Perspectives for antivirals to limit SARS-CoV-2 infection (COVID-19)

Compared with vaccines, antivirals for curbing COVID-19 (SARS-CoV-2 infection) have been developed at a much lower pace. Favipiravir has proven efficacious (in hamsters) but only at a very high dose which may not be feasible in humans. Remdesivir is the sole antiviral approved by the US FDA, but it has not been extensively evaluated for its safety. EIDD-1931 and EIDD-2801 have not been evaluated clinically. Mpro (protease) inhibitors likewise need to be subjected to clinical efficacy and safety studies. Remdesivir is a C-nucleoside and this class of compounds should be further evaluated. Polyanionic substances interfering with virus adsorption to the host cells have not been explored. They may possibly be administered by inhalation. Corticosteroids (such as dexamethasone), while virus-stimulating rather than inhibitory, may counteract the ‘cytokine storm’. Combination of (two or more of) the compounds mentioned above may offer an increased benefit through a synergistic interaction.

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Fidaxomicin for the treatment of Clostridioides difficile in children

Future Microbiology ◽

10.2217/fmb-2020-0104 ◽

2020 ◽

Vol 15 (11) ◽

pp. 967-979

Author(s):

Andrew M Skinner ◽

Tonya Scardina ◽

Larry K Kociolek

Keyword(s):

Clinical Trial ◽

Efficacy And Safety ◽

Narrow Spectrum ◽

Clostridioides Difficile ◽

Macrocyclic Antibiotic ◽

The Us ◽

Us Fda ◽

Multinational Clinical Trial

Fidaxomicin is an oral narrow-spectrum novel 18-membered macrocyclic antibiotic that was initially approved in 2011 by the US FDA for the treatment of Clostridioides difficile infections (CDI) in adults. In February 2020, the FDA approved fidaxomicin for the treatment of CDI in children age >6 months. In adults, fidaxomicin is as efficacious as vancomycin in treating CDI and reduces the risk of recurrent CDI. An investigator-blinded, randomized, multicenter, multinational clinical trial comparing the efficacy and safety of fidaxomicin with vancomycin in children was recently published confirming similar findings as previously reported in adults. Fidaxomicin is the first FDA-approved treatment for CDI in children and offers a promising option for reducing recurrent CDI in this population.

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Ixekizumab in the treatment of psoriatic arthritis

Immunotherapy ◽

10.2217/imt-2020-0225 ◽

2021 ◽

Vol 13 (1) ◽

pp. 19-33

Author(s):

Eric Lespessailles ◽

Hechmi Toumi

Keyword(s):

Psoriatic Arthritis ◽

Deep Understanding ◽

Critical Factor ◽

Therapeutic Agents ◽

Published Data ◽

Efficacy And Safety ◽

High Affinity ◽

The Us ◽

Us Fda ◽

Pathophysiologic Mechanisms

Psoriatic arthritis (PsA) is a heterogeneous chronic rheumatic disorder with numerous phenotypic facets. A better in deep understanding of the pathophysiologic mechanisms leading to psoriasis and PsA has contributed to the introduction of novel therapeutic agents. IL-17 is at the heart and a critical factor in the onset of PsA. Ixekizumab, a high-affinity monoclonal antibody against IL-17 A, has been approved by the US FDA in March 2016 for baseline psoriasis and Dec 2017 for PsA; by the EMA in April 2016 and January 2018, respectively. This article reviews the published data relating to ixekizumab efficacy and safety in the PsA treatment.

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UPDATE: Should Hydroxychloroquine (HCQ) or Chloroquine (CQ) be used in the treatment of COVID-19?

