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1.
Viruses ; 14(9)2022 09 09.
Article in English | MEDLINE | ID: covidwho-2143622

ABSTRACT

Evusheld® (tixagevimab + cilgavimab; AZD7442) was the first anti-Spike monoclonal antibody (mAb) cocktail designed not only for treatment but also with pre-exposure prophylaxis in mind. The immunoglobulins were engineered for prolonged half-life by modifying the Fc fragment, thus creating a long-acting antibody (LAAB). We review here preclinical development, baseline and treatment-emergent resistance, clinical efficacy from registration trials, and real-world post-marketing evidence. The combination was initially approved for pre-exposure prophylaxis at the time of the SARS-CoV-2 Delta VOC wave based on a trial conducted in unvaccinated subjects when the Alpha VOC was dominant. Another trial also conducted at the time of the Alpha VOC wave proved efficacy as early treatment in unvaccinated patients and led to authorization at the time of the BA.4/5 VOC wave. Tixagevimab was ineffective against any Omicron sublineage, so cilgavimab has so far been the ingredient which has made a difference. Antibody monotherapy has a high risk of selecting for immune escape variants in immunocompromised patients with high viral loads, which nowadays represent the main therapeutic indication for antibody therapies. Among Omicron sublineages, cilgavimab was ineffective against BA.1, recovered efficacy against BA.2 and BA.2.12.1, but lost efficacy again against BA.4/BA.5 and BA.2.75. Our analysis indicated that Evusheld® has been used during the Omicron VOC phase without robust clinical data of efficacy against this variant and suggested that several regulatory decisions regarding its use lacked consistency. There is an urgent need for new randomized controlled trials in vaccinated, immunocompromised subjects, using COVID-19 convalescent plasma as a control arm.


Subject(s)
COVID-19 , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , COVID-19/drug therapy , COVID-19/prevention & control , COVID-19/therapy , Clinical Trials as Topic , Drug Combinations , Humans , Immunization, Passive , Immunoglobulin Fc Fragments , SARS-CoV-2
2.
Front Endocrinol (Lausanne) ; 13: 935906, 2022.
Article in English | MEDLINE | ID: covidwho-2123396

ABSTRACT

Background: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a pandemic in many countries around the world. The virus is highly contagious and has a high fatality rate. Lung adenocarcinoma (LUAD) patients may have higher susceptibility and mortality to COVID-19. While Paxlovid is the first oral drug approved by the U.S. Food and Drug Administration (FDA) for COVID-19, its specific drug mechanism for lung cancer patients infected with COVID-19 remains to be further studied. Methods: COVID-19 related genes were obtained from NCBI, GeneCards, and KEGG, and then the transcriptome data for LUAD was downloaded from TCGA. The drug targets of Paxlovid were revealed through BATMAN-TCM, DrugBank, SwissTargetPrediction, and TargetNet. The genes related to susceptibility to COVID-19 in LUAD patients were obtained through differential analysis. The interaction of LUAD/COVID-19 related genes was evaluated and displayed by STRING, and a COX risk regression model was established to screen and evaluate the correlation between genes and clinical characteristics. The Venn diagram was drawn to select the candidate targets of Paxlovid against LUAD/COVID-19, and the functional analysis of the target genes was performed using KEGG and GO enrichment analysis. Finally, Cytoscape was used to screen and visualize the Hub Gene, and Autodock was used for molecular docking between the drug and the target. Result: Bioinformatics analysis was performed by combining COVID-19-related genes with the gene expression and clinical data of LUAD, including analysis of prognosis-related genes, survival rate, and hub genes screened out by the prognosis model. The key targets of Paxlovid against LUAD/COVID-19 were obtained through network pharmacology, the most important targets include IL6, IL12B, LBP. Furthermore, pathway analysis showed that Paxlovid modulates the IL-17 signaling pathway, the cytokine-cytokine receptor interaction, during LUAD/COVID-19 treatment. Conclusions: Based on bioinformatics and network pharmacology, the prognostic signature of LUAD/COVID-19 patients was screened. And identified the potential therapeutic targets and molecular pathways of Paxlovid Paxlovid in the treatment of LUAD/COVID. As promising features, prognostic signatures and therapeutic targets shed light on improving the personalized management of patients with LUAD.


