BACKGROUND: Ensitrelvir fumaric acid (ensitrelvir) is an orally active 3C-like protease inhibitor used to treat severe acute respiratory syndrome coronavirus 2 infection. Ensitrelvir was granted an emergency use authorization in Japan in 2022, but reports on the effectiveness and safety of ensitrelvir in actual clinical settings are limited.
METHODS: Here, we report a case series of 9 patients with laboratory-confirmed symptomatic coronavirus disease of 2019 (COVID-19) who completed a 5-day course of ensitrelvir at Tomita Hospital from November 2022 to April 2023. Data on clinical symptoms, oxygen saturation, and food intake were collected for 14 days, beginning on the first day of ensitrelvir administration. The outcome of COVID-19 in each patient was also evaluated during this period.
RESULTS: All patients were female, 80 years old or older, and the mean age was 90.2 ± 5.5 years. All patients received ensitrelvir within 2 days after the onset of COVID-19. At baseline, 7 among the 9 patients had their body temperature above 37.5 °C and all of them had oxygen saturation levels of 94% or higher. All patients recovered without worsening of COVID-19, and none received oxygen or additional antiviral drugs during the observation period; no deaths were reported within 14 days. After receiving ensitrelvir for 5 days, all patients had resolution of fever (<37 °C). There was no significant decrease in food intake of patients due to COVID-19. All patients maintained oxygen saturation above 93%.
CONCLUSIONS: Our results provide information on the real-world usage of ensitrelvir in elderly, hospitalized patients with COVID-19, and suggests that ensitrelvir is an option for treatment of COVID-19 in these population.

UNASSIGNED: The use of oral fibrinolytic agent (DLBS1033) has been proven for adjuvant treatment in venous thromboembolism, however until now there is no published report about its uses and effectiveness as an addition to the standard therapy of severe COVID-19 cases and hypercoagulopathy. We present two cases of severe confirmed COVID-19 from PCR tests, seen at Ngimbang Hospital, Lamongan, East Java in October and November, 2020. The first patient was a 51-year-old male who presented to ER with fever, dyspnoea, cough, and oxygen desaturation (SpO2 room air 87%), with comorbids of pulmonary hypertension (PH), atrial fibrillation, heart failure secondary to corpulmonale, and hypercoagulopathy. The second patient was a 56-yearold female who presented with fever, dyspnoea, and oxygen desaturation (Sp02 room air 88%), with comorbid ARDS, hypertension, hyperglycaemia, hypercoagulopathy, heart failure, and CAD. Both of the patients were treated with standard treatment therapy for severe COVID-19 and comorbid therapy, and DLBS1033 in addition to fondaparinux due to limited hospital resources. Both patients showed good clinical outcomes after the course of treatment and had no adverse effects.
CONCLUSIONS: Our two case reports were the first that showed good clinical outcome and safety of DLBS1033 treatment in addition to fondaparinux for hypercoagulopathy therapy.

With some exceptions, global policymakers have recommended against the use of existing monoclonal antibodies in COVID-19 due to loss of neutralization of newer variants. The purpose of this study was to investigate the impact of Ronapreve on compartmental viral replication using paradigms for susceptible and insusceptible variants. Virological efficacy and impact on pathogenicity was assessed in K18-hACE2 mice inoculated with either the Delta or BA.1 Omicron variants. Ronapreve reduced sub-genomic viral RNA levels in lung and nasal turbinate, 4 and 6 days post-infection, for the Delta variant but not the Omicron variant. It also blocked brain infection, which is seen with high frequency in K18-hACE2 mice after Delta variant infection. At day 6, the inflammatory response to lung infection with the Delta variant was altered to a multifocal granulomatous inflammation in which the virus appeared to be confined. The current study provides evidence of an altered tissue response to SARS-CoV-2 after treatment with a monoclonal antibody combination that retains neutralization activity. These data demonstrate that experimental designs that reflect treatment use cases are achievable in animal models for monoclonal antibodies. Extreme caution should be taken when interpreting prophylactic experimental designs that may not be representative of treatment.IMPORTANCEFollowing the emergence of the SARS-CoV-2 Omicron variant, the WHO recommended against the use of Ronapreve in its COVID-19 treatment guidelines due to a lack of efficacy based on current pharmacokinetic-pharmacodynamic understanding. However, the continued use of Ronapreve, specifically in vulnerable patients, was advocated by some based on in vitro neutralization data. Here, the virological efficacy of Ronapreve was demonstrated in both the lung and brain compartments using Delta as a paradigm for a susceptible variant. Conversely, a lack of virological efficacy was demonstrated for the Omicron variant. Comparable concentrations of both monoclonal antibodies were observed in the plasma of Delta- and Omicron-infected mice. This study made use of a reliable murine model for SARS-CoV-2 infection, an experimental design reflective of treatment, and demonstrated the utility of this approach when assessing the effectiveness of monoclonal antibodies.

