Lessons learned from a double-blind randomised placebo-controlled study with a iota-carrageenan nasal spray as medical device in children with acute symptoms of common cold

Fazekas, Tamás; Eickhoff, Philipp; Pruckner, Nathalie; Vollnhofer, Georg; Fischmeister, Gustav; Diakos, Christopher; Rauch, Margit; Verdianz, Maria; Zoubek, A.; Gadner, Helmut; Lion, Thomas

doi:10.1186/1472-6882-12-147

Cited by 62 publications

(115 citation statements)

References 26 publications

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“…Carrageenans have shown antiviral activity against a number of viral pathogens, including HPV (43), HIV (44), dengue virus (45), and influenza A virus (46). Importantly, iota-carrageenan has been used safely in human trials in the form of a nasal spray to reduce viral infection (47)(48)(49).…”

Section: Iota-carrageenan Inhibits Hmpv Infection In Human Respiratormentioning

confidence: 99%

Inhibition of Human Metapneumovirus Binding to Heparan Sulfate Blocks Infection in Human Lung Cells and Airway Tissues

Klimyte

Smith

Oreste³

et al. 2016

J Virol

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Human metapneumovirus (HMPV), a recently discovered paramyxovirus, infects nearly 100% of the world population and causes severe respiratory disease in infants, the elderly, and immunocompromised patients. We previously showed that HMPV binds heparan sulfate proteoglycans (HSPGs) and that HMPV binding requires only the viral fusion (F) protein. To characterize the features of this interaction critical for HMPV binding and the role of this interaction in infection in relevant models, we utilized sulfated polysaccharides, heparan sulfate mimetics, and occluding compounds. Iota-carrageenan demonstrated potent anti-HMPV activity by inhibiting binding to lung cells mediated by the F protein. Furthermore, analysis of a minilibrary of variably sulfated derivatives of Escherichia coli K5 polysaccharide mimicking the HS structure revealed that the highly O-sulfated K5 polysaccharides inhibited HMPV infection, identifying a potential feature of HS critical for HMPV binding. The peptide dendrimer SB105-A10, which binds HS, reduced binding and infection in an F-dependent manner, suggesting that occlusion of HS at the target cell surface is sufficient to prevent infection. HMPV infection was also inhibited by these compounds during apical infection of polarized airway tissues, suggesting that these interactions take place during HMPV infection in a physiologically relevant model. These results reveal key features of the interaction between HMPV and HS, supporting the hypothesis that apical HS in the airway serves as a binding factor during infection, and HS modulating compounds may serve as a platform for potential antiviral development. IMPORTANCE Human metapneumovirus (HMPV) is a paramyxovirus that causes respiratory disease worldwide. It has been previously shown that HMPV requires binding to heparan sulfate on the surfaces of target cells for attachment and infection.In this study, we characterize the key features of this binding interaction using heparan sulfate mimetics, identify an important sulfate modification, and demonstrate that these interactions occur at the apical surface of polarized airway tissues. These findings provide insights into the initial binding step of HMPV infection that has potential for antiviral development.A cute viral respiratory tract infection is the most frequently observed illness in humans worldwide (1). Human metapneumovirus (HMPV), an enveloped, negative-sense, singlestranded RNA virus in the Paramyxoviridae family, is a common cause of both upper and lower respiratory tract infections (2-4). First identified in 2001 in the Netherlands, HMPV is now known to be the cause of respiratory infections in humans since at least 1958 (2). Nearly every person is exposed to HMPV in the first decade of life; seroconversion occurs on average by the age of 5 years, and nearly 100% of individuals test seropositive for antibody reactivity to HMPV antigens by the age of 10 (5). In children, HMPV infection is the second most common cause of hospitalization due to respiratory infection after the ...

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Section: Iota-carrageenan Inhibits Hmpv Infection In Human Respiratormentioning

confidence: 99%

Inhibition of Human Metapneumovirus Binding to Heparan Sulfate Blocks Infection in Human Lung Cells and Airway Tissues

Klimyte

Smith

Oreste³

et al. 2016

J Virol

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“…Between 2008 and 2011, three randomized clinical trials (two in adults and one in children) were conducted comparing I-C nasal spray with saline solution (placebo). In all 3 trials, there were indications of efficacy, including significantly reduced cold symptoms [5]; positive effects on symptoms in patients in whom less co-medication or no co-medication was used [6]; significantly reduced viral loads [5][6][7]; and faster reduction of common cold symptoms [6,7]. Treatments were safe and well tolerated [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of iota-carrageenan nasal spray versus placebo in early treatment of the common cold in adults: the ICICC trial