Subject(s)
Adenocarcinoma of Lung , COVID-19 , Lung Neoplasms , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/metabolism , COVID-19/drug therapy , COVID-19/genetics , Computational Biology , Drug Combinations , Humans , Interleukin-17 , Interleukin-6 , Lactams , Leucine , Molecular Docking Simulation , Network Pharmacology , Nitriles , Proline , Receptors, Cytokine , Ritonavir , SARS-CoV-2/genetics , United States
3.
PLoS One ; 17(11): e0276751, 2022.
Article in English | MEDLINE | ID: covidwho-2116658

ABSTRACT

Despite new antivirals are being approved against SARS-CoV-2 they suffer from significant constraints and are not indicated for hospitalized patients, who are left with few antiviral options. Repurposed drugs have previously shown controversial clinical results and it remains difficult to understand why certain trials delivered positive results and other trials failed. Our manuscript contributes to explaining the puzzle: this might have been caused by a suboptimal drug exposure and, consequently, an incomplete virus suppression, also because the drugs have mostly been used as add-on monotherapies. As with other viruses (e.g., HIV and HCV) identifying synergistic combinations among such drugs could overcome monotherapy-related limitations. In a cell culture model for SARS-CoV-2 infection the following stringent criteria were adopted to assess drug combinations: 1) identify robust, synergistic antiviral activity with no increase in cytotoxicity, 2) identify the lowest drug concentration inhibiting the virus by 100% (LIC100) and 3) understand whether the LIC100 could be reached in the lung at clinically indicated drug doses. Among several combinations tested, remdesivir with either azithromycin or ivermectin synergistically increased the antiviral activity with no increase in cytotoxicity, improving the therapeutic index and lowering the LIC100 of every one of the drugs to levels that are expected to be achievable and maintained in the lung for a therapeutically relevant period of time. These results are consistent with recent clinical observations showing that intensive care unit admission was significantly delayed by the combination of AZI and RDV, but not by RDV alone, and could have immediate implications for the treatment of hospitalized patients with COVID-19 as the proposed "drug cocktails" should have antiviral activity against present and future SARS-CoV-2 variants without significant overlapping toxicity, while minimizing the onset of drug resistance. Our results also provide a validated methodology to help sort out which combination of drugs are most likely to be efficacious in vivo, based on their in vitro activity, potential synergy and PK profiles.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , COVID-19/drug therapy , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/pharmacology , Alanine/therapeutic use , Lung , Drug Combinations
4.
AIDS ; 36(15): 2171-2179, 2022 Dec 01.
Article in English | MEDLINE | ID: covidwho-2115651

ABSTRACT

BACKGROUND: Effective, safe, and affordable antivirals are needed for coronavirus disease 2019 (COVID-19). Several lines of research suggest that tenofovir may be effective against COVID-19, but no large-scale human studies with appropriate adjustment for comorbidities have been conducted. METHODS: We studied HIV-positive individuals on antiretroviral therapy (ART) in 2020 at 69 HIV clinics in Spain. We collected data on sociodemographics, ART, CD4+ cell count, HIV-RNA viral-load, comorbidities and the following outcomes: laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, COVID-19 hospitalization, intensive care unit (ICU) admission and death. We compared the 48-week risks for individuals receiving tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/FTC, abacavir (ABC)/lamivudine (3TC), and other regimes. All estimates were adjusted for clinical and sociodemographic characteristics via inverse probability weighting. RESULTS: Of 51 558 eligible individuals, 39.6% were on TAF/FTC, 11.9% on TDF/FTC, 26.6% on ABC/3TC, 21.8% on other regimes. There were 2402 documented SARS-CoV-2 infections (425 hospitalizations, 45 ICU admissions, 37 deaths). Compared with TAF/FTC, the estimated risk ratios (RR) (95% confidence interval) of hospitalization were 0.66 (0.43, 0.91) for TDF/FTC and 1.29 (1.02, 1.58) for ABC/3TC, the RRs of ICU admission were 0.28 (0.11, 0.90) for TDF/FTC and 1.39 (0.70, 2.80) for ABC/3TC, and the RRs of death were 0.37 (0.23, 1.90) for TDF/FTC and 2.02 (0.88-6.12) for ABC/3TC. The corresponding RRs of hospitalization for TDF/FTC were 0.49 (0.24, 0.81) in individuals ≥50 years and 1.15 (0.59, 1.93) in younger individuals. DISCUSSION: Compared with other antiretrovirals, TDF/FTC lowers COVID-19 severity among HIV-positive individuals with virological control. This protective effect may be restricted to individuals aged 50 years and older.


