes/uso terapéutico , Antígenos Bacterianos/orina , Azitromicina/uso terapéutico , Betacoronavirus , Ceftriaxona/uso terapéutico , Cobicistat/uso terapéutico , Coinfección/orina , Infecciones por Coronavirus/complicaciones , Estudios Transversales , Darunavir/uso terapéutico , Combinación de Medicamentos , Femenino , Heparina de Bajo-Peso-Molecular/uso terapéutico , Humanos , Hidroxicloroquina/uso terapéutico , Tiempo de Internación/estadística & datos numéricos , Levofloxacino/uso terapéutico , Lopinavir/uso terapéutico , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Pandemias , Neumonía Neumocócica/complicaciones , Neumonía Neumocócica/diagnóstico , Neumonía Neumocócica/orina , Neumonía Viral/complicaciones , Estudios Retrospectivos , Ritonavir/uso terapéutico , Streptococcus pneumoniae/inmunología
3.
Vestn Otorinolaringol ; 85(5): 40-43, 2020.
Artículo en Ruso | MEDLINE | ID: mdl-33140932

RESUMEN

The purpose of the study was to summarize data on modern antibiotic therapy for acute sinusitis, the role and place of topical antibacterial drugs, in particular Fluimucil-Antibiotic, in modern treatment strategies for this disease. METHODS: Search in the PUBMED electronic database (articles and related abstracts) for the keywords «acute sinusitis", «antibiotics¼, «thiamphenicol glycinate acetylcysteine¼ «biofilm¼, «respiratory tract infection¼, «N-acetylcysteine¼. RESULTS: The published research results indicate the high antibacterial activity of the Fluimucil-Antibiotic, in particular, for the topical drug use in the form of inhalations, applications, irrigation, and instillations. The published research results indicate a wide spectrum of antimicrobial action of Fluimucil-Antibiotic, its ability to destroy biofilms and prevent their formation, good pharmacokinetics, safety, which makes it possible to consider it as a potential treatment option for acute sinusitis in everyday practice.


Asunto(s)
Infecciones del Sistema Respiratorio , Sinusitis , Acetilcisteína , Enfermedad Aguda , Antibacterianos/uso terapéutico , Combinación de Medicamentos , Humanos , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Sinusitis/tratamiento farmacológico
4.
Braz Dent J ; 31(5): 511-515, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33146335

RESUMEN

This study aimed to assess the physicochemical properties of a repair material in the Brazilian market, BioMTA, in comparison to other two materials currently in use (Biodentine and MTA Angelus). The initial setting time was evaluated using Gillmore needle. The pH was measured with a pH-meter after 24 h, 3, 7, 14 and 21 days. The radiopacity was determined using the equivalence in millimeters of aluminum (mm Al) from digitized occlusal radiographs. Solubility was determined after immersion in water for 7 days. The data were analyzed by one-way ANOVA and Tukey tests (a=0.05). The BioMTA initial setting time (5.2 min) was lower than the other materials (p<0.05). All materials showed an alkaline pH at 21 days. At 24 h, BioMTA was the most alkaline material (p<0.05); and at 3, 7, 14 and 21 days there was no difference between BioMTA and Biodentine (p>0.05), both being more alkaline than MTA Angelus (p<0.05). The radiopacity of BioMTA (4.2 mm Al) was significantly higher compared to Biodentine (p<0.05) and lower than MTA Angelus (p<0.05). The solubility of the materials was -4.2%, -1.6% and 4.1% for BioMTA, MTA Angelus and Biodentine, respectively, with a significant difference between them (p<0.05). Therefore, it can be concluded that BioMTA displayed a shorter setting time, an alkaline pH, a higher radiopacity, and a gain in mass.


Asunto(s)
Materiales de Obturación del Conducto Radicular , Silicatos , Resinas Acrílicas , Compuestos de Aluminio , Brasil , Compuestos de Calcio , Combinación de Medicamentos , Ensayo de Materiales , Óxidos , Solubilidad , Agua
5.
BMC Pulm Med ; 20(1): 301, 2020 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-33198751

RESUMEN

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly reached pandemic proportions. Given that the main target of SARS-CoV-2 are lungs leading to severe pneumonia with hyperactivation of the inflammatory cascade, we conducted a prospective study to assess alveolar inflammatory status in patients with moderate to severe COVID-19. METHODS: Diagnostic bronchoalveolar lavage (BAL) was performed in 33 adult patients with SARS-CoV-2 infection by real-time PCR on nasopharyngeal swab admitted to the Intensive care unit (ICU) (n = 28) and to the Intermediate Medicine Ward (IMW) (n = 5). We analyze the differential cell count, ultrastructure of cells and Interleukin (IL)6, 8 and 10 levels. RESULTS: ICU patients showed a marked increase in neutrophils (1.24 × 105 ml- 1, 0.85-2.07), lower lymphocyte (0.97 × 105 ml- 1, 0.024-0.34) and macrophages fractions (0.43 × 105 ml- 1, 0.34-1.62) compared to IMW patients (0.095 × 105 ml- 1, 0.05-0.73; 0.47 × 105 ml- 1, 0.28-1.01 and 2.14 × 105 ml- 1, 1.17-3.01, respectively) (p < 0.01). Study of ICU patients BAL by electron transmission microscopy showed viral particles inside mononuclear cells confirmed by immunostaining with anti-viral capsid and spike antibodies. IL6 and IL8 were significantly higher in ICU patients than in IMW (IL6 p < 0.01, IL8 p < 0.0001), and also in patients who did not survive (IL6 p < 0.05, IL8 p = 0.05 vs. survivors). IL10 did not show a significant variation between groups. Dividing patients by treatment received, lower BAL concentrations of IL6 were found in patients treated with steroids as compared to those treated with tocilizumab (p < 0.1) or antivirals (p < 0.05). CONCLUSIONS: Alveolitis, associated with COVID-19, is mainly sustained by innate effectors which showed features of extensive activation. The burden of pro-inflammatory cytokines IL6 and IL8 in the broncho-alveolar environment is associated with clinical outcome.


