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J Med Chem ; 64(1): 890-904, 2021 01 14.
Artículo en Inglés | MEDLINE | ID: covidwho-997768


The sigma 1 receptor (S1R) is a molecular chaperone protein located in the endoplasmic reticulum and plasma membranes and has been shown to play important roles in various pathological disorders including pain and, as recently discovered, COVID-19. Employing structure- and QSAR-based drug design strategies, we rationally designed, synthesized, and biologically evaluated a series of novel triazole-based S1R antagonists. Compound 10 exhibited potent binding affinity for S1R, high selectivity over S2R and 87 other human targets, acceptable in vitro metabolic stability, slow clearance in liver microsomes, and excellent blood-brain barrier permeability in rats. Further in vivo studies in rats showed that 10 exhibited negligible acute toxicity in the rotarod test and statistically significant analgesic effects in the formalin test for acute inflammatory pain and paclitaxel-induced neuropathic pain models during cancer chemotherapy. These encouraging results promote further development of our triazole-based S1R antagonists as novel treatments for pain of different etiologies.

Manejo del Dolor/métodos , Receptores sigma/antagonistas & inhibidores , Triazoles/química , Animales , Sitios de Unión , Barrera Hematoencefálica/metabolismo , Diseño de Fármacos , Cobayas , Semivida , Humanos , Microsomas Hepáticos/metabolismo , Simulación de Dinámica Molecular , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Estructura Terciaria de Proteína , Relación Estructura-Actividad Cuantitativa , Ratas , Receptores sigma/metabolismo , Triazoles/metabolismo , Triazoles/uso terapéutico
Curr Opin Infect Dis ; 33(4): 290-297, 2020 08.
Artículo en Inglés | MEDLINE | ID: covidwho-641651


PURPOSE OF REVIEW: Although clinical outcomes in the treatment of aspergillosis have markedly improved with the availability of newer triazoles, the development of resistance to these antifungals, especially in Aspergillus fumigatus, is a growing concern. The purpose of this review is to provide an update on azole resistance mechanisms and their epidemiology in A. fumigatus, the clinical implications of azole resistance, and to discuss future treatment options against azole-resistant aspergillosis. RECENT FINDINGS: Resistance may develop through either patient or environmental azole exposure. Environmental exposure is the most prevalent means of resistance development, and these isolates can cause disease in various at-risk groups, which now include those with influenza, and potentially COVID-19. Although current treatment options are limited, newer therapies are in clinical development. These include agents with novel mechanisms of action which have in vitro and in vivo activity against azole-resistant A. fumigatus. SUMMARY: Azole-resistant A. fumigatus is an emerging threat that hampers our ability to successfully treat patients with aspergillosis. Certain geographic regions and patient populations appear to be at increased risk for this pathogen. As new patient groups are increasingly recognized to be at increased risk for invasive aspergillosis, studies to define the epidemiology and management of azole-resistant A. fumigatus are critically needed. While treatment options are currently limited, new agents under clinical development may offer hope.

Antifúngicos/farmacología , Aspergilosis/inmunología , Aspergillus fumigatus/inmunología , Infecciones por Coronavirus/inmunología , Farmacorresistencia Fúngica Múltiple/inmunología , Neumonía Viral/inmunología , Triazoles/farmacología , Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Aspergilosis/microbiología , Aspergillus fumigatus/efectos de los fármacos , Betacoronavirus/inmunología , Exposición a Riesgos Ambientales , Humanos , Huésped Inmunocomprometido/inmunología , Pruebas de Sensibilidad Microbiana , Pandemias , Triazoles/uso terapéutico
Psychosomatics ; 61(5): 544-550, 2020.
Artículo en Inglés | MEDLINE | ID: covidwho-616923

Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Antipsicóticos/uso terapéutico , Infecciones por Coronavirus/terapia , Delirio/tratamiento farmacológico , Hipnóticos y Sedantes/efectos adversos , Neumonía Viral/terapia , Agitación Psicomotora/tratamiento farmacológico , Fármacos Inductores del Sueño/uso terapéutico , Anciano , Analgésicos Opioides/efectos adversos , Azepinas/uso terapéutico , Betacoronavirus , Depresores del Sistema Nervioso Central/uso terapéutico , Clordiazepóxido/efectos adversos , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/fisiopatología , Infecciones por Coronavirus/psicología , Delirio/etiología , Delirio/fisiopatología , Delirio/psicología , Dexmedetomidina/efectos adversos , Femenino , Guanfacina/uso terapéutico , Haloperidol/uso terapéutico , Humanos , Hidromorfona/efectos adversos , Unidades de Cuidados Intensivos , Ketamina/efectos adversos , Melatonina/uso terapéutico , Midazolam/efectos adversos , Oxicodona/efectos adversos , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/fisiopatología , Neumonía Viral/psicología , Propofol/efectos adversos , Agitación Psicomotora/etiología , Agitación Psicomotora/fisiopatología , Agitación Psicomotora/psicología , Respiración Artificial , Trastornos del Sueño del Ritmo Circadiano/tratamiento farmacológico , Trastornos del Sueño del Ritmo Circadiano/etiología , Trastornos del Sueño del Ritmo Circadiano/fisiopatología , Traqueostomía , Triazoles/uso terapéutico , Ácido Valproico/uso terapéutico
Mycoses ; 63(6): 528-534, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: covidwho-547397