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BACKGROUND: There have been reports of serious side effects of Remdesivir, including cardiovascular complications. The present study aimed to determine the adverse cardiovascular effects of Remdesivir and the factors affecting them in COVID-19 patients.
METHODS: The patients were classified into two groups: those receiving Remdesivir without cardiac complications and those receiving Remdesivir with cardiovascular complications. After reviewing the patient\'s medical records, the relationship of some factors with the incidence of adverse cardiovascular effects was measured.
RESULTS: Chi-square test showed that the distribution of complications in men was significantly higher than in women (P=0.001). The independent t-test revealed that the mean age in the group with complications was significantly higher than the group without complications (P=0.013). Fisher\'s exact test demonstrated a significant relationship between smoking and cardiovascular complications (P=0.05). According to the Mann-Whitney test, a significant difference was found in the mean changes of Bilirubin (P=0.02) and ALKP (P=0.01) before and after treatment in the groups with and without heart complications.
CONCLUSIONS: Our findings indicated that most of the COVID-19 patients suffered from sinus bradycardia, and the distribution of complications was more pronounced in men than in women. The mean age in the group with complications was higher than the group without complications. Smoking was found to be associated with the occurrence of cardiovascular complications and the mean changes of Bilirubin and ALKP before and after treatment were significantly different in the groups with and without cardiovascular complications.

BACKGROUND: Coronavirus disease 19 (COVID-19), an infectious disease resulting from a virus known as severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), was discovered in China in 2019 and causes several mild to moderate respiratory conditions. This study aimed to reveal the changes in serum interleukin-10 (IL-10) and other parameters in Iraqi COVID-19 patients compared with healthy controls by studying the effects of enoxaparin and evaluating the potential of IL-10 as a disease activity marker.
METHODS: This was a case-control study that included 180 samples: 90 patients hospitalized with COVID-19 from November 2022 to 20 April 2023 (40 patients had never used enoxaparin, whereas 50 patients had taken enoxaparin) and 90 healthy, age- and sex-matched control. There were 44 female patients and 46 male patients. The mean age of the patients and controls was 53.8 years vs. 50.8 years, respectively. The sandwich enzyme-linked immunosorbent assay (ELISA) method was used to measure IL-10 levels, while other parameters were assessed using the colorimetric method.
RESULTS: The results of the study indicated highly significant changes between the patients and healthy controls in IL-10, D-dimer, and C-reactive protein (CRP) levels, as well as liver and renal functions. These findings elucidated a significant change between enoxaparin patients and non-enoxaparin patients in IL-10, D-dimer, and CRP levels. However, the liver and renal functions were not significantly altered. The Spearman\'s rank correlation test investigated the relationship between serum IL-10 and CRP.
CONCLUSIONS: The results displayed a strong positive relationship between IL-10 and CRP. There were no significant differences between the other analyzed parameters; consequently, the patients had higher concentrations of IL-10, D-dimer, and some other parameters than the healthy controls. Additionally, IL-10 may be used as a marker of disease activity. Enoxaparin will likely help control IL-10 and D-dimer concentrations in patients since IL-10 levels decreased in patients treated with enoxaparin.