Asunto(s)
Líquido del Lavado Bronquioalveolar/inmunología , Infecciones por Coronavirus/inmunología , Inflamación/inmunología , Interleucina-6/inmunología , Interleucina-8/inmunología , Leucocitos/inmunología , Pulmón/inmunología , Macrófagos Alveolares/inmunología , Neumonía Viral/inmunología , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Corticoesteroides/uso terapéutico , Anciano , Alanina/análogos & derivados , Alanina/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antivirales/uso terapéutico , Betacoronavirus , Lavado Broncoalveolar , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/virología , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/terapia , Combinación de Medicamentos , Femenino , Humanos , Hidroxicloroquina/uso terapéutico , Unidades de Cuidados Intensivos , Interleucina-10/inmunología , Italia , Leucocitos Mononucleares/virología , Lopinavir/uso terapéutico , Pulmón/citología , Pulmón/virología , Linfocitos/inmunología , Masculino , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Neutrófilos/inmunología , Pandemias , Neumonía Viral/terapia , Pronóstico , Estudios Prospectivos , Respiración Artificial/métodos , Ritonavir/uso terapéutico , Glicoproteína de la Espiga del Coronavirus/metabolismo , Tasa de Supervivencia , Virión/metabolismo , Virión/ultraestructura
6.
BMJ Open ; 10(11): e040110, 2020 11 12.
Artículo en Inglés | MEDLINE | ID: mdl-33184083

RESUMEN

INTRODUCTION: Lopinavir/ritonavir (LPV/r) has been proposed as repurposed drugs for pre-exposure and postexposure prophylaxis as well as therapy of COVID-19. Coronavirus postexposure prophylaxis (COPEP) trial aims at assessing their efficacy as postexposure ring-prophylaxis among adults exposed to SARS-CoV-2. METHODS AND ANALYSIS: COPEP is a two-arm open-label cluster-randomised trial conducted in three cantons of Switzerland. Asymptomatic contacts (≥16 years) of individuals diagnosed with COVID-19 will be randomised (2:1) to either LPV/r (400 mg/100 mg two times per day) for 5 days, or a standard of care arm (no treatment). Asymptomatic individuals may be either SARS-CoV-2 positive or negative. Contacts living in the single household will form a cluster and will be randomised into the same arm. All participants will be followed-up for 21 days and undergo daily monitoring for COVID-19 symptoms. The primary endpoint is 21-day incidence of laboratory-confirmed COVID-19 with ≥1 compatible symptom, analysed in an intention-to-treat (ITT) analysis. The secondary endpoints include the 21-day incidence of COVID-19 as well as SARS-CoV-2 infection in a modified ITT analysis, excluding participants who had a positive SARS-CoV-2 RT-PCR from oropharyngeal swab and/or a positive SARS-CoV-2 IgG serology at baseline. Assuming a 21-day incidence for COVID-19 of 20% among contacts without postexposure chemoprophylaxis, to detect a relative risk reduction of 60% (ie, translating in an absolute reduction from 20% to 8%), with a power of 80%, an alpha of 5%. Accounting for design effect of cluster design of circa 1.1, we plan to enrol 200 participants to the LPV/r arm and 100 to the standard of care arm, 300 participants in total. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Commission Cantonale d'Ethique de la Recherche, Ethikkommission Nordwest- und Zentralschweiz and Comitato Etico Cantonale (ref 2020-00864) and Swissmedic (2020DR3056). Results from this trial will be disseminated via journal articles and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov Registry (NCT04364022); Swiss National Clinical Trial Portal Registry (SNCTP 000003732). REGISTERED REPORT IDENTIFIER: CCER 2020-0864.


Asunto(s)
Antivirales/uso terapéutico , Infecciones por Coronavirus/prevención & control , Lopinavir/uso terapéutico , Pandemias/prevención & control , Neumonía Viral/prevención & control , Profilaxis Posexposición/métodos , Ritonavir/uso terapéutico , Betacoronavirus , Combinación de Medicamentos , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Suiza
7.
Folia Biol (Praha) ; 66(3): 104-110, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33069189