Subject(s)
Anti-HIV Agents , COVID-19 , HIV Infections , Humans , Middle Aged , Aged , Emtricitabine/therapeutic use , Lamivudine/therapeutic use , Tenofovir/therapeutic use , HIV Infections/complications , HIV Infections/drug therapy , Antiretroviral Therapy, Highly Active , Anti-HIV Agents/therapeutic use , SARS-CoV-2 , Drug Combinations
5.
Ann Intern Med ; 173(7): 536-541, 2020 10 06.
Article in English | MEDLINE | ID: covidwho-2110869

ABSTRACT

BACKGROUND: The incidence and severity of coronavirus disease 2019 (COVID-19) among HIV-positive persons receiving antiretroviral therapy (ART) have not been characterized in large populations. OBJECTIVE: To describe the incidence and severity of COVID-19 by nucleos(t)ide reverse transcriptase inhibitor (NRTI) use among HIV-positive persons receiving ART. DESIGN: Cohort study. SETTING: HIV clinics in 60 Spanish hospitals between 1 February and 15 April 2020. PARTICIPANTS: 77 590 HIV-positive persons receiving ART. MEASUREMENTS: Estimated risks (cumulative incidences) per 10 000 persons and 95% CIs for polymerase chain reaction-confirmed COVID-19 diagnosis, hospitalization, intensive care unit (ICU) admission, and death. Risk and 95% CIs for COVID-19 diagnosis and hospital admission by use of the NRTIs tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/FTC, abacavir (ABC)/lamivudine (3TC), and others were estimated through Poisson regression models. RESULTS: Of 77 590 HIV-positive persons receiving ART, 236 were diagnosed with COVID-19, 151 were hospitalized, 15 were admitted to the ICU, and 20 died. The risks for COVID-19 diagnosis and hospitalization were greater in men and persons older than 70 years. The risk for COVID-19 hospitalization was 20.3 (95% CI, 15.2 to 26.7) among patients receiving TAF/FTC, 10.5 (CI, 5.6 to 17.9) among those receiving TDF/FTC, 23.4 (CI, 17.2 to 31.1) among those receiving ABC/3TC, and 20.0 (CI, 14.2 to 27.3) for those receiving other regimens. The corresponding risks for COVID-19 diagnosis were 39.1 (CI, 31.8 to 47.6), 16.9 (CI, 10.5 to 25.9), 28.3 (CI, 21.5 to 36.7), and 29.7 (CI, 22.6 to 38.4), respectively. No patient receiving TDF/FTC was admitted to the ICU or died. LIMITATION: Residual confounding by comorbid conditions cannot be completely excluded. CONCLUSION: HIV-positive patients receiving TDF/FTC have a lower risk for COVID-19 and related hospitalization than those receiving other therapies. These findings warrant further investigation in HIV preexposure prophylaxis studies and randomized trials in persons without HIV. PRIMARY FUNDING SOURCE: Instituto de Salud Carlos III and National Institutes of Health.


Subject(s)
Antiretroviral Therapy, Highly Active , Coronavirus Infections/epidemiology , HIV Infections/drug therapy , Pneumonia, Viral/epidemiology , Adenine/analogs & derivatives , Adult , Aged , Betacoronavirus , COVID-19 , Coronavirus Infections/mortality , Dideoxynucleosides , Drug Combinations , Emtricitabine , Female , HIV Infections/mortality , Hospitalization/statistics & numerical data , Humans , Incidence , Intensive Care Units/statistics & numerical data , Lamivudine , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Severity of Illness Index , Spain/epidemiology , Tenofovir
6.
Ann Intern Med ; 175(8): JC92, 2022 08.
Article in English | MEDLINE | ID: covidwho-2090816

ABSTRACT

SOURCE CITATION: Levin MJ, Ustianowski A, De Wit S, et al. Intramuscular AZD7442 (tixagevimab-cilgavimab) for prevention of Covid-19. N Engl J Med. 2022;386:2188-200. 35443106.


