scholarly journals Zanamivir aqueous solution in severe influenza: A global Compassionate Use Program, 2009–2019

2021 ◽  
Author(s):  
Jie Wang-Jairaj ◽  
Tharaka Jayabalan ◽  
Aditya Joshi ◽  
Irene Miller ◽  
Peter Zammit-Tabona ◽  
...  
Keyword(s):  
Influenza A ◽  
Influenza Infection ◽  
Treatment Options ◽  
Fatal Outcome ◽  
Kidney Injury ◽  
Neuraminidase Inhibitor ◽  
Case Report Form ◽  
Compassionate Use ◽  
Serious Adverse Events ◽  
Safety Database

Background Zanamivir is a neuraminidase inhibitor effective against influenza A and B viruses. In 2009, GlaxoSmithKline (GSK) began clinical development of intravenous (IV) zanamivir, and initiated a global Compassionate Use Program (CUP) in response to the evolving H1N1 global pandemic. The goal of the CUP was to provide zanamivir to critically ill patients with limited treatment options. Methods Zanamivir was administered to patients with suspected or confirmed influenza infection, who were not suitable for other approved antiviral treatments. Reporting of serious adverse events (SAEs) was mandatory and recorded in the GSK safety database. A master summary tracking sheet captured requests and patient characteristics. A case report form was available for detailing medical conditions, dosing, treatment duration, and clinical outcomes. Results In total, 4033 requests were made for zanamivir treatment of hospitalized patients from 38 countries between 2009 and 2019. Europe had the highest number of requests (n=3051) followed by North America (n=713). At least 20 patients were aged ≤6 months, of whom 12 were born prematurely. The GSK safety database included 466 patients with ≥1 SAE, of whom 374 (80%) had a fatal outcome. Drug-related SAEs were reported in 41 (11%) patients, including hepatic failure (n=6 [2%]) and acute kidney injury (n=5 [1%)]. Conclusions The CUP fulfilled the need to provide global access to zanamivir prior to product approval. No new safety concerns were identified in the CUP compared with IV zanamivir clinical studies.

scholarly journals Survival from paraquat induced renal impairment in a 17 years old male

2021 ◽  
Vol 8 (2) ◽  
pp. 300
Author(s):  
Medo M. Kuotsu ◽  
N. Biplab Singh ◽  
Nyamnyei Konyak ◽  
Vikie-o Khruomo ◽  
Senjele Kath ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Treatment Options ◽  
Fatal Outcome ◽  
Radical Scavenging ◽  
Case Fatality ◽  
Kidney Injury ◽  
Organ Damage ◽  
Paraquat Poisoning ◽  
Adequate Hydration ◽  
Life Threatening

N, N’-dimethyl-4, 4’-bipyridinium dichloride (paraquat) is a herbicide commonly used in India that leads to fatal outcome on ingestion. Paraquat interferes in the intracellular electron transfer systems inhibiting the reduction of NADP to NADPH resulting in accumulation of superoxide radical causing lipid cell membranes destruction leading to various organ damage. Life threatening effects such as acute kidney injury as paraquat elimination is mainly by kidney, acute respiratory distress syndrome and multi-organ failure are the causes of mortality in paraquat poisoning. There is no specific antidotes for paraquat poisoning so prevention and aggressive decontamination remains the mainstay of management in case of exposure or ingestion. Paraquat poisoning presentation may vary in cases depending on the amount of paraquat consumed and thus the outcome. Here we report a case of a 17 years old male who presented with acute kidney injury following ingestion of paraquat in a suicidal attempt. In our case, induced vomiting of the stomach content readily after ingestion of the poison, early haemodialysis, use of immunosuppression such as methylprednisolone, cyclophosphamide and antioxidants such as acetylcysteine, Vitamin C and Vitamin E as free radical scavenging agent , supportive measures such as adequate hydration and antibiotics might have helped in the patient’s survival. The case fatality remains very high in paraquat poisoning till date owing to lack of effective treatment options.

scholarly journals Efficacy, Mechanism and Antiviral Resistance of Neuraminidase Inhibitors and Adamantane against Avian Influenza

2019 ◽  
Vol 29 (2) ◽  
pp. 61
Author(s):  
Dyah Ayu Hewajuli ◽  
NLPI Dharmayanti
Keyword(s):  
Avian Influenza ◽  
Ion Channel ◽  
Influenza A ◽  
Influenza Infection ◽  
Antiviral Drug ◽  
Neuraminidase Inhibitor ◽  
M2 Protein ◽  
New Variant ◽  
Amantadine Resistance ◽  
Ion Channel Inhibitors