RESUMEN

Cancer development is a highly complicated process in which tumour growth depends on the development of its vascularization system. To support their own growth, tumour cells significantly modify their microenvironment. One of such modifications inflicted by tumours is stimulation of endothelial cell migration and proliferation. There is accumulating evidence that extracellular vesicles (EVs) secreted by tumour cells (tumour-derived EVs, TEVs) may be regarded as "messengers" with the potential for affecting the biological activities of target cells. Interaction of TEVs with different cell types occurs in an auto- and paracrine manner and may lead to changes in the function of the latter, e.g., promoting motility, proliferation, etc. This study analysed the proangiogenic activity of EVs derived from human pancreatic adenocarcinoma cell line (HPC-4, TEVHPC) in vitro and their effect in vivo on Matrigel matrix vascularization in severe combined immunodeficient (SCID) mice. TEVHPC enhanced proliferation of HPC-4 cells and induced their motility. Moreover, TEVHPC stimulated human umbilical vein endothelial cell (HUVEC) proliferation and migration in vitro. Additionally, TEVHPC influenced secretion of proangiogenic factors (IL-8, VEGF) by HUVEC cells and supported Matrigel matrix haemoglobinization in vivo. These data show that TEVs may support tumour propagation in an autocrine manner and may support vascularization of the tumour. The presented data are in line with the theory that tumour cells themselves are able to modulate the microenvironment via TEVs to maximize their growth potential.


Asunto(s)
Carcinoma Ductal Pancreático/patología , Vesículas Extracelulares/patología , Neoplasias Pancreáticas/patología , Animales , Comunicación Autocrina , División Celular , Línea Celular Tumoral , Quimiotaxis , Colágeno , Combinación de Medicamentos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Laminina , Ratones , Ratones SCID , Trasplante de Neoplasias , Neovascularización Patológica/etiología , Proteoglicanos , ARN Mensajero/biosíntesis , Microambiente Tumoral , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo
8.
Vestn Oftalmol ; 136(5): 96-102, 2020.
Artículo en Ruso | MEDLINE | ID: mdl-33056969

RESUMEN

PURPOSE: To study the hypotensive effectiveness and safety of Bimoptic Plus (bimatoprost 0.03% + timolol 0.5%) in patients with developed primary open-angle glaucoma (POAG). MATERIAL AND METHODS: The study included 30 patients aged 57 to 72 years (45 eyes). The 1st group included 15 patients (24 eyes) who were first diagnosed with developed glaucoma with moderately elevated and high intraocular pressure (IOP) and prescribed the drug as starting therapy. Patients of the 2nd group (15 patients, 21 eyes) were prescribed Bimoptic Plus with insufficient effectiveness of monotherapy with prostaglandin analogues. The follow-up period was 6 months. RESULTS: The study was completed by 26 patients (41 eyes). Three patients (10%) has stopped using Bimoptic Plus due to side effects, one (3.3%) - due to insufficient hypotensive effect. In the 1st group, the maximum IOP decrease was recorded at the 1st month of the study and amounted to 8.34±1.47 mm Hg (32.2%) compared to baseline, while after 2 weeks, 3 and 6 months it decreased to 8.1±1.52 mm Hg (31.3%), 7.93±1.35 mm Hg (30.6%) and 7.9±1.42 mm Hg (30.5%), respectively. In patients of the 2nd group, additional IOP decrease after 2 weeks, 1, 3, and 6 months from the start of therapy was 4.68±1.24 mm Hg (20.5%), 4.94±1.18 mm Hg (21.7%), 4.55±1.23 mm Hg (20%), 4.5±1.26 mm Hg (19.7%), respectively. CONCLUSION: Bimoptic Plus effectively reduces the IOP level and has the least amount adverse reactions. It can be recommended for wide use in the treatment of patients with POAG.


Asunto(s)
Cloprostenol , Glaucoma de Ángulo Abierto , Anciano , Antihipertensivos/efectos adversos , Combinación de Medicamentos , Glaucoma de Ángulo Abierto/diagnóstico , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Humanos , Presión Intraocular , Persona de Mediana Edad
9.
Indian J Pharmacol ; 52(4): 313-323, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33078733

RESUMEN

BACKGROUND: Being protease inhibitors and owing to their efficacy in SARS-CoV, lopinavir + ritonavir (L/R) combination is being used in the management of COVID-19. In this systematic review and meta-analysis, we have evaluated the comparative safety and efficacy of L/R combination. MATERIALS AND METHODS: Comparative, observational studies and controlled clinical trials comparing L/R combination to standard of care (SOC)/control or any other antiviral agent/combinations were included. A total of 10 databases were searched to identify 13 studies that fulfilled the predefined inclusion/exclusion criteria. RESULTS: No discernible beneficial effect was seen in the L/R group in comparison to SOC/control in terms of "progression to more severe state" (4 studies, odds ratio [OR]: 1.446 [0.722-2.895]), "mortality" (3 studies, OR: 1.208 [0.563-2.592]), and "virological cure on days 7-10" (3 studies, OR: 0.777 [0.371-1.630]), while the L/R combination arm performed better than the SOC/control arm in terms of "duration of hospital stay" (3 studies, mean difference (MD): -1.466 [-2.403 to - 0.529]) and "time to virological cure" (3 studies, MD: -3.272 [-6.090 to - 0.454]). No difference in efficacy was found between L/R versus hydroxychloroquine (HCQ) and L/R versus arbidol. However, in a single randomized controlled trail (open label), chloroquine (CQ) performed better than L/R. The combination L/R with arbidol may be beneficial (in terms of virological clearance and radiological improvement); however, we need more dedicated studies. Single studies report efficacy of L/R + interferon (IFN, either alpha or 1-beta) combination. We need more studies to delineate the proper effect size. Regarding adverse effects, except occurrence of diarrhea (higher in the L/R group), safety was comparable to SOC. CONCLUSION: In our study, no difference was seen between the L/R combination and the SOC arm in terms of "progression to more severe state," "mortality," and virological cure on days 7-10;" however, some benefits in terms of "duration of hospital stay" and "time to virological cure" were seen. No significant difference in efficacy was seen when L/R was compared to arbidol and HCQ monotherapy. Except for the occurrence of diarrhea, which was higher in the L/R group, safety profile of L/R is comparable to SOC. Compared to L/R combination, CQ, L/R + arbidol, L/R + IFN-α, and L/R + IFN-1ß showed better efficacy, but the external validity of these findings is limited by limited number of studies (1 study each).