Subject(s)
COVID-19 , Antibodies, Monoclonal , Antibodies, Neutralizing , COVID-19/prevention & control , Drug Combinations , Humans , Vaccination
7.
Nature ; 610(7932): 540-546, 2022 10.
Article in English | MEDLINE | ID: covidwho-2084529

ABSTRACT

The spread of antibiotic resistance is attracting increased attention to combination-based treatments. Although drug combinations have been studied extensively for their effects on bacterial growth1-11, much less is known about their effects on bacterial long-term clearance, especially at cidal, clinically relevant concentrations12-14. Here, using en masse microplating and automated image analysis, we systematically quantify Staphylococcus aureus survival during prolonged exposure to pairwise and higher-order cidal drug combinations. By quantifying growth inhibition, early killing and longer-term population clearance by all pairs of 14 antibiotics, we find that clearance interactions are qualitatively different, often showing reciprocal suppression whereby the efficacy of the drug mixture is weaker than any of the individual drugs alone. Furthermore, in contrast to growth inhibition6-10 and early killing, clearance efficacy decreases rather than increases as more drugs are added. However, specific drugs targeting non-growing persisters15-17 circumvent these suppressive effects. Competition experiments show that reciprocal suppressive drug combinations select against resistance to any of the individual drugs, even counteracting methicillin-resistant Staphylococcus aureus both in vitro and in a Galleria mellonella larva model. As a consequence, adding a ß-lactamase inhibitor that is commonly used to potentiate treatment against ß-lactam-resistant strains can reduce rather than increase treatment efficacy. Together, these results underscore the importance of systematic mapping the long-term clearance efficacy of drug combinations for designing more-effective, resistance-proof multidrug regimes.


Subject(s)
Anti-Bacterial Agents , Drug Resistance, Microbial , Staphylococcus aureus , Humans , Anti-Bacterial Agents/pharmacology , beta-Lactamase Inhibitors/pharmacology , beta-Lactams/pharmacology , Drug Combinations , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Staphylococcus aureus/cytology , Staphylococcus aureus/drug effects , Drug Resistance, Microbial/drug effects , Drug Synergism
8.
Int J Pharm ; 628: 122329, 2022 Nov 25.
Article in English | MEDLINE | ID: covidwho-2083078

ABSTRACT

Recently, the U.S. Food and Drug Administration (FDA) approved the first oral antiviral drug to treat mild to moderate cases of coronavirus disease. The combination of nirmatrelvir with an already used protease inhibitor class drug, ritonavir, has led to Paxlovid®. Several studies considered drug repositioning as the first trial for new drugs. The precise identification and quantification of polymorphs in raw materials and finished products are important to researchers involved in pharmaceutical development and quality control processes. In this work, we study the solid-state behavior of the antiretroviral drugs ritonavir and lopinavir in raw materials and in milled compositions. The results indicate that mixtures of ritonavir Forms I and II are found in different batches of raw materials from the same manufacturer; besides three equal crystalline samples, an amorphous batch was found in lopinavir. Furthermore, the milling process of the already amorphous lopinavir seems to facilitate the amorphization of ritonavir as well as the production of some unexpected crystalline forms of ritonavir. A phase transition of ritonavir Form I to Form II is only observed when co-milling with amorphous lopinavir. These findings reveal significant variations in phase purity of raw materials that affect the processing and solid-state properties, representing risks for the product quality.


Subject(s)
Coronavirus Infections , Ritonavir , Humans , Lopinavir/chemistry , Antiviral Agents , Coronavirus Infections/drug therapy , Drug Combinations
11.
Med Sci Monit ; 28: e938532, 2022 Oct 01.
Article in English | MEDLINE | ID: covidwho-2056393

