Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. The coronavirus 3-chymotrypsin-like protease (3CLpro) controls virus replication and is therefore considered a major target and promising opportunity for rational-based antiviral discovery with direct acting agents. Here we review first-generation SARS-CoV-2 3CLpro inhibitors PF-07304814, GC-376, and CDI-45205 that are being delivered either by injection or inhalation due to their low intrinsic oral bioavailability. In addition, PF-07321332 is now emerging as a promising second-generation clinical candidate for oral delivery. A key challenge to the development of novel 3CLpro inhibitors is the poor understanding of the predictive value of in vitro potency toward clinical efficacy, an issue complicated by the involvement of host proteases in virus entry. Further preclinical and clinical validation will be key to establishing 3CLpro inhibitors as a bona fide class for future SARS-CoV-2 therapeutics for both hospitalized and outpatient populations.

Vitamin C in the Treatment of COVID-19.

Vitamin C is an essential nutrient that serves as antioxidant and plays a major role as co-factor and modulator of various pathways of the immune system. Its therapeutic effect during infections has been a matter of debate, with conflicting results in studies of respiratory infections and in critically ill patients. This comprehensive review aimed to summarize the current evidence regarding the use of vitamin C in the prevention or treatment of patients with SARS-CoV2 infection, based on available publications between January 2020 and February 2021. Overall, 21 publications were included in this review, consisting of case-reports and case-series, observational studies, and some clinical trials. In many of the publications, data were incomplete, and in most clinical trials the results are still pending. No studies regarding prevention of COVID-19 with vitamin C supplementation were found. Although some clinical observations reported improved medical condition of patients with COVID-19 treated with vitamin C, available data from controlled studies are scarce and inconclusive. Based on the theoretical background presented in this article, and some preliminary encouraging studies, the role of vitamin C in the treatment of patients with SARS-CoV-2 infection should be further investigated.

Impact of Dose Delays and Alternative Dosing Regimens on Pertuzumab Pharmacokinetics.

PERJETA (pertuzumab), administered with Herceptin (trastuzumab), is used in the treatment of human epidermal growth factor receptor 2-positive breast cancer. Pertuzumab is currently approved with an initial loading dose of 840 mg, followed by a 420-mg maintenance dose intravenously every 3 weeks. A reloading dose is required if there is a ≥6-week delay in treatment. In response to the potential treatment disruption due to COVID-19, the impact of dose delays and alternative dosing regimens on intravenous pertuzumab for human epidermal growth factor receptor 2-positive breast cancer treatment is presented. Simulations were conducted by using the validated population pharmacokinetic model for pertuzumab, and included (1) 4-, 6-, and 9-week dose delays of the 840 mg/420 mg every 3 weeks dosing regimen and (2) 840 mg/420 mg every 4 weeks and 840 mg every 6 weeks alternative dosing regimens. Simulations were compared with the currently approved pertuzumab dosing regimen. The simulations in 1000 virtual patients showed that a dose reload (840 mg) is required following a dose delay of ≥6 weeks to maintain comparable Ctrough (lowest concentration before the next dose is given) levels to clinical trials. The 840 mg/420 mg every 4 weeks and 840 mg every 6 weeks alternative dosing regimens decrease median steady-state Ctrough by ≈40% compared with the approved regimen, and <90% of patients will be above the target Ctrough . Thus, the alternative 840 mg/420 mg every 4 weeks and 840 mg every 6 weeks pertuzumab dosing regimens are not recommended. Flexibility for intravenous PERJETA-based regimens is available with an alternative route of pertuzumab administration (subcutaneous vs intravenous).

Pharmaceutical care in hospitalized patients. (Management of the COVID-19 pandemic crisis. A new challenge for pharmacy services).

During the pandemic caused by the SARS-CoV-2 virus, pharmacy services have  had to adapt their service portfolio, and yet ensure efficient, equitable and  quality pharmaceutical care. Given the limited scientific evidence available, most drugs have been used off-label or in the context of clinical trials, which should be the preferred option in order to create new evidence. Among kind different  situations we have faced are the increase in workload, the expansion of  coverage to new wards and ICUs and shortages, which have caused the use of  alternative drugs and even other routes of administration. Given that covid-19  affects elderly population with greater severity and many of them are  polymedicated, great effort have been focused on monitoring interactions, both  pharmacokinetic and pharmacodynamic (specially prolongation of the QT  interval), monitoring correct concentrations of electrolytes, nutritional support,  adaptation of chemotherapy treatment protocols and anticoagulant  management, among others. The use of personal protective equipment added  difficulty for nursing work and some measures had been taken to minimize the  number of entries into the rooms. Eventually, team's split to guarantee care, the challenge of teleworking, remote validation, telemedicine and telepharmacy for  communication between professionals and patients, as well as training in this pandemic situation have been a challenge for our profession. These  difficulties have risen up new learning opportunities we hope will be useful to us  in the event we have to face similar situations in the future.