Asunto(s)
Antivirales/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Lopinavir/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Ritonavir/uso terapéutico , Combinación de Medicamentos , Humanos , Resultados Negativos , Pandemias , Resultado del Tratamiento
10.
BMC Bioinformatics ; 21(1): 460, 2020 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-33059599

RESUMEN

BACKGROUND: Treating patients with combinations of drugs that have synergistic effects has become widespread practice in the clinic. Drugs work synergistically when the observed effect of a drug combination is larger than the effect predicted by the reference model. The reference model is a theoretical null model that returns the combined effect of given doses of drugs under the assumption that these drugs do not interact. There is ongoing debate on what it means for drugs to not interact. The controversy transcends mathematical punctuality, as different non-interaction principles result in different reference models. A famous reference model that has been in existence for already a long time is Loewe's reference model. Loewe's vision on non-interaction was purely intuitive: two drugs do not interact if all combinations of doses that result in a certain given effect lie on a straight line. RESULTS: We show that Loewe's reference model can be obtained from much more fundamental principles. First, we introduce the new notion of complementary dose. Secondly, we reformulate the existing concept of equivalent dose, whereby our formulation is more general than existing ones. Finally, a very general non-interaction principle is put forward. The proposed non-interaction principle represents a certain interplay between complementary and equivalent doses: drugs are non-interacting if complementarity is preserved under equivalence. It is then shown that Loewe's reference model naturally follows from these principles by an appropriate choice of complementarity. CONCLUSIONS: The presented work increases insight into Loewe's reference model for drug combinations, which is realized by the introduction of a very general non-interaction principle that does not refer to any specific dose-response curve, nor to any property of applicable dose-response curves.


Asunto(s)
Combinación de Medicamentos , Modelos Teóricos , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Sinergismo Farmacológico , Humanos , Preparaciones Farmacéuticas/metabolismo , Estándares de Referencia
11.
Viruses ; 12(10)2020 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-33080984

RESUMEN

Combination therapies have become a standard for the treatment for HIV and hepatitis C virus (HCV) infections. They are advantageous over monotherapies due to better efficacy, reduced toxicity, as well as the ability to prevent the development of resistant viral strains and to treat viral co-infections. Here, we identify new synergistic combinations against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), echovirus 1 (EV1), hepatitis C virus (HCV) and human immunodeficiency virus 1 (HIV-1) in vitro. We observed synergistic activity of nelfinavir with convalescent serum and with purified neutralizing antibody 23G7 against SARS-CoV-2 in human lung epithelial Calu-3 cells. We also demonstrated synergistic activity of nelfinavir with EIDD-2801 or remdesivir in Calu-3 cells. In addition, we showed synergistic activity of vemurafenib with emetine, homoharringtonine, anisomycin, or cycloheximide against EV1 infection in human lung epithelial A549 cells. We also found that combinations of sofosbuvir with brequinar or niclosamide are synergistic against HCV infection in hepatocyte-derived Huh-7.5 cells, and that combinations of monensin with lamivudine or tenofovir are synergistic against HIV-1 infection in human cervical TZM-bl cells. These results indicate that synergy is achieved when a virus-directed antiviral is combined with another virus- or host-directed agent. Finally, we present an online resource that summarizes novel and known antiviral drug combinations and their developmental status.


Asunto(s)
Antivirales/administración & dosificación , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Células A549 , Anticuerpos Neutralizantes/farmacología , Anticuerpos Neutralizantes/uso terapéutico , Antineoplásicos/farmacología , Antivirales/farmacología , Línea Celular , Infecciones por Coronavirus/virología , Bases de Datos Farmacéuticas , Combinación de Medicamentos , Descubrimiento de Drogas , Sinergismo Farmacológico , Enterovirus Humano B/efectos de los fármacos , VIH-1/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Humanos , Pandemias , Neumonía Viral/virología
12.
N Engl J Med ; 383(17): 1645-1656, 2020 10 22.
Artículo en Inglés | MEDLINE | ID: mdl-33026741