ABSTRACT

One of the most recently described clinical associations with SARS-CoV-2 infection is rebound COVID-19, which occurs between five and eight days following the cessation of antiviral treatment. Most case reports of rebound COVID-19 have been associated with cessation of treatment with the combined oral antiviral agent nirmatrelvir/ritonavir (Paxlovid). On 24 May 2022, the US Centers for Disease Control and Prevention (CDC) issued a Health Alert Network (HAN) Health Advisory update for patients, healthcare providers, and public health departments on COVID-19 rebound or recurrence of COVID-19. However, population data from the US showed no significant differences in the risk of developing rebound COVID-19 between patients treated with Paxlovid and Molnupiravir. The mechanisms of rebound COVID-19 remain unclear but may involve the development of resistance to the antiviral drug, impaired immunity to the virus, or insufficient drug dosing. A further explanation may be the persistence of a high viral load of SARS-CoV-2 in individuals who are no longer symptomatic. This Editorial aims to provide an update on what is known about rebound COVID-19 and the current public health implications.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cytidine/analogs & derivatives , Drug Combinations , Humans , Hydroxylamines , Lactams , Leucine , Nitriles , Proline , Ritonavir/therapeutic use
12.
Microbiol Spectr ; 10(5): e0333122, 2022 Oct 26.
Article in English | MEDLINE | ID: covidwho-2053144

ABSTRACT

Three directly acting antivirals (DAAs) demonstrated substantial reduction in COVID-19 hospitalizations and deaths in clinical trials. However, these agents did not completely prevent severe illness and are associated with cases of rebound illness and viral shedding. Combination regimens can enhance antiviral potency, reduce the emergence of drug-resistant variants, and lower the dose of each component in the combination. Concurrently targeting virus entry and virus replication offers opportunities to discover synergistic drug combinations. While combination antiviral drug treatments are standard for chronic RNA virus infections, no antiviral combination therapy has been approved for SARS-CoV-2. Here, we demonstrate that combining host-targeting antivirals (HTAs) that target TMPRSS2 and hence SARS-CoV-2 entry, with the DAA molnupiravir, which targets SARS-CoV-2 replication, synergistically suppresses SARS-CoV-2 infection in Calu-3 lung epithelial cells. Strong synergy was observed when molnupiravir, an oral drug, was combined with three TMPRSS2 (HTA) oral or inhaled inhibitors: camostat, avoralstat, or nafamostat. The combination of camostat plus molnupiravir was also effective against the beta and delta variants of concern. The pyrimidine biosynthesis inhibitor brequinar combined with molnupiravir also conferred robust synergistic inhibition. These HTA+DAA combinations had similar potency to the synergistic all-DAA combination of molnupiravir plus nirmatrelvir, the protease inhibitor found in paxlovid. Pharmacodynamic modeling allowed estimates of antiviral potency at all possible concentrations of each agent within plausible therapeutic ranges, suggesting possible in vivo efficacy. The triple combination of camostat, brequinar, and molnupiravir further increased antiviral potency. These findings support the development of HTA+DAA combinations for pandemic response and preparedness. IMPORTANCE Imagine a future viral pandemic where if you test positive for the new virus, you can quickly take some medicines at home for a few days so that you do not get too sick. To date, only single drugs have been approved for outpatient use against SARS-CoV-2, and we are learning that these have some limitations and may succumb to drug resistance. Here, we show that combinations of two oral drugs are better than the single ones in blocking SARS-CoV-2, and we use mathematical modeling to show that these drug combinations are likely to work in people. We also show that a combination of three oral drugs works even better at eradicating the virus. Our findings therefore bode well for the development of oral drug cocktails for at home use at the first sign of an infection by a coronavirus or other emerging viral pathogens.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Antiviral Agents/pharmacology , COVID-19/drug therapy , Protease Inhibitors/pharmacology , Drug Combinations , Pyrimidines
14.
J Neurol ; 269(10): 5606-5614, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2041278