La pandemia ocasionada por el virus SARS-CoV-2 ha hecho que los servicios de  farmacia hayan tenido que adaptar su cartera de servicios, y sin embargo  asegurar una atención farmacéutica eficiente, equitativa y de calidad. Dada la  escasa evidencia científica disponible, la mayoría de los medicamentos se han  empleado fuera de indicación o en el contexto de ensayos clínicos, que debería  ser la opción preferente para generar nueva evidencia. Entre las diversas  situaciones que se han tenido que afrontar se encuentran el incremento de  trabajo asistencial, la ampliación de la cobertura a nuevas salas y unidades de  cuidados intensivos y los desabastecimientos, que han ocasionado el uso de  fármacos alternativos e incluso otras vías de administración. Dado que la  COVID-19 afecta con mayor gravedad a población de edad avanzada, muchos de ellos polimedicados, se ha tenido que dedicar un gran esfuerzo al seguimiento de interacciones, tanto farmacocinéticas como farmacodinámicas (en especial,  prolongación del intervalo QT), monitorización de concentraciones correctas de  electrolitos, soporte nutricional, adaptación de pautas de quimioterapia y manejo e los anticoagulantes, entre otros. La dificultad adicional para enfermería de la  administración de medicamentos con equipos de protección individual ha  supuesto la adaptación de formas de administración para minimizar el número  de entradas en las habitaciones. Por último, el fraccionamiento del equipo para  garantizar la atención, el reto del teletrabajo, la validación en remoto, la  telemedicina y la telefarmacia para la comunicación entre profesionales y  pacientes, así como la formación en esta situación de pandemia, han supuesto  un reto para nuestra profesión. Estos desafíos han creado nuevas oportunidades  de aprendizaje que esperemos nos puedan ser de utilidad en el caso de que  tuviéramos que afrontar situaciones semejantes en el futuro.

Few bacterial co-infections but frequent empiric antibiotic use in the early phase of hospitalized patients with COVID-19: results from a multicentre retrospective cohort study in The Netherlands.

BACKGROUND: Knowledge on bacterial co-infections in COVID-19 is crucial to use antibiotics appropriately. Therefore, we aimed to determine the incidence of bacterial co-infections, antibiotic use and application of antimicrobial stewardship principles in hospitalized patients with COVID-19. METHODS: We performed a retrospective observational study in four hospitals (1 university, 2 non-university teaching, 1 non-teaching hospital) in the Netherlands from March to May 2020 including consecutive patients with PCR-confirmed COVID-19. Data on first microbiological investigations obtained at the discretion of the physician and antibiotic use in the first week of hospital admission were collected. RESULTS: Twelve (1.2%) of the 925 patients included had a documented bacterial co-infection (75.0% pneumonia) within the first week. Microbiological testing was performed in 749 (81%) patients: sputum cultures in 105 (11.4%), blood cultures in 711 (76.9%), pneumococcal urinary antigen testing in 202 (21.8%), and Legionella urinary antigen testing in 199 (21.5%) patients, with clear variation between hospitals. On presentation 556 (60.1%; range 33.3-73.4%) patients received antibiotics for a median duration of 2 days (IQR 1-4). Intravenous to oral switch was performed in 41 of 413 (9.9%) patients who received intravenous treatment >48 h. Mean adherence to the local guideline on empiric antibiotic therapy on day 1 was on average 60.3% (range 45.3%-74.7%). CONCLUSIONS: On presentation to the hospital bacterial co-infections are rare, while empiric antibiotic use is abundant. This implies that in patients with COVID-19 empiric antibiotic should be withheld. This has the potential to dramatically reduce the current overuse of antibiotics in the COVID-19 pandemic.

Hospital Pharmacy Compounding against COVID-19 pandemic.