RESUMEN

BACKGROUND: Whether combined treatment with recombinant interferon beta-1b and lopinavir-ritonavir reduces mortality among patients hospitalized with Middle East respiratory syndrome (MERS) is unclear. METHODS: We conducted a randomized, adaptive, double-blind, placebo-controlled trial that enrolled patients at nine sites in Saudi Arabia. Hospitalized adults with laboratory-confirmed MERS were randomly assigned to receive recombinant interferon beta-1b plus lopinavir-ritonavir (intervention) or placebo for 14 days. The primary outcome was 90-day all-cause mortality, with a one-sided P-value threshold of 0.025. Prespecified subgroup analyses and safety analyses were conducted. Because of the pandemic of coronavirus disease 2019, the data and safety monitoring board requested an unplanned interim analysis and subsequently recommended the termination of enrollment and the reporting of the results. RESULTS: A total of 95 patients were enrolled; 43 patients were assigned to the intervention group and 52 to the placebo group. A total of 12 patients (28%) in the intervention group and 23 (44%) in the placebo group died by day 90. The analysis of the primary outcome, with accounting for the adaptive design, yielded a risk difference of -19 percentage points (upper boundary of the 97.5% confidence interval [CI], -3; one-sided P = 0.024). In a prespecified subgroup analysis, treatment within 7 days after symptom onset led to lower 90-day mortality than use of placebo (relative risk, 0.19; 95% CI, 0.05 to 0.75), whereas later treatment did not. Serious adverse events occurred in 4 patients (9%) in the intervention group and in 10 (19%) in the placebo group. CONCLUSIONS: A combination of recombinant interferon beta-1b and lopinavir-ritonavir led to lower mortality than placebo among patients who had been hospitalized with laboratory-confirmed MERS. The effect was greatest when treatment was started within 7 days after symptom onset. (Funded by the King Abdullah International Medical Research Center; MIRACLE ClinicalTrials.gov number, NCT02845843.).


Asunto(s)
Infecciones por Coronavirus/tratamiento farmacológico , Interferon beta-1b/uso terapéutico , Lopinavir/uso terapéutico , Ritonavir/uso terapéutico , Administración Oral , Adulto , Anciano , Infecciones por Coronavirus/mortalidad , Método Doble Ciego , Combinación de Medicamentos , Quimioterapia Combinada , Femenino , Hospitalización , Humanos , Inyecciones Subcutáneas , Interferon beta-1b/efectos adversos , Estimación de Kaplan-Meier , Lopinavir/efectos adversos , Masculino , Persona de Mediana Edad , Ritonavir/efectos adversos , Estadísticas no Paramétricas , Tiempo de Tratamiento
13.
Medicine (Baltimore) ; 99(43): e22712, 2020 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-33120766

RESUMEN

BACKGROUND: Although dexmedetomidine has been used as either the anesthetic agent for light sedation or as an adjunct to other sedatives, no study has investigated the usefulness of dexmedetomidine as the main sedative agent for invasive and painful procedures. The purpose of this study was to compare the safety of dexmedetomidine-remifentanil and propofol-remifentanil during monitored anesthesia care (MAC) for hysteroscopy. METHODS: Female patients undergoing hysteroscopy were randomly assigned to either the dexmedetomidine (group D) or the propofol group (group P). The study drug (0.6 ml/kg; dexmedetomidine 2 µg/ml or propofol 4 mg/ml) was loaded for 10 minutes followed by 0.1 to 0.5 ml/kg/hour to maintain a bispectral index of 60 to 80 during the procedure. In both groups, remifentanil was infused using a target-controlled-infusion system with a target concentration of 2 ng/ml and titrated during the procedure. The incidence rates of intraoperative respiratory depression in both groups were compared. Postoperative pain and patients satisfaction were also compared. RESULTS: A total of 69 female patients were included in this study. Dexmedetomidine significantly decrease the incidence of respiratory depression compared with propofol (15/34 [44.1%] vs 5/35 [14.3%], P = .006, group P and D, respectively). Postoperative pain and patients satisfaction score did not differ between the groups. CONCLUSION: The combination of dexmedetomidine-remifentanil can reduce the incidence of respiratory depression without increasing hemodynamic complications compared with propofol-remifentanil for MAC during hysteroscopy.


Asunto(s)
Analgésicos Opioides/administración & dosificación , Anestésicos Intravenosos/administración & dosificación , Dexmedetomidina/administración & dosificación , Hipnóticos y Sedantes/administración & dosificación , Histeroscopía , Monitoreo Intraoperatorio , Propofol/administración & dosificación , Remifentanilo/administración & dosificación , Adulto , Combinación de Medicamentos , Femenino , Humanos , Persona de Mediana Edad , Método Simple Ciego
14.
Medicine (Baltimore) ; 99(43): e22780, 2020 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-33120790

RESUMEN

RATIONALE: Currently, the 5-year survival rate remains poor for patients with metastatic colorectal cancer (mCRC), and the purpose of therapy is to prolong survival while maintaining the quality of life. Trifluridine/tipiracil, an oral drug combining trifluorothymidine and a thymidine phosphorylase inhibitor, is indicated as salvage therapy for mCRC patients who have progressed after all available regimens. Combination of local treatments with systemic therapy such as trifluridine/tipiracil represents an apt management strategy for mCRC patients. PATIENT CONCERNS: A 72-year-old man diagnosed with stage IV rectal adenocarcinoma (KRAS mutation) with peritoneal carcinomatosis and liver metastases developed resistance to 2 lines of treatment (bevacizumab/irinotecan/S-1 and bevacizumab/oxaliplatin/HDFL [high-dose 24-hour infusion of 5-fluorouracil and leucovorin regimen]) within 5 months. DIAGNOSIS: Refractory stage IV rectal adenocarcinoma. INTERVENTIONS: Systemic treatment of trifluridine/tipiracil has been given for approximately 15 months in addition to radiotherapy, Yttrium-90 radioembolization, and trans-arterial chemoembolization for peritoneal and liver metastases. OUTCOMES: After 15 months, the patient was still taking trifluridine/tipiracil for disease control with a good quality of life. LESSONS: Trifluridine/tipiracil plus other appropriate local therapy may significantly prolong patients survival with a satisfactory quality of life for patients with refractory mCRC. The favorable safety profile of trifluridine/tipiracil renders it a suitable option to be combined with other local therapies for metastatic lesions.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Pirrolidinas/uso terapéutico , Neoplasias del Recto/tratamiento farmacológico , Timina/uso terapéutico , Trifluridina/uso terapéutico , Adenocarcinoma/patología , Anciano , Combinación de Medicamentos , Humanos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Masculino , Estadificación de Neoplasias , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/terapia , Pirrolidinas/administración & dosificación , Calidad de Vida , Neoplasias del Recto/patología , Terapia Recuperativa , Timina/administración & dosificación , Trifluridina/administración & dosificación
15.
Nat Commun ; 11(1): 5465, 2020 10 29.
Artículo en Inglés | MEDLINE | ID: mdl-33122660