ABSTRACT

INTRODUCTION: Levodopa/carbidopa intestinal gel (LCIG) is an effective treatment in patients with advanced Parkinson's disease (PD) with consolidated evidence of clinical efficacy. However, only few studies have assessed long-term safety, causes of discontinuation, mortality, and relative predictors. METHODS: We conducted a retrospective analysis of 79 PD patients treated with LCIG between 2005 and 2020 in two Italian Neurological Centers, recording all adverse events (AEs), including weight loss (WL). Kaplan-Meier curve was used to estimate the time to discontinuation and survival. Cox proportional hazard model was employed to identify predictors of discontinuation and mortality, while Pearson's correlation was used to analyze predictors of WL. RESULTS: The average follow-up was 47.7 ± 40.5 months and the median survival from disease onset was 25 years. There were three cases of polyradiculoneuropathy Guillain-Barre syndrome-like, all occurred in the early years of LCIG treatment. Twenty-five patients died (32%), 18 on LCIG (including one suicide) and seven after discontinuation. The mean WL was 3.62 ± 7.5 kg, which correlated with levodopa dose at baseline (p = 0.002), levodopa equivalent daily dose (LEDD) baseline (p = 0.017) and off-duration (p = 0.0014), but not dyskinesia. Peristomal complications emerged as a negative predictor of discontinuation (p = 0.008). CONCLUSIONS: LCIG has a relatively satisfactory long-term safety profile and efficacy and a relatively low rate of discontinuation. Peristomal complications may represent a predictor of longer duration of therapy. According to the mortality analysis, LCIG patients show a long lifespan. Delaying the initiation of LCIG does not affect the sustainability of LCIG therapy.


Subject(s)
Carbidopa , Parkinson Disease , Antiparkinson Agents/adverse effects , Drug Combinations , Gels/therapeutic use , Humans , Levodopa/therapeutic use , Parkinson Disease/drug therapy , Retrospective Studies , Weight Loss
15.
Am J Nurs ; 122(10): 59, 2022 Oct 01.
Article in English | MEDLINE | ID: covidwho-2037547

ABSTRACT

According to this study: In a phase 2/phase 3 study of Paxlovid use in patients at standard risk for developing severe COVID-19, the primary end point of self-reported sustained alleviation of all symptoms for four consecutive days wasn't met.A nonsignificant risk reduction in hospitalizations and death was seen in a subgroup of patients who had at least one risk factor for severe COVID-19.


Subject(s)
COVID-19 , Drug Combinations , Hospitalization , Humans , Lactams , Leucine , Nitriles , Proline , Ritonavir , SARS-CoV-2 , Time Factors
16.
Trials ; 23(1): 790, 2022 Sep 20.
Article in English | MEDLINE | ID: covidwho-2038854

ABSTRACT

BACKGROUND: Despite the fast establishment of new therapeutic agents in the management of COVID-19 and large-scale vaccination campaigns since the beginning of the SARS-CoV-2 pandemic in early 2020, severe disease courses still represent a threat, especially to patients with risk factors. This indicates the need for alternative strategies to prevent respiratory complications like acute respiratory distress syndrome (ARDS) associated with COVID-19. Aviptadil, a synthetic form of human vasoactive intestinal peptide, might be beneficial for COVID-19 patients at high risk of developing ARDS because of its ability to influence the regulation of exaggerated pro-inflammatory proteins and orchestrate the lung homeostasis. Aviptadil has recently been shown to considerably improve the prognosis of ARDS in COVID-19 when applied intravenously. An inhaled application of aviptadil has the advantages of achieving a higher concentration in the lung tissue, fast onset of activity, avoiding the hepatic first-pass metabolism, and the reduction of adverse effects. The overall objective of this project is to assess the efficacy and safety of inhaled aviptadil in patients hospitalized for COVID-19 at high risk of developing ARDS. METHODS: This multicenter, placebo-controlled, double-blinded, randomized trial with 132 adult patients hospitalized for COVID-19 and at high risk for ARDS (adapted early acute lung injury score ≥ 2 points) is conducted in five public hospitals in Europe. Key exclusion criteria are mechanical ventilation at baseline, need for intensive care at baseline, and severe hemodynamic instability. Patients are randomly allocated to either inhale 67 µg aviptadil or normal saline (three times a day for 10 days), in addition to standard care, stratified by center. The primary endpoint is time from hospitalization to clinical improvement, defined as either hospital discharge, or improvement of at least two levels on the nine-level scale for clinical status suggested by the World Health Organization. DISCUSSION: Treatment strategies for COVID-19 are still limited. In the context of upcoming new variants of SARS-CoV-2 and possible inefficacy of the available vaccines and antibody therapies, the investigation of alternative therapy options plays a crucial role in decreasing associated mortality and improving prognosis. Due to its unique immunomodulating properties also targeting the SARS-CoV-2 pathways, inhaled aviptadil may have the potential to prevent ARDS in COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04536350 . Registered 02 September 2020.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Adult , Drug Combinations , Humans , Multicenter Studies as Topic , Phentolamine , Randomized Controlled Trials as Topic , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2 , Saline Solution , Vasoactive Intestinal Peptide
18.
Crit Care Med ; 50(11): 1545-1554, 2022 Nov 01.
Article in English | MEDLINE | ID: covidwho-2018225