As in other areas of the health system, COVID-19 has had a dramatic impact on  hospital compounding. This area has faced numerous challenges, including the  shortage of frequent-use products (hydroalcoholic solutions, lopinavir/ritonavir  suspension), the use of new preparations for SARS-CoV-2 (tocilizumab,  remdesivir), or requests from overwhelmed wards unable to assume the safe  preparation of a high volume of medications (intravenous solutions). The  demand for all types of preparations (topic and oral medications, intravenous  solutions) has increased dramatically. This increase has highlighted the shortage of resources allocated to this area, which has made it difficult to meet the high  demand for preparations. In addition, the pandemic has revealed the scarcity of  research on such basic aspects as agent stability and drug compatibility. One of  the most relevant conclusions drawn from the COVID-19 pandemic is that the  basic areas of hospital pharmacy, along with other, must be maintained and  reinforced, as these are the areas that make us essential.

Como todo el sector sanitario, la farmacotecnia hospitalaria ha sufrido el impacto de la pandemia de la COVID-19, enfrentándose a la necesidad de cubrir el  desabastecimiento de productos de uso frecuente (soluciones hidroalcohólicas,  lopinavir/ritonavir suspensión), a nuevas preparaciones surgidas de las nuevas  necesidades provocadas por el SARS-CoV-2 (tocilizumab, remdesivir), o a  peticiones de plantas desbordadas por la carga asistencial, incapaces de asumir  con un mínimo de seguridad la preparación de numerosos medicamentos  (mezclas intravenosas). El incremento de actividad ha sido en todo tipo de  preparados (tópicos, orales y mezclas intravenosas) y ha puesto de manifiesto la escasez de recursos destinados a esta área, que se ha traducido en serios  problemas para afrontar todas las elaboraciones necesarias, así como la falta de  investigación en aspectos tan básicos como la estabilidad o la compatibilidad de  medicamentos. Probablemente, una de las conclusiones más importantes que  podemos extraer tras la COVID-19 es que ­sin menospreciar otras áreas de la  farmacia hospitalaria que también deben desarrollarse­ debemos mantener y  potenciar las áreas básicas de nuestra profesión. Aquellas que nos hacen imprescindibles.

Anticipatory prescribing in community end-of-life care in the UK and Ireland during the COVID-19 pandemic: online survey.

BACKGROUND: Anticipatory prescribing (AP) of injectable medications in advance of clinical need is established practice in community end-of-life care. Changes to prescribing guidelines and practice have been reported during the COVID-19 pandemic. AIMS AND OBJECTIVES: To investigate UK and Ireland clinicians' experiences concerning changes in AP during the COVID-19 pandemic and their recommendations for change. METHODS: Online survey of participants at previous AP national workshops, members of the Association for Palliative Medicine of Great Britain and Ireland and other professional organisations, with snowball sampling. RESULTS: Two hundred and sixty-one replies were received between 9 and 19 April 2020 from clinicians in community, hospice and hospital settings across all areas of the UK and Ireland. Changes to AP local guidance and practice were reported: route of administration (47%), drugs prescribed (38%), total quantities prescribed (35%), doses and ranges (29%). Concerns over shortages of nurses and doctors to administer subcutaneous injections led 37% to consider drug administration by family or social caregivers, often by buccal, sublingual and transdermal routes. Clinical contact and patient assessment were more often remote via telephone or video (63%). Recommendations for regulatory changes to permit drug repurposing and easier community access were made. CONCLUSIONS: The challenges of the COVID-19 pandemic for UK community palliative care has stimulated rapid innovation in AP. The extent to which these are implemented and their clinical efficacy need further examination.

Use of corticosteroids in asthma and COPD patients with or without COVID-19.

The potential detrimental effects of steroids on the immune system to fight viral infections had always been a concern for patients on long term steroids in chronic conditions. A recent warning from WHO on systemic corticosteroid use amid COVID-19 raised suspicion among public and healthcare professionals regarding the safety of steroid use during the SARS-CoV-2 pandemic. The corticosteroids (inhaled and oral) are commonly prescribed in the management of asthma and COPD patients and any unsolicited changes in medications use may lead to potentially severe exacerbations and may risk patient lives. This article provides a critical review of clinical evidence and offers a detailed discussion on the safety and efficacy of corticosteroids in asthma and COPD patients, both with and without COVID-19.