Vaccination and antiviral drug are often used to control influenza. However, the effectiveness of vaccine was impaired due to the emergence of new variant of virus strain. Antiviral drug consists of prophylactic and curative substances, namely M2 ion channel inhibitors (adamantane; amantadine and rimantadine) and neuraminidase (NA) inhibitors (NAIs; oseltamivir, zanamivir, peramivir, laninamivir). The synthesis and modification of antiviral neuraminidase (NA) inhibitors (NAIs) and adamantanes increased the antiviral effectiveness. The mechanism of the neuraminidase inhibitor is to prevent influenza infection by inhibiting the release of the virus from internal cells. Adamantane is antiviral drug that selectively inhibits the flow of H+ ions through M2 protein to prevent the uncoating virus particles getting into the endosome. The substitution of (H275Y, S247N, I223L, K150N, R292K, I222T, R152K, R118K, E119V) on NA protein caused resistance of avian influenza virus against the neuraminidase inhibitor. The combination of mutations (S247N, I223L, K150N) increased the resistance of influenza A (H5N1) virus. The diffusion of adamantane resistance varies among HA subtypes, the species of host, the period of isolation, and region. Mutations at residues of 26, 27, 30, 31 or 34 transmembrane M2 protein caused adamantane resistance. The unique substitution (V27I) of M2 protein of clade 2.3.2 H5N1 subtype isolated in Indonesia in 2016 has been contributed to the amantadine resistance. Antiviral combination of M2 ion channel inhibitors and neuraminidase (NA) inhibitors is effective treatments for the resistance.

Ipilimumab (Ipi) expanded access program (EAP) for patients (pts) with stage III/IV melanoma: 10 mg/kg cohort interim results.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8508-8508 ◽  
Author(s):  
Omid Hamid ◽  
Wen-Jen Hwu ◽  
Jon M. Richards ◽  
Jeffrey S. Weber ◽  
Jedd D. Wolchok ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Treatment Options ◽  
Stage Iii ◽  
Controlled Clinical Trials ◽  
Serious Adverse Events ◽  
Safety Database ◽  
Expanded Access Program ◽  
Unresectable Stage ◽  
The Us ◽  
Access Program

8508 Background: The EAP (CA184-045), begun in 8/07, currently provides the largest safety database for Ipi outside of controlled clinical trials (CCTs) and included pts with brain metastases (BM) and primary ocular (OM) and mucosal (MM) melanoma. The EAP was amended in 10/08 to administer a 3 mg/kg dose based on the current label (Hodi et al. NEJM 2010). We now report interim data from pts treated in the US at 10 mg/kg from 8/07-10/08. Methods: Pts with unresectable Stage III or IV melanoma who progressed on at least 1 systemic therapy or had no alternate treatment options were eligible. Pts received 10 mg/kg Ipi i.v. q 3 wks up to 4 doses (induction) followed by 10 mg/kg q 12 wks (maintenance) until no longer clinically benefiting or unacceptable/unmanageable toxicity occurred. All serious adverse events (SAEs) and on-study deaths were collected; overall survival (OS) was assessed retrospectively. Results: Of 906 treated pts, 830 were included in the analysis; 39 from prior Ipi trials + 37 from sites whose IRB did not agree to collect OS were excluded. Pts got a median of 4 doses; 31% got ≥5 doses. ECOG 0/1/2 was 53%/39%/8% (1 pt was ECOG 3); 27% had BM, 5% had OM, and 4% MM. Primary reasons for discontinuation were disease progression (67%) and drug toxicity (11%). Incidence of drug-related SAEs was 27% with diarrhea 10%, colitis 8%, endocrinopathies 4%, and dermatitis 0.8%. 2 pts (0.24%) had on-study hepatitis SAEs, both considered drug-related and resulted in discontinuation. There were 3 (0.36%) drug-related intestinal perforations. 2 deaths (0.24%) were the outcome of drug-related SAEs; 1 multi-organ failure and 1 acute respiratory distress syndrome (both ≤70 days from last induction dose). 72 (9%) pts currently remain on treatment (i.e. >3 years). Available OS data showed that 138 pts (17%) were still at risk after 3 years. For 27% of pts the last known alive date was >30 days before data cutoff (with most >2 yrs). Conclusions: Data from the US EAP must be interpreted with caution compared to CCTs. To date, incidence of SAEs for hepatitis and intestinal perforation, and drug-related death at 10 mg/kg Ipi monotherapy is consistent with that seen in BMS clinical trials. Durable OS (>3 yrs) was observed in at least 17% of pts.

