RESUMEN
Worldwide, the turmoil of the SARS-CoV-2 (COVID-19) pandemic has generated a burst of research efforts in search of effective prevention and treatment modalities. Current recommendations on natural supplements arise from mostly anecdotal evidence in other viral infections and expert opinion, and many clinical trials are ongoing. Here the authors review the evidence and rationale for the use of natural supplements for prevention and treatment of COVID-19, including those with potential benefit and those with potential harms. Specifically, the authors review probiotics, dietary patterns, micronutrients, antioxidants, polyphenols, melatonin, and cannabinoids. Authors critically evaluated and summarized the biomedical literature published in peer-reviewed journals, preprint servers, and current guidelines recommended by expert scientific governing bodies. Ongoing and future trials registered on clinicaltrials.gov were also recorded, appraised, and considered in conjunction with the literature findings. In light of the controversial issues surrounding the manufacturing and marketing of natural supplements and limited scientific evidence available, the authors assessed the available data and present this review to equip clinicians with the necessary information regarding the evidence for and potential harms of usage to promote open discussions with patients who are considering dietary supplements to prevent and treat COVID-19.
Asunto(s)
Antioxidantes/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Suplementos Dietéticos , Micronutrientes/uso terapéutico , Extractos Vegetales/uso terapéutico , Antioxidantes/farmacología , Cannabinoides/farmacología , Cannabinoides/uso terapéutico , Humanos , Melatonina/farmacología , Melatonina/uso terapéutico , Micronutrientes/farmacología , Niacinamida/farmacología , Niacinamida/uso terapéutico , Extractos Vegetales/farmacología , Polifenoles/farmacología , Polifenoles/uso terapéutico , Probióticos/uso terapéutico , SARS-CoV-2RESUMEN
Second-generation bromodomain and extra terminal (BET) inhibitors, which selectively target one of the two bromodomains in the BET proteins, have begun to emerge in the literature. These inhibitors aim to help determine the roles and functions of each domain and assess whether they can demonstrate an improved safety profile in clinical settings compared to pan-BET inhibitors. Herein, we describe the discovery of a novel BET BD2-selective chemotype using a structure-based drug design from a hit identified by DNA-encoded library technologies, showing a structural differentiation from key previously reported greater than 100-fold BD2-selective chemotypes GSK620, GSK046, and ABBV-744. Following a structure-based hypothesis for the selectivity and optimization of the physicochemical properties of the series, we identified 60 (GSK040), an in vitro ready and in vivo capable BET BD2-inhibitor of unprecedented selectivity (5000-fold) against BET BD1, excellent selectivity against other bromodomains, and good physicochemical properties. This novel chemical probe can be added to the toolbox used in the advancement of epigenetics research.
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ADN/química , Descubrimiento de Drogas , Proteínas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Estructura Molecular , Dominios Proteicos/efectos de los fármacos , Proteínas/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
Rates of drug use remain substantially higher among gay and bisexual men (GBM) and people living with HIV (PLHIV) in Sydney, New South Wales, Australia. The use of drugs to enhance sexual pleasure within cultures of Party and Play creates opportunities to discuss sexual health, mental health, consent and wellbeing. Community organisations with a history of HIV prevention, care, treatment are well-placed to respond. ACON's (formerly the AIDS Council of New South Wales) multi-dimensional response to 'chemsex' includes: direct client services support for individuals seeking to manage or reduce their use; health promotion activities that support peer education; partnerships with research institutions to better understand cultures of chemsex; and policy submissions that call for drug use to be approached as a health, rather than a criminal, issue. The approach speaks the language of Party and Play subcultures; employs culturally relevant terminology and imagery; uses content designed, created and delivered by peers; and operates within a pleasure-positive, harm-reduction and community-led framework. These interventions have led to increased service uptake, strong community engagement, robust research partnerships and the recognition of GBM as a priority population in relevant strategies.
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Terapia Conductista/métodos , Reducción del Daño , Promoción de la Salud/métodos , Homosexualidad Masculina/psicología , Homosexualidad Masculina/estadística & datos numéricos , Trastornos Relacionados con Sustancias/prevención & control , Adulto , Humanos , Masculino , Persona de Mediana Edad , Nueva Gales del Sur/epidemiología , Estudios de Casos Organizacionales , Asunción de Riesgos , Trastornos Relacionados con Sustancias/epidemiologíaRESUMEN
Niemann-Pick type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 gene. NPC is characterised by storage of multiple lipids in the late endosomal/lysosomal compartment, resulting in cellular and organ system dysfunction. The underlying molecular mechanisms that lead to the range of clinical presentations in NPC are not fully understood. While evaluating potential small molecule therapies in Npc1-/- mice, we observed a consistent pattern of toxicity associated with drugs metabolised by the cytochrome P450 system, suggesting a potential drug metabolism defect in NPC1 disease. Investigation of the P450 system in the context of NPC1 dysfunction revealed significant changes in the gene expression of many P450 associated genes across the full lifespan of Npc1-/- mice, decreased activity of cytochrome P450 reductase, and a global decrease of multiple cytochrome P450 catalysed dealkylation reactions. In vivo drug metabolism studies using a prototypic P450 metabolised drug, midazolam, confirmed dysfunction in drug clearance in the Npc1-/- mouse. Expression of the Phase II enzyme uridinediphosphate-glucuronosyltransferase (UGT) was also significantly reduced in Npc1-/- mice. Interestingly, reduced activity within the P450 system was also observed in heterozygous Npc1+/- mice. The reduced activity of P450 enzymes may be the result of bile acid deficiency/imbalance in Npc1-/- mice, as bile acid treatment significantly rescued P450 enzyme activity in Npc1-/- mice and has the potential to be an adjunctive therapy for NPC disease patients. The dysfunction in the cytochrome P450 system were recapitulated in the NPC1 feline model. Additionally, we present the first evidence that there are alterations in the P450 system in NPC1 patients.