RESUMEN

Eicosapentaenoic acid (EPA), an omega-3 fatty acid, has been widely used to prevent cardiovascular disease (CVD) and treat brain diseases alone or in combination with docosahexaenoic acid (DHA). However, the impact of EPA and DHA supplementation on normal cognitive function and the molecular targets of EPA and DHA are still unknown. We show that acute administration of EPA impairs learning and memory and hippocampal LTP in adult and prepubescent mice. Similar deficits are duplicated by endogenously elevating EPA in the hippocampus in the transgenic fat-1 mouse. Furthermore, the damaging effects of EPA are mediated through enhancing GABAergic transmission via the 5-HT6R. Interestingly, DHA can prevent EPA-induced impairments at a ratio of EPA to DHA similar to that in marine fish oil via the 5-HT2CR. We conclude that EPA exhibits an unexpected detrimental impact on cognitive functions, suggesting that caution must be exercised in omega-3 fatty acid supplementation and the combination of EPA and DHA at a natural ratio is critical for learning and memory and synaptic plasticity.


Asunto(s)
Cognición/efectos de los fármacos , Ácido Eicosapentaenoico/efectos adversos , Neuronas GABAérgicas/efectos de los fármacos , Receptor de Serotonina 5-HT2C/efectos de los fármacos , Animales , Suplementos Dietéticos/efectos adversos , Ácidos Docosahexaenoicos/farmacología , Combinación de Medicamentos , Ácido Eicosapentaenoico/farmacología , Ácidos Grasos Omega-3/efectos adversos , Aceites de Pescado/efectos adversos , Aceites de Pescado/farmacología , Humanos , Aprendizaje/efectos de los fármacos , Trastornos de la Memoria/etiología , Trastornos de la Memoria/patología , Ratones
16.
BMC Infect Dis ; 20(1): 723, 2020 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-33008327

RESUMEN

BACKGROUND: The global pandemic of coronavirus disease 2019 (COVID-19) infection is ongoing and associated with high mortality. The aim of this study was to investigate the efficacy and safety of subcutaneous injection of interferon alpha-2b (IFN alpha-2b) combined with lopinavir/ritonavir (LPV/r) in the treatment of COVID-19 infection, compared with that of using LPV/r alone. METHODS: Patients diagnosed with laboratory-confirmed COVID-19 infection in Wuhan Red Cross hospital during the period from January 23, 2020 to March 19, 2020 were included. The length of stay, the time to viral clearance and adverse reactions during hospitalization were compared between patients using oral LPV/r and combined therapy of LPV/r and subcutaneous injection of IFN alpha-2b. RESULTS: A total of 22 patients were treated with LPV/r alone and 19 with combined therapy with subcutaneous injection of IFN alpha-2b. The average length of hospitalization in the combination group was shorter than that of LPV/r group (16 ± 9.7 vs 23 ± 10.5 days; P = 0.028). Moreover, the days of hospitalization in early intervention group decreased from 25 ± 8.5 days to 10 ± 2.9 days compared with delayed intervention group (P = 0.001). Combined therapy with IFN alpha-2b also significantly reduced the duration of detectable virus in the upper respiratory tract. No patient in each group was transferred to intensive care unit (ICU) or died during the treatment. There was no significant difference in the adverse effect composition between two groups. CONCLUSIONS: Subcutaneous injection of IFN alpha-2b combined with LPV/r shortened the length of hospitalization and accelerated viral clearance in COVID-19 patients, which deserves further investigation in clinical practice.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Interferón alfa-2/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Anciano , Combinación de Medicamentos , Femenino , Humanos , Inyecciones Subcutáneas , Interferón alfa-2/administración & dosificación , Lopinavir/uso terapéutico , Masculino , Persona de Mediana Edad , Pandemias , Ritonavir/uso terapéutico
17.
J Contemp Dent Pract ; 21(7): 760-764, 2020 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-33020359