scholarly journals Compassionate Use of REGEN-COV ® in Patients with COVID-19 and Immunodeficiency-Associated Antibody Disorders

2021 ◽  
Author(s):  
David Stein ◽  
Ernesto Oviedo-Orta ◽  
Wendy A Kampman ◽  
Jennifer McGinniss ◽  
George Betts ◽  
...  
Keyword(s):  
Adverse Events ◽  
Retrospective Analysis ◽  
Treatment Options ◽  
Clinical Status ◽  
Outcome Data ◽  
Compassionate Use ◽  
Rt Pcr ◽  
Serious Adverse Events ◽  
Oxygenation Status ◽  
Related Reaction

Abstract Background Patients with immunodeficiency-associated antibody disorders are at a higher risk of prolonged/persistent COVID-19 infection, having no viable treatment options. Methods A retrospective analysis of patients with primary and/or secondary immunodeficiency-associated antibody disorders who received casirivimab and imdevimab (REGEN-COV ®) under emergency compassionate use. Objectives describe safety and response to REGEN-COV, focusing on the subset of patients who had COVID-19 duration ≥21 days before treatment. Results Quantitative (change in oxygenation status and/or viral load) and/or qualitative (physician-reported clinical status) patient outcomes data are reported from 64 patients who received REGEN-COV. Improvement in ≥1 outcome was observed in 90.6% of the overall patient group. Thirty-seven of these had COVID-19 duration ≥21 days before treatment; median time from diagnosis to REGEN-COV was 60.5 days. Of the 29 patients with COVID-19 duration ≥21 days before treatment and available outcome data, 96.6% showed improvement in ≥1 outcome. In the 14 patients with post-treatment RT-PCR results available, 11 (78.6%) reported a negative RT-PCR following treatment, with 5 (45.5%) reporting a negative RT-PCR within 5 days and 8 (72.7%) within 21 days of treatment. Ten of 85 patients (11.8%) experienced serious adverse events, only one was an infusion-related reaction, possibly related to REGEN-COV. Two deaths were reported, neither were attributed to REGEN-COV. Conclusions In this retrospective analysis of immunodeficient patients granted REGEN-COV under the compassionate use program, REGEN-COV treatment was associated with rapid viral clearance and clinical improvement in patients with long-standing COVID-19. Adverse events were consistent with COVID-19 and its associated complications, and due to patients’ concurrent medical conditions.

scholarly journals Preclinical Activity of VX-787, a First-in-Class, Orally Bioavailable Inhibitor of the Influenza Virus Polymerase PB2 Subunit

2014 ◽  
Vol 59 (3) ◽  
pp. 1569-1582 ◽  
Author(s):  
Randal A. Byrn ◽  
Steven M. Jones ◽  
Hamilton B. Bennett ◽  
Chris Bral ◽  
Michael P. Clark ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Influenza Infection ◽  
Antiviral Agent ◽  
Neuraminidase Inhibitor ◽  
Titration Calorimetry ◽  
Viral Polymerase ◽  
Replication Assay ◽  
Log Reduction ◽  
Orally Bioavailable

ABSTRACTVX-787 is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support for the idea that VX-787 occupies the 7-methyl GTP (m7GTP) cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with aKD(dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC50(the concentration of compound that ensures 50% cell viability of an uninfected control) for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC50in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs). VX-787 was highly efficacious in both prophylaxis and treatment models of mouse influenza and was superior to the neuraminidase inhibitor, oseltamivir, including in delayed-start-to-treat experiments, with 100% survival at up to 96 h postinfection and partial survival in groups where the initiation of therapy was delayed up to 120 h postinfection. At different doses, VX-787 showed a 1-log to >5-log reduction in viral load (relative to vehicle controls) in mouse lungs. Overall, these favorable findings validate the PB2 subunit of the viral polymerase as a drug target for influenza therapy and support the continued development of VX-787 as a novel antiviral agent for the treatment of influenza infection.