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Sistema Enzimático del Citocromo P-450/metabolismo , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , 2-Hidroxipropil-beta-Ciclodextrina , Animales , Conducta Animal/efectos de los fármacos , Gatos , Cromatografía Líquida de Alta Presión , Sistema Enzimático del Citocromo P-450/genética , Suplementos Dietéticos , Humanos , Péptidos y Proteínas de Señalización Intracelular , Hígado/efectos de los fármacos , Hígado/enzimología , Espectrometría de Masas , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Midazolam/sangre , Midazolam/metabolismo , Midazolam/farmacología , Modelos Animales , Proteína Niemann-Pick C1 , Enfermedad de Niemann-Pick Tipo C/patología , Proteínas/genética , Proteínas/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Ácido Ursodesoxicólico/metabolismo , Ácido Ursodesoxicólico/farmacología , beta-Ciclodextrinas/metabolismo , beta-Ciclodextrinas/uso terapéuticoRESUMEN
A novel series of indazole non-steroidal glucocorticoid receptor agonist has been discovered. This series features a sulfonamide central core and meta amides which interact with the extended ligand binding domain. This series has produced some of the most potent and least lipophilic agonists of which we are aware such as 20a (NFκB pIC(50) 8.3 (100%), clogP 1.9). Certain analogues in this series also display evidence for modulated pharmacology.
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Indazoles/química , Receptores de Glucocorticoides/agonistas , Sulfonamidas/síntesis química , Sitios de Unión , Línea Celular Tumoral , Simulación por Computador , Evaluación Preclínica de Medicamentos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Indazoles/síntesis química , Indazoles/farmacología , Receptores de Glucocorticoides/metabolismo , Relación Estructura-Actividad , Sulfonamidas/farmacologíaRESUMEN
PURPOSE: Preoperative chemoradiotherapy is a primary treatment option for patients with resectable esophageal cancer. Combination regimens using newer agents may improve patient outcomes. This multicenter community-based phase I/II trial examined a modern triplet regimen comprised of oxaliplatin, docetaxel, and capecitabine (ODC) combined with radiation therapy (RT). PATIENTS AND METHODS: The primary end point was the pathologic complete response (pCR) rate. Eligibility criteria included resectable stage I to III cancer of the mid-/distal-esophagus or gastroesophageal junction, measurable disease, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. Treatment included oxaliplatin 40 mg/m(2), docetaxel 20 mg/m(2) (intravenous, weekly x 5); capecitabine 1,000 mg/m(2) orally twice daily on days 1 to 7, 15 to 21, and 29 to 35; and concurrent RT (45 Gy). Resection was performed during weeks 9 to 12. ODC and RT safety was determined in a phase I portion (n = 10) preceding phase II. RESULTS: Fifty-nine patients were enrolled (September 2005 to February 2008; phase I/cohort 1, 10 patients; phase I/cohort 2/phase II, 49 patients). Baseline characteristics included median age of 63 years; 84% male; ECOG PS 0 and 1, 51% and 49%, respectively; adenocarcinoma and squamous cell, 69% and 18%, respectively; stage I, II, and III, 12%, 41%, and 45%, respectively. Phase I revealed no dose-limiting toxicity. Responses: pCR rate, 49%; objective response rate, 61% (24 complete and six partial responses); stable disease, 6%; and progressive disease, 2%. Sixty-nine percent of patients underwent surgery. Survival: median follow-up, 116 weeks; median disease-free survival (DFS) and overall survival (OS) were 16.3 and 24.1 months, respectively. Two-year DFS and OS were 45.1% and 52.2%, respectively. Most common (>or= 5%) grade 3 to 4 nonhematologic toxicities were anorexia (20%), dehydration (16%), diarrhea (8%), dysphagia (10%), esophagitis (20%), fatigue (12%), hyperglycemia (6%), nausea (16%), pulmonary symptoms (14%), sepsis (6%), and vomiting (16%). All other grade 3 to 4 hematologic and nonhematologic toxicities were uncommon (< 5%). CONCLUSION: Preoperative ODC plus RT is active and relatively safe in patients with locoregional esophageal cancer. Importantly, this therapy can be administered within 8 weeks. This regimen warrants additional study in this setting and in combination with newer biologic agents.