et al. 2015

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Iota-carrageenan (I-C) is active against respiratory viruses in vitro and was effective as nasal spray in three previous clinical trials. The current trial served to further investigate I-C in patients with early common cold symptoms.MethodsThis randomized, placebo-controlled, double-blind phase IV trial was conducted in 200 adult patients with self-diagnosed colds of <48 h’ duration that were confirmed by baseline cold symptom scores. Patients were to self-administer 0.12 % I-C or placebo spray (NaCl 0.5 %) four times daily for four to ten days and record symptom information for ten days. Common respiratory viruses were quantified by RT-PCR during pretreatment and on Day 3 or 4. The primary endpoint was the mean total symptom score (TSS) of eight cold symptoms on Days 2–4 (TSS2–4).ResultsPatients in both treatment groups had similar baseline TSSs (mean TSS: 6.75 for I-C and 6.79 for placebo). Viruses were detected in baseline samples from 53 of 98 I-C patients (54.1 %) and 54 of 97 placebo patients (55.7 %). Mean ± SE for TSS2–4 was 5.78 ± 0.25 for I-C patients and 6.39 ± 0.25 for placebo (p = 0.0895). Exploratory analyses after unblinding (TSS2–4 excluding a patient with aberrantly high symptom scores [TSS2–4, ex 1pt]; mean of TSS over Days 1–4 [TSS1–4]; change in TSS1–4 relative to baseline [TSS1–4, rel]) demonstrated treatment differences in favor of I-C (p = 0.0364, p = 0.0495 and p = 0.0421, respectively). For patients with quantifiable rhinovirus/enterovirus at baseline, there was a trend towards greater reduction of virus load at Day 3 or 4 (p = 0.0958; I-C: 90.2 % reduction in viral load; placebo: 72.0 %). Treatments were well tolerated with no differences in adverse event rates.ConclusionsThe primary endpoint did not demonstrate a statistically significant difference between I-C and placebo but showed a trend towards I-C benefit. Exploratory analyses indicated significant reduction of cold symptoms in the I-C group relative to placebo during the first four days when symptoms were most severe, and also substantiated I-C’s activity against rhinovirus/enterovirus.Trial registrationNCT01944631 (clinicaltrials.gov)

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“…It was recently shown that iota-carrageenan (a sulfated polysaccharide found in some species of red seaweed) exerts potent activity against respiratory viruses by directly binding to the infectious particles; however, carrageenan does not enter the host cell and is not expected to exert pharmacologic or immune activities [51]. Although iota-carrageenan was found to be effective as nasal spray in three clinical trials [1,51,52], it failed to achieve statistically significant outcomes for the primary and secondary endpoints in the most recent study [53]. Nasal irrigation with saline is often employed as an adjunct treatment for acute upper respiratory tract infections -particularly in children -and might relieve the symptoms to some extent [54].…”

Section: Discussionmentioning

confidence: 99%

A marine-sourced fucoidan solution inhibits Toll-like-receptor-3-induced cytokine release by human bronchial epithelial cells

Dutot

Grassin-Delyle

Salvator

et al. 2019

International Journal of Biological Macromolecules

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Fucoidans are sulfated polysaccharides from brown algae, known to have immunomodulatory activity. Their effects on the response of airway epithelial cells to Toll-like receptor 3 (TLR3) stimulation have not been characterized. Our objective was to evaluate the effects of a marine-sourced fucoidan solution (MFS) on the TLR3-induced expression and/or production of cytokines and prostaglandin by human primary bronchial epithelial cells as a model of the airway epithelium. The cells were incubated with MFS in the presence or absence of Poly(I:C) (a TLR3 agonist that mimics viral RNA). Cytokine expression and production were assessed using RT-qPCR and ELISA. The expression of cyclooxygenase-2 and the production of prostaglandin E2 were also measured. Relative to control, exposure to MFS was associated with lower Poly(I:C)-induced mRNA expression of various cytokines and chemokines, and lower COX-2 production. The MFS inhibited the production of some cytokines (IL-1α, IL-1β, TNFα, and IL-6), chemokines (CCL5, CCL22, CXCL1, CXCL5 and CXCL8) and prostaglandin E2 but did not alter the production of IL-12/25, CCL2 and CCL20. At clinically relevant concentrations, the MFS inhibited the TLR3mediated production of inflammatory mediators by human primary bronchial epithelial cells -suggesting that locally applied MFS might help to reduce airway inflammation in viral infections.

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Lessons learned from a double-blind randomised placebo-controlled study with a iota-carrageenan nasal spray as medical device in children with acute symptoms of common cold

Cited by 62 publications

References 26 publications

Inhibition of Human Metapneumovirus Binding to Heparan Sulfate Blocks Infection in Human Lung Cells and Airway Tissues

Inhibition of Human Metapneumovirus Binding to Heparan Sulfate Blocks Infection in Human Lung Cells and Airway Tissues

Efficacy and safety of iota-carrageenan nasal spray versus placebo in early treatment of the common cold in adults: the ICICC trial

A marine-sourced fucoidan solution inhibits Toll-like-receptor-3-induced cytokine release by human bronchial epithelial cells

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