scholarly journals Differential Expression of Serum Exosome microRNAs and Cytokines in Influenza A and B Patients Collected in the 2016 and 2017 Influenza Seasons

Pathogens ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 149
Author(s):  
Sreekumar Othumpangat ◽  
William G. Lindsley ◽  
Donald H. Beezhold ◽  
Michael L. Kashon ◽  
Carmen N. Burrell ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Influenza A ◽  
Influenza Infection ◽  
Cell Types ◽  
Airway Epithelial Cells ◽  
Differentially Expressed ◽  
Influenza B ◽  
Airway Epithelial ◽  
Monocyte Chemoattractant Protein 1 ◽  
Novel Approach

MicroRNAs (miRNAs) have remarkable stability and are key regulators of mRNA transcripts for several essential proteins required for the survival of cells and replication of the virus. Exosomes are thought to play an essential role in intercellular communications by transporting proteins and miRNAs, making them ideal in the search for biomarkers. Evidence suggests that miRNAs are involved in the regulation of influenza virus replication in many cell types. During the 2016 and 2017 influenza season, we collected blood samples from 54 patients infected with influenza and from 30 healthy volunteers to identify the potential role of circulating serum miRNAs and cytokines in influenza infection. Data comparing the exosomal miRNAs in patients with influenza B to healthy volunteers showed 76 miRNAs that were differentially expressed (p < 0.05). In contrast, 26 miRNAs were differentially expressed between patients with influenza A (p < 0.05) and the controls. Of these miRNAs, 11 were commonly expressed in both the influenza A and B patients. Interferon (IFN)-inducing protein 10 (IP-10), which is involved in IFN synthesis during influenza infection, showed the highest level of expression in both influenza A and B patients. Influenza A patients showed increased expression of IFNα, GM-CSF, interleukin (IL)-13, IL-17A, IL-1β, IL-6 and TNFα, while influenza B induced increased levels of EGF, G-CSF, IL-1α, MIP-1α, and TNF-β. In addition, hsa-miR-326, hsa-miR-15b-5p, hsa-miR-885, hsa-miR-122-5p, hsa-miR-133a-3p, and hsa-miR-150-5p showed high correlations to IL-6, IL-15, IL-17A, IL-1β, and monocyte chemoattractant protein-1 (MCP-1) with both strains of influenza. Next-generation sequencing studies of H1N1-infected human lung small airway epithelial cells also showed similar pattern of expression of miR-375-5p, miR-143-3p, 199a-3p, and miR-199a-5p compared to influenza A patients. In summary, this study provides insights into the miRNA profiling in both influenza A and B virus in circulation and a novel approach to identify the early infections through a combination of cytokines and miRNA expression.

Absence of SP-A modulates innate and adaptive defense responses to pulmonary influenza infection

2002 ◽  
Vol 282 (3) ◽  
pp. L563-L572 ◽  
Author(s):  
Ann Marie LeVine ◽  
Kevan Hartshorn ◽  
James Elliott ◽  
Jeffrey Whitsett ◽  
Thomas Korfhagen
Keyword(s):  
Lung Inflammation ◽  
Influenza A ◽  
Influenza Infection ◽  
Pulmonary Inflammation ◽  
Defense Responses ◽  
Interferon Γ ◽  
Viral Clearance ◽  
Myeloperoxidase Activity ◽  
Respiratory Pathogens ◽  
Innate Defense

Mice lacking surfactant protein SP-A [SP-A(−/−)] and wild type SP-A(+/+) mice were infected with influenza A virus (IAV) by intranasal instillation. Decreased clearance of IAV was observed in SP-A(−/−) mice and was associated with increased pulmonary inflammation. Treatment of SP-A(−/−) mice with exogenous SP-A enhanced viral clearance and decreased lung inflammation. Uptake of IAV by alveolar macrophages was similar in SP-A(−/−) and SP-A(+/+) mice. Myeloperoxidase activity was reduced in isolated bronchoalveolar lavage neutrophils from SP-A(−/−) mice. B lymphocytes and activated T lymphocytes were increased in the lung and spleen, whereas T helper (Th) 1 responses were increased [interferon-γ, interleukin (IL)-2, and IgG2a] and Th2 responses were decreased (IL-4, and IL-10, and IgG1) in the lungs of SP-A(−/−) mice 7 days after IAV infection. In the absence of SP-A, impaired viral clearance was associated with increased lung inflammation, decreased neutrophil myeloperoxidase activity, and increased Th1 responses. Because the airway is the usual portal of entry for IAV and other respiratory pathogens, SP-A is likely to play a role in innate defense and adaptive immune responses to IAV.