BACKGROUND: Hiccups are among the rare complications of COVID-19 infections. There are several published reports of persistent hiccups presenting during the acute COVID-19 period. However, there are very few published reports of persistent hiccups occurring in the post-acute COVID-19 period. Consequently, most clinicians may not be aware of this rare presentation. This case highlights an atypical presentation of persistent hiccups that manifested during the post-acute COVID -19 period that clinicians need to be aware of. The caseadds to the ever increasing body of knowledge about symptoms and signs associated with Severe Acute Respiratory Syndrome Corona Virus type 2 (SARS CoV-2) infection.
METHODS: A 27 year old male black Zambian patient presented to the emergency department of our hospital with persistent hiccup, 35 days after the initial acute episode of COVID-19. This was associated with breathlessness. There were no other symptoms. He had no history of pulmonary, gastrointestinal, neurological disease or malignancy. He did not take any alcohol or smoke. He had never used any recreational drugs. He was employed as a monitoring and evaluation officer at one of the main COVID centres in the capital. On examination, the patient was anxious. Blood pressure was 141/82, pulse rate was 95 beats per minute, respiratory rate was 26 breaths per minute, temperature was 36.8C and oxygen saturation was 97% on room air. Systemic examination was normal. Chest X-ray and abdominal ultrasonography were normal. A rapid COVID-19 antigen test, and COVID-19 Polymerase Chain Reaction (PCR) test that were done the following day were negative. All other haematological and biochemical tests, including D-dimer and C-reactive protein (CRP), were also normal. A diagnosis of post-acute COVID-19 associated hiccups was made. The patient responded well to treatment with chlorpromazine 25 mg 8 hourly. The hiccups disappeared completely after the fourth dose of chlorpromazine.
CONCLUSIONS: This is one of the few published cases of COVID-19 associated persistent hiccups, occurring more than a month after the initial presentation. Most of the published cases report hiccups occurring in the acute COVID-19 period. Consequently, hiccups occurring in the post-acute COVID-19 period may not be attributable to COVID-19. This case has highlighted the need to consider post-acute COVID-19 in the differential diagnosis of persistent hiccup.

OBJECTIVE: Drug inhalation is generally accepted as the preferred administration method for treating respiratory diseases. To achieve effective inhaled drug delivery for an individual, it is necessary to use an interdisciplinary approach that can cope with inter-individual differences. The paper aims to present an individualised pulmonary drug deposition model based on Computational Fluid and Particle Dynamics simulations within a time frame acceptable for clinical use.
METHODS: We propose a model that can analyse the inhaled drug delivery efficiency based on the patient\'s airway geometry as well as breathing pattern, which has the potential to also serve as a tool for a sub-regional diagnosis of respiratory diseases. The particle properties and size distribution are taken for the case of drug inhalation by using nebulisers, as they are independent of the patient\'s breathing pattern. Finally, the inhaled drug doses that reach the deep airways of different lobe regions of the patient are studied.
RESULTS: The numerical accuracy of the proposed model is verified by comparison with experimental results. The difference in total drug deposition fractions between the simulation and experimental results is smaller than 4.44% and 1.43% for flow rates of 60 l/min and 15 l/min, respectively. A case study involving a COVID-19 patient is conducted to illustrate the potential clinical use of the model. The study analyses the drug deposition fractions in relation to the breathing pattern, aerosol size distribution, and different lobe regions.
CONCLUSIONS: The entire process of the proposed model can be completed within 48 h, allowing an evaluation of the deposition of the inhaled drug in an individual patient\'s lung within a time frame acceptable for clinical use. Achieving a 48-hour time window for a single evaluation of patient-specific drug delivery enables the physician to monitor the patient\'s changing conditions and potentially adjust the drug administration accordingly. Furthermore, we show that the proposed methodology also offers a possibility to be extended to a detection approach for some respiratory diseases.

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Molnupiravir, an oral direct-acting antiviral effective in vitro against SARS-CoV-2, has been largely employed during the COVID-19 pandemic, since December 2021. After marketing and widespread usage, a progressive increase in SARS-CoV-2 lineages characterized by a higher transition/transversion ratio, a characteristic signature of molnupiravir action, appeared in the Global Initiative on Sharing All Influenza Data (GISAID) and International Nucleotide Sequence Database Collaboration (INSDC) databases. Here, we assessed the drug effects by SARS-CoV-2 whole-genome sequencing on 38 molnupiravir-treated persistently positive COVID-19 outpatients tested before and after treatment. Seventeen tixagevimab/cilgavimab-treated outpatients served as controls. Mutational analyses confirmed that SARS-CoV-2 exhibits an increased transition/transversion ratio seven days after initiation of molnupiravir. Moreover we observed an increased G->A ratio compared to controls, which was not related to apolipoprotein B mRNAediting enzyme, catalytic polypeptide-like (APOBEC) activity. In addition, we demonstrated for the first time an increased diversity and complexity of the viral quasispecies.