OBJECTIVES: Patients with acute respiratory distress syndrome (ARDS) due to viral infection are at risk for secondary complications like invasive aspergillosis. Our study evaluates coronavirus disease 19 (COVID-19) associated invasive aspergillosis at a single centre in Cologne, Germany. METHODS: A retrospective chart review of all patients with COVID-19 associated ARDS admitted to the medical or surgical intensive care unit at the University Hospital of Cologne, Cologne, Germany. RESULTS: COVID-19 associated invasive pulmonary aspergillosis was found in five of 19 consecutive critically ill patients with moderate to severe ARDS. CONCLUSION: Clinicians caring for patients with ARDS due to COVID-19 should consider invasive pulmonary aspergillosis and subject respiratory samples to comprehensive analysis to detect co-infection.

Infecciones por Coronavirus/complicaciones , Neumonía Viral/complicaciones , Aspergilosis Pulmonar/complicaciones , /complicaciones , Anciano , Antifúngicos/uso terapéutico , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/virología , Infecciones por Coronavirus/diagnóstico por imagen , Femenino , Alemania , Hemorragia/etiología , Hospitales de Enseñanza , Humanos , Unidades de Cuidados Intensivos , Enfermedades Pulmonares/etiología , Masculino , Mananos/análisis , Metapneumovirus/aislamiento & purificación , Persona de Mediana Edad , Nitrilos/uso terapéutico , Pandemias , Infecciones por Paramyxoviridae/etiología , Neumonía Viral/diagnóstico por imagen , Aspergilosis Pulmonar/diagnóstico por imagen , Piridinas/uso terapéutico , Estudios Retrospectivos , Tórax/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Triazoles/uso terapéutico , Voriconazol/uso terapéutico
FASEB J ; 34(6): 7253-7264, 2020 06.
Artículo en Inglés | MEDLINE | ID: covidwho-175986


Drug repurposing is potentially the fastest available option in the race to identify safe and efficacious drugs that can be used to prevent and/or treat COVID-19. By describing the life cycle of the newly emergent coronavirus, SARS-CoV-2, in light of emerging data on the therapeutic efficacy of various repurposed antimicrobials undergoing testing against the virus, we highlight in this review a possible mechanistic convergence between some of these tested compounds. Specifically, we propose that the lysosomotropic effects of hydroxychloroquine and several other drugs undergoing testing may be responsible for their demonstrated in vitro antiviral activities against COVID-19. Moreover, we propose that Niemann-Pick disease type C (NPC), a lysosomal storage disorder, may provide new insights into potential future therapeutic targets for SARS-CoV-2, by highlighting key established features of the disorder that together result in an "unfavorable" host cellular environment that may interfere with viral propagation. Our reasoning evolves from previous biochemical and cell biology findings related to NPC, coupled with the rapidly evolving data on COVID-19. Our overall aim is to suggest that pharmacological interventions targeting lysosomal function in general, and those particularly capable of reversibly inducing transient NPC-like cellular and biochemical phenotypes, constitute plausible mechanisms that could be used to therapeutically target COVID-19.

Antivirales/farmacocinética , Betacoronavirus/fisiología , Infecciones por Coronavirus/tratamiento farmacológico , Reposicionamiento de Medicamentos , Endosomas/virología , Hidroxicloroquina/farmacología , Lisosomas/virología , Enfermedad de Niemann-Pick Tipo C/patología , Neumonía Viral/tratamiento farmacológico , Proteína ADAM17/fisiología , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacología , Adenosina Monofosfato/uso terapéutico , Alanina/análogos & derivados , Alanina/farmacología , Alanina/uso terapéutico , Antivirales/farmacología , Antivirales/uso terapéutico , Bencilisoquinolinas/farmacología , Bencilisoquinolinas/uso terapéutico , Transporte Biológico , Catepsina L/fisiología , Endocitosis , Endosomas/efectos de los fármacos , Endosomas/fisiología , Glicopéptidos/farmacología , Glicopéptidos/uso terapéutico , Humanos , Hidroxicloroquina/farmacocinética , Hidroxicloroquina/uso terapéutico , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Péptidos y Proteínas de Señalización Intracelular/fisiología , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Lípidos de la Membrana/metabolismo , Microdominios de Membrana/fisiología , Enfermedad de Niemann-Pick Tipo C/metabolismo , Oxiesteroles/metabolismo , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Receptores Virales/metabolismo , Serina Endopeptidasas/fisiología , Triazoles/farmacología , Triazoles/uso terapéutico , Internalización del Virus/efectos de los fármacos