Acta Medica Philippina ◽

10.47895/amp.v54i0.2446 ◽

2020 ◽

Vol 54 ◽

Author(s):

Lia M. Palileo-Villanueva ◽

Elenore Judy B. Uy

Keyword(s):

Clinical Benefit ◽

Common Adverse Event ◽

Hospitalized Patients ◽

Efficacy And Safety ◽

Quality Of Evidence ◽

Randomized Controlled ◽

The Us ◽

Us Fda ◽

Meta Analyses

KEY FINDINGS There is insufficient evidence to support the routine use of HCQ or CQ for the treatment of COVID-19. Results from interim analyses of 2 large RCTs, the Recovery and the Solidarity trials, reportedly showed no clinical benefit from HCQ for hospitalized patients with COVID-19. There are 3 randomized controlled trials that investigated the efficacy and safety of HCQ compared to standard therapy. Overall quality of evidence was very low. Meta-analyses from the “COVID-19 Living Data” project suggests that the use of HCQ may increase the incidence of adverse events at day 14 to day 28 (RR 2.49, 95% confidence interval: 1.04 to 5.98, moderate quality of evidence); the most common adverse event across the two trials is diarrhea (n=8). In a statement dated June 5, 2020, the investigators of the Recovery trial announced their decision to halt further enrollment to the HCQ arm of the trial because an interim analysis showed no clinical benefit from the use of HCQ in hospitalized patients with COVID. On June 15, 2020, the US FDA revoked the emergency use authorization for HCQ and CQ as treatment for COVID-19. On June 18, 2020, the WHO announced that recruitment to the HCQ arm of the Solidarity trial has been halted.

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The US FDA is recommending against co-administration of boceprevir [Victrelis] and certain ritonavir-boosted HIV protease inhibitors.

Reactions Weekly ◽

10.2165/00128415-201214000-00005 ◽

2012 ◽

Vol &NA; (1400) ◽

pp. 2

Author(s):

&NA;

Keyword(s):

Protease Inhibitors ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

The Us ◽

Us Fda

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AI-guided discovery of the invariant host response to viral pandemics

10.1101/2020.09.21.305698 ◽

2020 ◽

Cited By ~ 1

Author(s):

Debashis Sahoo ◽

Gajanan D. Katkar ◽

Soni Khandelwal ◽

Mahdi Behroozikhah ◽

Amanraj Claire ◽

...

Keyword(s):

Immune Response ◽

Disease Severity ◽

Neutralizing Antibodies ◽

Nk Cell ◽

Gene Signature ◽

Host Cells ◽

High Dose ◽

Cytokine Storm ◽

Guided Discovery ◽

Therapeutic Goals

ABSTRACTWe sought to define the host immune response, a.k.a, the “cytokine storm” that has been implicated in fatal COVID-19 using an AI-based approach. Over 45,000 transcriptomic datasets of viral pandemics were analyzed to extract a 166-gene signature using ACE2 as a ‘seed’ gene; ACE2 was rationalized because it encodes the receptor that facilitates the entry of SARS-CoV-2 (the virus that causes COVID-19) into host cells. Surprisingly, this 166-gene signature was conserved in all viral pandemics, including COVID-19, and a subset of 20-genes classified disease severity, inspiring the nomenclatures ViP and severe-ViP signatures, respectively. The ViP signatures pinpointed a paradoxical phenomenon wherein lung epithelial and myeloid cells mount an IL15 cytokine storm, and epithelial and NK cell senescence and apoptosis determines severity/fatality. Precise therapeutic goals were formulated and subsequently validated in high-dose SARS-CoV-2-challenged hamsters using neutralizing antibodies that abrogate SARS-CoV-2•ACE2 engagement. IL15/IL15RA were elevated in the lungs of patients with fatal disease, and plasma levels of the cytokine tracked with disease severity. Thus, the ViP signatures provide a quantitative and qualitative framework for titrating the immune response in viral pandemics and may serve as a powerful unbiased tool to rapidly assess disease severity and vet candidate drugs.