RESUMEN

AIM: One of the most vital characteristics of an ideal root filling material is the capability to inhibit the growth of the microorganisms. Mineral trioxide aggregate (MTA) is one of the most used root repair materials, with approved antibacterial effect. A newly introduced root repair material is nano-fast cement (NFC) which should be investigated. The antibacterial and antifungal activities of NFC were evaluated in the present study. MATERIALS AND METHODS: Enterococcus faecalis (PTCC 1394), Escherichia coli (ATTC 15224), and Candida albicans (PTCC 5027) were employed for the antimicrobial assessment. The following were the steps used to conduct the agar diffusion test (ADT): six agar plates were used. 0.5 McFarland concentration of each strain was cultured on two plates by a sterile cotton-tipped swab. Three holes with 5mm diameter were created on each plate. Freshly mixed cement was placed in the holes of the related plate. After two hours, the plates were incubated at 37°C for 24 hours. Then, the diameter of the growth inhibition zones were measured, and the mean values were used for the analysis. Direct contact test (DCT) was done by using the following steps: Freshly mixed materials were placed in the 96-well microtiter plate. 10 µL of each bacterial suspension was added to the tested cement. After one-hour incubation at 37°C, 245 µL of BHI broth was added to each well, and the plate was vortexed for 2 minutes. About 15 µL of this bacterial suspension was added to a new well which contained 215 µL of fresh medium. The kinetics of the bacterial outgrowth were measured by the microplate spectrophotometer hourly for 12 hours. RESULTS: No significant differences were observed between the diameters of the growth inhibition zones of MTA and NFC groups in ADT. In DCT, the MTA inhibits E. coli more effectively than NFC (p value < 0.001). Both cements had the same inhibitory effect on E. faecalis and C. albicans. CONCLUSION: The MTA and NFC are almost equally effective against the tested microorganisms. CLINICAL SIGNIFICANCE: The antibacterial characteristic of any dental material is an important matter. As well, the antibacterial efficacy of the NFC should be evaluated.


Asunto(s)
Antifúngicos/farmacología , Escherichia coli , Compuestos de Aluminio , Antibacterianos/farmacología , Compuestos de Calcio , Combinación de Medicamentos , Óxidos , Materiales de Obturación del Conducto Radicular , Silicatos
18.
Medicine (Baltimore) ; 99(43): e22920, 2020 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-33120844

RESUMEN

RATIONALE: Reversible splenial lesion syndrome (RESLES) is a recently identified clinico-radiological syndrome, the etiology is miscellaneous. Atrial septal defect (ASD) as an underlying etiology for RESLES has not been reported. We first report a rare case of RESLES associated with ASD. The clinical, radiological, and ultrasonic profiles were presented and the pathophysiological mechanism was analyzed. PATIENT CONCERNS: A 23-year-old man presented with headache, drowsiness, occasional paraphasia, and paroxysmal dry cough. Brain magnetic resonance imaging (MRI) on admission showed an ovoid isolated lesion in the splenium of corpus callosum, which exhibited hyperintensity on diffusion-weighted imaging and hypointensity on apparent diffusion coefficient, and completely disappeared on the follow-up MRI 14 days later. ASD was found by transthoracic echocardiography, Right-to-left shunts were detected on color Doppler of transesophageal echocardiography, and microemboli were captured by transcranial Doppler ultrasound. DIAGNOSES: According to his clinical history and imaging results, we confirmed the diagnosis of RESLES associated with ASD. INTERVENTIONS: The patient was treated by oral aspirin and lopidogrel sulfate to inhibit platelet aggregation. In addition, oral nimodipine to suppress vasoconstriction. OUTCOMES: After 14 days treatment, all the symptoms presenting on admission resolved completely. Subsequently, a repair surgery of ASD under thoracoscopy was successfully performed. LESSONS: To our knowledge, this is the first reported case of ASD may be an underlying etiology for RESLES and need require an etiotropic treatment.


Asunto(s)
Encefalopatías/etiología , Cuerpo Calloso/diagnóstico por imagen , Imagen de Difusión por Resonancia Magnética/métodos , Defectos del Tabique Interatrial/complicaciones , Administración Oral , Antihipertensivos/administración & dosificación , Antihipertensivos/uso terapéutico , Aspirina/administración & dosificación , Aspirina/uso terapéutico , Encefalopatías/diagnóstico por imagen , Encefalopatías/patología , Cuerpo Calloso/patología , Combinación de Medicamentos , Quimioterapia Combinada , Ecocardiografía/métodos , Estudios de Seguimiento , Cefalea/etiología , Defectos del Tabique Interatrial/diagnóstico por imagen , Defectos del Tabique Interatrial/tratamiento farmacológico , Defectos del Tabique Interatrial/cirugía , Humanos , Lopinavir/administración & dosificación , Lopinavir/uso terapéutico , Masculino , Nimodipina/administración & dosificación , Nimodipina/uso terapéutico , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/uso terapéutico , Ritonavir/administración & dosificación , Ritonavir/uso terapéutico , Síndrome , Resultado del Tratamiento , Ultrasonografía Doppler Transcraneal/métodos , Adulto Joven
19.
Pharmacol Res Perspect ; 8(6): e00674, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33124786

RESUMEN

SARS-CoV-2, a member of the coronavirus family, has caused a global public health emergency. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously reasoned that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) should inhibit coronaviruses, including SARS-CoV-2. Here, using model polymerase extension experiments, we demonstrate that the active triphosphate form of Sofosbuvir is incorporated by low-fidelity polymerases and SARS-CoV RNA-dependent RNA polymerase (RdRp), and blocks further incorporation by these polymerases; the active triphosphate form of Sofosbuvir is not incorporated by a host-like high-fidelity DNA polymerase. Using the same molecular insight, we selected 3'-fluoro-3'-deoxythymidine triphosphate and 3'-azido-3'-deoxythymidine triphosphate, which are the active forms of two other anti-viral agents, Alovudine and AZT (an FDA-approved HIV/AIDS drug) for evaluation as inhibitors of SARS-CoV RdRp. We demonstrate the ability of two of these HIV reverse transcriptase inhibitors to be incorporated by SARS-CoV RdRp where they also terminate further polymerase extension. Given the 98% amino acid similarity of the SARS-CoV and SARS-CoV-2 RdRps, we expect these nucleotide analogues would also inhibit the SARS-CoV-2 polymerase. These results offer guidance to further modify these nucleotide analogues to generate more potent broad-spectrum anti-coronavirus agents.