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Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/terapia , Neoplasias Esofágicas/terapia , Esofagectomía , Unión Esofagogástrica/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/radioterapia , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Capecitabina , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirugía , Quimioterapia Adyuvante , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Docetaxel , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/radioterapia , Neoplasias Esofágicas/cirugía , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Radioterapia Adyuvante/efectos adversos , Taxoides/administración & dosificación , Factores de Tiempo , Resultado del Tratamiento , Estados UnidosRESUMEN
PURPOSE: This phase II study was designed to determine the feasibility, toxicity, and therapeutic efficacy of a novel outpatient combined-modality preoperative regimen in patients with localized esophageal cancer. PATIENTS AND METHODS: One hundred twenty-nine eligible patients with previously untreated, potentially resectable, clinical stage I-III carcinoma of the esophagus were treated between July 1995 and July 1999. Combined-modality treatment included: paclitaxel, 200 mg/m2, 1-hour i.v. infusion, days 1 and 22; carboplatin, an area under the concentration time curve 6.0 i.v., days 1 and 22; 5-fluorouracil, 225 mg/m2/day, continuous i.v. infusion, days 1-42; and radiation therapy, 45 Gy, 1.8-Gy single daily fractions 5 days weekly, beginning day 1. All patients underwent surgical resection 4-8 weeks after completion of the preoperative therapy. RESULTS: One hundred twenty-three patients (95%) completed preoperative therapy, 105 patients (81%) underwent attempted resection, and 96 patients (74%) had definitive resection. A pathological complete response was achieved in 47 of 123 evaluable patients (38%); an additional 30 patients (24%) had only microscopic residual tumor. With a median follow-up of 45 months, the median survival is 22 months (95% CI = 15-32 months), with actuarial 1-, 2-, and 3-year survivals of 71%, 47%, and 41%, respectively. The most frequent grade 3/4 toxicities of the neoadjuvant program were leukopenia (73%) and esophagitis (43%). Although 73 patients (57%) required brief hospitalizations during preoperative therapy, there were no treatment-related deaths, and 94% of patients remained candidates for resection after the completion of treatment. Six patients (6%) died after surgery. CONCLUSIONS: This novel combined-modality regimen is highly active in the treatment of locoregional esophageal cancer, producing an actuarial 3-year survival of 41%. Although this preoperative regimen produced moderate acute toxicity, there were no treatment-related deaths and the large majority of patients were able to undergo subsequent esophageal resection. These results, obtained in a community-based setting and involving multiple surgeons, radiation oncologists, and medical oncologists, compare favorably with those of previous single-center and multicenter results. Further evaluation of novel combined-modality programs is warranted, as is the incorporation of epidermal growth factor receptor antagonists or other targeted agents.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/radioterapia , Esofagectomía , Terapia Neoadyuvante , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Carboplatino/administración & dosificación , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Quimioterapia Adyuvante/efectos adversos , Esquema de Medicación , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/cirugía , Femenino , Fluorouracilo/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/efectos adversos , Terapia Neoadyuvante/métodos , Paclitaxel/administración & dosificación , Radioterapia Adyuvante/efectos adversos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: The purpose of this study was to evaluate the feasibility, toxicity, and efficacy of a novel combined-modality treatment for patients with locally advanced squamous carcinoma of the head and neck. PATIENTS AND METHODS: In this multicenter, community-based phase 11 study, 123 previously untreated patients with locally advanced squamous carcinoma of the head and neck received 6 weeks of induction chemotherapy followed by concurrent high-dose radiation therapy and weekly chemotherapy. Induction chemotherapy included paclitaxel (200 mg/m2, 1-hour i.v. infusion) on days 1 and 22, carboplatin (AUC 6.0 i.v.) on days 1 and 22, and 5-fluorouracil (225 mg/m2 per day, 24-hour continuous i.v. infusion) on days 1-43. After 1 week without therapy, radiation therapy, 1.8 Gy/day, 5 days weekly, to a total dose of 68.4 Gy, was administered to the primary site and the bilateral cervical lymph nodes. During radiation therapy, patients also received six weekly doses of paclitaxel (50 mg/m2, 1-hour i.v. infusion) and carboplatin (AUC 1.0 i.v). After completion of therapy, patients were restaged with computed tomographic and endoscopic examination; patients in complete remission were followed up without further treatment. RESULTS: One hundred twenty-three patients (74% with stage IV disease) entered this trial, and 111 patients (90%) completed the entire treatment course. Seventy of 116 evaluable patients (60%; 95% Cl, 51%-69%)had a clinical complete response to treatment. After a median follow-up of 24 months, the 2-and 3-year actuarial survivals were 66% and 51%, respectively. Local toxicity was moderately severe during combined-modality therapy; however, xerostomia has been the only frequent chronic toxicity of this program. CONCLUSIONS: This novel combined-modality treatment program, containing paclitaxel and avoiding the use of cisplatin, is feasible, is highly active, and can be administered with acceptable toxicity in a community-based setting. Aggressive nutritional support should be considered in patients receiving this regimen, to improve acute palliation and to maximize the delivery of combined-modality therapy. Further evaluation of this treatment program is warranted. Incorporation of various novel biologic agents, particularly the epidermal growth factor receptor antagonists, may further improve efficacy.