ABSTRACT

OBJECTIVES: Respiratory failure is a lethal complication of COVID-19 that has remained resistant to drug therapy. Vasoactive intestinal peptide (VIP) is shown in nonclinical studies to upregulate surfactant production, inhibit cytokine synthesis, prevent cytopathy, and block replication of the severe acute respiratory syndrome coronavirus 2 virus in pulmonary cells. The study aims to determine whether Aviptadil (synthetic VIP) can improve survival and recovery in patients with COVID-19 respiratory failure compared with placebo and demonstrate biological effects in such patients. DESIGN: A multicenter, placebo-controlled trial. SETTING: Ten U.S. hospitals: six tertiary-care hospitals and four community hospitals. PATIENTS: A total of 196 patients with COVID-19 respiratory failure. INTERVENTIONS: Participants were randomized 2:1 to receive 3 days of IV Aviptadil or placebo. MEASUREMENTS AND MAIN RESULTS: The primary end point (alive and free from respiratory failure at day 60) did not reach statistical significance (odds ratio [OR], 1.6; 95% CI, 0.86-3.11) for patients treated with Aviptadil when controlling for baseline ventilation status as prespecified in the protocol. There was, however, a statistically significant two-fold odds of improved survival (OR, 2.0; 95% CI, 1.1-3.9) at 60 days ( p = 0.035). There was significant improvement in respiratory distress ratio and reduced interleukin 6 cytokine release ( p = 0.02) by day 3.Subgroup analysis identified a statistically significant likelihood of achieving primary end point among those treated with high-flow nasal oxygen at baseline ( p = 0.039). Subjects on mechanical ventilation also experienced a 10-fold increased odds of survival with drug versus placebo ( p = 0.031). CONCLUSIONS: The primary end point did not reach statistical significance, indicating that there was no difference between Aviptadil versus placebo. However, Aviptadil improves the likelihood of survival from respiratory failure at day 60 in critical COVID-19 across all sites of care. Given the absence of drug-related serious adverse events and acceptable safety profile, we believe the benefit versus risk for the use of Aviptadil is favorable for patient treatment.


Subject(s)
COVID-19 , Respiratory Insufficiency , COVID-19/drug therapy , Drug Combinations , Humans , Interleukin-6 , Oxygen , Phentolamine , Respiratory Insufficiency/drug therapy , Surface-Active Agents , Vasoactive Intestinal Peptide/therapeutic use
19.
Obstet Gynecol ; 140(3): 447-449, 2022 Sep 01.
Article in English | MEDLINE | ID: covidwho-2018210

ABSTRACT

This is a descriptive study of pregnant patients who received nirmatrelvir-ritonavir therapy from April 16, 2022, through May 18, 2022. Patients were eligible to receive nirmatrelvir-ritonavir if they were diagnosed with mild-to-moderate coronavirus disease 2019 (COVID-19) with symptom onset within 5 days, did not require oxygen therapy or hospital admission, and had no contraindications to nirmatrelvir-ritonavir. During the study time frame, 11 patients were identified as candidates for nirmatrelvir-ritonavir treatment. All patients agreed to nirmatrelvir-ritonavir treatment after a telehealth consultation; seven patients completed the treatment. All patients who received nirmatrelvir-ritonavir experienced symptom resolution without the need for additional care. All but one patient tolerated nirmatrelvir-ritonavir without immediate adverse effects, and no adverse fetal or neonatal effects were observed.


Subject(s)
COVID-19 , Pregnancy Complications, Infectious , Female , Infant, Newborn , Pregnancy , Humans , Ritonavir/therapeutic use , Ritonavir/adverse effects , COVID-19/drug therapy , Lopinavir/therapeutic use , SARS-CoV-2 , Pregnancy Outcome , Antiviral Agents/therapeutic use , Drug Combinations , Pregnancy Complications, Infectious/drug therapy
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