Asunto(s)
Antivirales/farmacología , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , ARN Replicasa/antagonistas & inhibidores , Betacoronavirus/enzimología , Carbamatos/farmacología , Infecciones por Coronavirus/virología , Didesoxinucleótidos/farmacología , Combinación de Medicamentos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Pandemias , Neumonía Viral/virología , Sofosbuvir/farmacología , Nucleótidos de Timina/farmacología , Zidovudina/análogos & derivados , Zidovudina/farmacología
20.
Trials ; 21(1): 886, 2020 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-33109246

RESUMEN

OBJECTIVES: We will evaluate the efficacy and safety of favipiravir and interferon beta-1a compared to lopinavir/ritonavir and interferon beta-1a in patients with confirmed COVID-19, who are moderately ill. TRIAL DESIGN: This is a phase 3, single-center, randomized, open-label, controlled trial with a parallel-group design carried out at Shahid Mohammadi Hospital, Bandar Abbas, Iran. PARTICIPANTS: All patients with age ≥ 20 years admitted at the Severe Acute Respiratory Syndrome Departments of the Shahid Mohammadi Hospital, Bandar Abbas, Iran, will be screened for the following criteria. INCLUSION CRITERIA: 1. Confirmed diagnosis of infection with SARS-CoV-2 using polymerase chain reaction and/or antibody tests. 2. Moderate COVID-19 pneumonia (via computed tomography and/or X-ray imaging), requiring hospitalization. 3. Hospitalized ≤ 48 h. 4. Signing informed consent and willingness of the participant to accept randomization to any assigned treatment arm. EXCLUSION CRITERIA: 1. Underlying conditions, including chronic hepatitis, cirrhosis, cholestatic liver diseases, cholecystitis, peptic ulcers, acute and chronic renal failure, and peptic ulcers. 2. Severe and critical COVID-19 pneumonia. 3. History of allergy to favipiravir, lopinavir/ritonavir, and interferon beta-1a. 4. Pregnancy and breastfeeding. INTERVENTION AND COMPARATOR: Intervention group: favipiravir (Zhejiang Hisun, China) with interferon beta-1a (CinnaGen, Iran). This group will receive 1600 mg favipiravir twice a day for the first day and 600 mg twice a day for the following 4 days with five doses of 44 mcg interferon beta-1a every other day. CONTROL GROUP: lopinavir/ritonavir (Heterd Company, India) with interferon beta-1a (CinnaGen, Iran). This group will receive 200/50 mg lopinavir/ritonavir twice a day for 7 days with five doses of 44 mcg interferon beta-1a every other day. Other supportive and routine care will be the same in both groups. MAIN OUTCOMES: The primary outcome of the trial is the viral load of SARS-CoV-2 in the nasopharyngeal samples assessed by RT-PCR after 7 days of randomization as well as clinical improvement of fever and O2 saturation within 7 days of randomization. The secondary outcomes are the length of hospital stay and the incidence of serious adverse drug reactions within 7 days of randomization. RANDOMIZATION: Eligible patients will be allocated to one of the study arms using block randomization in a 1:1 ratio (each block consists of 10 patients). A web-based system will be used to generate random numbers for the allocation sequence. Each number relates to one of the study arms. BLINDING (MASKING): This is an open-label trial without blinding and placebo control. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): A total of 60 patients will be randomized into two groups (30 patients in the intervention group and 30 patients in the control group). TRIAL STATUS: The trial protocol is version 1.0, 22 July 2020. Recruitment began on 25 July 2020 and is anticipated to be completed by 25 September 2020. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT) IRCT20200506047323N3 . Registered on 22 July 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting the 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)
Amidas , Infecciones por Coronavirus , Quimioterapia Combinada/métodos , Interferones , Lopinavir , Pandemias , Neumonía Viral , Pirazinas , Ritonavir , Adulto , Amidas/administración & dosificación , Amidas/efectos adversos , Antivirales/administración & dosificación , Antivirales/efectos adversos , Betacoronavirus/efectos de los fármacos , Betacoronavirus/aislamiento & purificación , Técnicas de Laboratorio Clínico/métodos , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/tratamiento farmacológico , Combinación de Medicamentos , Monitoreo de Drogas/métodos , Femenino , Humanos , Interferones/administración & dosificación , Interferones/efectos adversos , Irán , Lopinavir/administración & dosificación , Lopinavir/efectos adversos , Masculino , Neumonía Viral/diagnóstico , Neumonía Viral/tratamiento farmacológico , Pirazinas/administración & dosificación , Pirazinas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Ritonavir/administración & dosificación , Ritonavir/efectos adversos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Carga Viral/métodos
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