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Guselkumab in the treatment of moderate-to-severe plaque psoriasis

Immunotherapy ◽

10.2217/imt-2020-0040 ◽

2020 ◽

Vol 12 (6) ◽

pp. 355-371

Author(s):

Cristina López-Sánchez ◽

Lluís Puig

Keyword(s):

Plaque Psoriasis ◽

Clinical Effectiveness ◽

Therapeutic Agents ◽

Published Data ◽

Human Antibody ◽

Efficacy And Safety ◽

Effector Cells ◽

Severe Plaque Psoriasis ◽

The Us ◽

Us Fda

Recent advances in our understanding of the immunopathogenesis of psoriasis have resulted in novel therapeutic agents. IL-23, mainly produced by dendritic cells, maintains the differentiation of naive T cells to Th17 cells, the keystone effector cells in psoriasis. The clinical effectiveness of therapeutic agents targeting this cytokine has been demonstrated in moderate-to-severe plaque psoriasis. Guselkumab (Tremfya®, Janssen Biotech, Inc., PA, USA) is the first human antibody against the p40 subunit of the IL-23 receptor approved by the US FDA and the EMA for this indication in adult patients (2017). It has also been approved for treatment of psoriatic arthritis in Japan (April 2018). This article reviews the published data relating to the efficacy and safety of guselkumab for treatment of moderate-to-severe plaque psoriasis.

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Subgroup Analysis of US and Non-US Patients in a Global Study of High-Dose Donepezil (23 mg) in Moderate and Severe Alzheimer’s Disease

American Journal of Alzheimer s Disease & Other Dementias® ◽

10.1177/1533317512454708 ◽

2012 ◽

Vol 27 (6) ◽

pp. 421-432 ◽

Cited By ~ 13

Author(s):

Stephen Salloway ◽

Jacobo Mintzer ◽

Jeffrey L. Cummings ◽

David Geldmacher ◽

Yijun Sun ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

High Dose ◽

Efficacy And Safety ◽

Global Function ◽

The Us ◽

The World ◽

Cognitive Benefits ◽

Post Hoc ◽

Patient Subgroups

To better understand responses in the large number of US-based patients included in a global trial of donepezil 23 mg/d versus 10 mg/d for moderate-to-severe Alzheimer’s disease (AD), post hoc exploratory analyses were performed to assess the efficacy and safety in US and non-US (rest of the world [RoW]) patient subgroups. In both subgroups, donepezil 23 mg/d was associated with significantly greater cognitive benefits than donepezil 10 mg/d. Significant global function benefits of donepezil 23 mg/d over 10 mg/d were also observed in the US subgroup only. Compared with RoW patients, US patients had relatively more severe AD, had been treated with donepezil 10 mg/d for longer periods prior to the start of the study, and a higher proportion took concomitant memantine. In both subgroups, donepezil had acceptable tolerability; overall incidence of treatment-emergent adverse events was higher in patients receiving donepezil 23 mg/d compared with donepezil 10 mg/d.

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Vernakalant hydrochloride for the treatment of atrial fibrillation: evaluation of its place in clinical practice

Future Cardiology ◽

10.2217/fca-2020-0039 ◽

2020 ◽

Cited By ~ 1

Author(s):

Leona A Ritchie ◽

Shuguang Qin ◽

Peter E Penson ◽

Neil C Henney ◽

Gregory YH Lip

Keyword(s):

Atrial Fibrillation ◽

Clinical Practice ◽

Clinical Evidence ◽

Acute Onset ◽

Efficacy And Safety ◽

Channel Activity ◽

Pharmacological Profile ◽

The Us ◽

Us Fda ◽

Onset Atrial Fibrillation

Vernakalant is an intravenous anti-arrhythmic drug available in Europe, Canada and some countries in Asia for the restoration of sinus rhythm in acute onset atrial fibrillation. Currently, it is not available in USA because the US FDA have ongoing concerns about its safety. Vernakalant has a unique pharmacological profile of multi-ion channel activity and atrial-specificity that distinguishes it from other anti-arrhythmic drugs. This is thought to enhance efficacy but there are concerns of adverse events stemming from its diverse pharmacology. This ambiguity has prompted a review of the available clinical evidence on efficacy and safety to help re-evaluate its place in clinical practice.

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