scholarly journals In Vivo Influenza Virus-Inhibitory Effects of the Cyclopentane Neuraminidase Inhibitor RWJ-270201

2001 ◽  
Vol 45 (3) ◽  
pp. 749-757 ◽  
Author(s):  
Robert W. Sidwell ◽  
Donald F. Smee ◽  
John H. Huffman ◽  
Dale L. Barnard ◽  
Kevin W. Bailey ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Hong Kong ◽  
Influenza A ◽  
Arterial Oxygen Saturation ◽  
Virus Titer ◽  
Neuraminidase Inhibitor ◽  
Arterial Oxygen ◽  
Virus Infections ◽  
Inhibitory Effects ◽  
Lung Consolidation

ABSTRACT The cyclopentane influenza virus neuraminidase inhibitor RWJ-270201 was evaluated against influenza A/NWS/33 (H1N1), A/Shangdong/09/93 (H3N2), A/Victoria/3/75 (H3N2), and B/Hong Kong/05/72 virus infections in mice. Treatment was by oral gavage twice daily for 5 days beginning 4 h pre-virus exposure. The influenza virus inhibitor oseltamivir was run in parallel, and ribavirin was included in studies with the A/Shangdong and B/Hong Kong viruses. RWJ-270201 was inhibitory to all infections using doses as low as 1 mg/kg/day. Oseltamivir was generally up to 10-fold less effective than RWJ-270201. Ribavirin was also inhibitory but was less tolerated by the mice at the 75-mg/kg/day dose used. Disease-inhibitory effects included prevention of death, lessening of decline of arterial oxygen saturation, inhibition of lung consolidation, and reduction in lung virus titers. RWJ-270201 and oseltamivir, at doses of 10 and 1 mg/kg/day each, were compared with regard to their effects on daily lung parameters in influenza A/Shangdong/09/93 virus-infected mice. Maximum virus titer inhibition was seen on day 1, with RWJ-270201 exhibiting the greater inhibitory effect, a titer reduction of >104 cell culture 50% infective doses (CCID50)/g. By day 8, the lung virus titers in mice treated with RWJ-270201 had declined to 101.2 CCID50/g, whereas titers from oseltamivir-treated animals were >103CCID50/g. Mean lung consolidation was also higher in the oseltamivir-treated animals on day 8. Both neuraminidase inhibitors were well tolerated by the mice. RWJ-270201 was nontoxic at doses as high as 1,000 mg/kg/day. These data indicate potential for the oral use of RWJ-270201 in the treatment of influenza virus infections in humans.

scholarly journals Pharmacological interventions for drug-using offenders: an update to a systematic review and meta-analysis

2021 ◽  
Author(s):  
J. M. Glanville ◽  
A. E. Perry ◽  
M. Martyn-St James ◽  
C. Hewitt ◽  
S. Swami ◽  
...  
Keyword(s):  
Systematic Review ◽  
Drug Use ◽  
Meta Analysis ◽  
Treatment Options ◽  
Criminal Activity ◽  
Cochrane Collaboration ◽  
Pharmacological Interventions ◽  
Serious Adverse Events ◽  
Male Adult ◽  
The Impact

Abstract This updated systematic review assesses the effects of pharmacological interventions for drug-using offenders. Methods Systematic review protocols and conventions of the Cochrane Collaboration were followed to identify eligible studies. Studies were pooled in a meta-analysis to assess the impact of pharmacological interventions on drug use and criminal activity. An economic appraisal was conducted. Results The search strategies identified 22 studies containing 4372 participants. Meta-analyses revealed a small statistically significant mean difference favouring pharmacological interventions relative to psychological interventions in reducing drug use and criminal activity. When comparing the drugs to one another there were no significant differences between those included (methadone versus buprenorphine, naltrexone and cyclazocine). Conclusion Overall, the findings of this review suggest that methadone and naltrexone may have some impact on reducing drug use and reincarceration. Individual pharmacological drugs had differing (generally non-significant) effects. One study identified serious adverse events. Three studies reported cost and consequences information sufficient to conduct a full economic analysis but this was not comprehensive enough to be able to make judgements across all treatment options. Full economic analyses should be encouraged. The study findings were limited mainly to male adult offenders.

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