Prophylactic Intranasal Treatment with Iota-Carrageenan for Acute Upper Respiratory Tract Viral Infections

Ronald Eccles

Cardiff School of Biosciences, Cardiff University, Cardiff, UK.

DOI: 10.4236/ojrd.2025.151003                

Abstract

The common cold is caused by a large range of respiratory viruses and is the most common disease of mankind. There is a great need for a prophylactic treatment for colds. Specific antiviral treatments are only effective against one group of viruses and there is a need for a non-specific treatment that can be used against all respiratory viruses. Carrageenan is a general term used to describe a range of sulfated polysaccharides extracted from edible seaweeds. Large polyanionic molecules such as carrageenan have been shown to have antiviral activity against a wide range of viruses in vitro. The strong anionic charge of carrageenan attracts and traps viruses that have positively charged areas on their surface. The trapped viruses are then unable to infect epithelial cells. Iota-carrageenan exerts its’ antiviral activity by physical means due to its high anionic charge and it does not have any pharmacological properties and therefore does not have any toxicology or known side effects from treatment. Iota-carrageenan does not have any taste or smell and, when used as a nasal spray, does not have any adverse effects. Iota-carrageenan is an ideal prophylactic treatment for the common cold and is safe for use in children. Treatment of common cold with iota-carrageenan has to date been studied in five placebo-controlled clinical trials and these trials support both efficacy as a prophylactic treatment for colds and the safety and tolerability of iota-carrageenan.

Keywords

Iota-Carrageenan, Common Cold, Children, Toxicology, Safety

1. Introduction

Acute respiratory viral infections (URTI) are the most common diseases of mankind. All known respiratory viruses are capable of causing the syndrome of symptoms known as the common cold [1]. The common cold syndrome is caused by a wide range of viruses such as rhinoviruses, coronaviruses (now including SARS-CoV-2), influenza viruses, respiratory syncytial viruses (RSV), parainfluenza viruses, adenoviruses, enteroviruses, metapneumoviruses and unknown viruses which may be responsible for 20% - 30% of cases of common cold [2] [3]. Specific antiviral treatments such as the neuraminidase inhibitors used to treat influenza are only effective against one group of viruses and there is a great need for a non-specific antiviral therapy with a broad spectrum of activity for the treatment of URTI. Antivirals are only effective when used at the earliest signs of infection as once the inflammatory response of the immune system is activated; it is too late to inhibit the effects of the inflammatory mediators such as bradykinin and prostaglandins which mediate the symptoms of common cold [3]. Prophylactic treatments for the common cold have been sought for many years and in 1938 a study on prophylactic treatments for colds commented that “The great number of so-called treatments and prophylactics bears testimony to our failure to cope with the problem” [4]. The large number of prophylactic medicines and vitamin supplements available today for treatment of common cold indicates that little has changed since 1938 and there is still a great need for a safe and effective prophylactic treatment [5]. The term prophylaxis is derived from the Greek word “phylax” which means to guard against, and prophylactic treatments guard against disease by making an early intervention and taking action ahead of time [6]. This review article will discuss the role of iota-carrageenan administered as an intranasal spray as a prophylactic treatment for a common cold.

2. Iota-Carrageenan

Carrageenan is a general term used to describe a range of sulfated polysaccharides extracted from edible seaweeds [7]. Red algae (seaweeds) are unique amongst plants because of the sulfated polysaccharide composition of their cell walls [7]. Carrageenans are extracted on an industrial scale by boiling red algae with alkalis [8]. Carrageenan is widely used in the food and cosmetic industries for its thickening and gel-like properties and is commonly used as a thickening agent in sauces and ice creams [9]. Commercially important carrageenans are iota-, kappa- and lambda-carrageenans. These carrageenans are composed of long chain molecules of disaccharide repeating units (dimers), with kappa, iota and lambda dimers having one, two and three sulfate ester groups respectively. The dimer structure of iota-carrageenan is illustrated in Figure 1 which shows that the dimer has two negatively charged sulfate groups. The iota-carrageenan used in nasal sprays is pharma grade Gelcarin 379F obtained from DuPont. This source of iota-carrageenan is mainly produced from the seaweed Eceuma denticulatum which is sometimes named Echeuma spinosum. The carrageenan in nasal sprays is mainly (>90%) iota-carrageenan plus kappa-carrageenan (<10%) but does not contain any lambda-carrageenan (personal communication from Marinomed company, Vienna Austria 2018).

Figure 1. Structure of iota-carrageenan dimer, illustrating the repeating disaccharide units with two negatively charged sulfate groups.

3. Antiviral Activity of Carrageenan

The in vitro antiviral activity of carrageenan was first described in 1958 when agar, containing carrageenan, was shown to exert a marked inhibitory effect on the growth of influenza B virus and mumps virus in embryonated chicken eggs [10]. The antiviral properties of a range of sulfated polysaccharides, such as heparin and components of agar were studied in the 1960s, and it was demonstrated that it was the negative electrostatic charge of these molecules that was responsible for trapping viruses [11]-[13]. In the 1980s, studies focussed on a range of polysaccharides with antiviral properties, and since carrageenans were already widely available as food additives and generally recognised as safe (GRAS), these polysaccharides were a good therapeutic target for development of antiviral therapies for human use [14]. Carrageenan has been shown to have antiviral activity in vitro against a wide range of viruses such as hepatitis A virus [15], herpes simplex virus [16], rhinovirus [17], papillomavirus [18], dengue virus [19], various enveloped viruses such as cytomegalovirus, vesicular stomatitis virus and human immunodeficiency virus [20], porcine reproductive and respiratory syndrome virus [21] influenza A virus [22] and SARS-CoV-2 [23]. This broad spectrum of antiviral activity indicates that carrageenan does not have a specific interaction with viruses or their cell receptors but exerts antiviral activity by a non-specific physical interaction with viruses [24].

4. In-Vitro Studies Demonstrating Antiviral Activity

The antiviral activity of carrageenan was first discovered in an in-vitro study in 1958 [10], and since then, numerous studies have demonstrated antiviral activity against a wide range of viruses. Some of the studies demonstrating in-vitro antiviral activity of iota-carrageenan are summarised in Table 1 with the relevant publications, Grassauer 2008 [17], Morokutti-Kurz 2017 [25], Graf 2018 [26], Leibbrandt 2010 [27], Morokutti-Kurz 2015 [28], Varese 2021 [29], Alsaidi 2021 [30], Froba 2021 [23]. The studies in Table 1 are designated as prophylactic when it was shown that incubation of culture cells with iota-carrageenan prior to infection inhibited viral replication. Grassauer et al. 2008 [17] speculate that their results indicate that iota-carrageenan can prevent infection by creating a hostile environment for respiratory viruses and therby block viral entry into cells and replication, and this can be viewed as a prophylactic treatment.

Table 1. In vitro studies demonstrating antiviral efficacy of iota-carrageenan. Prophylactic use is stated in brackets.

VIRUS	PUBLICATION
Human rhinoviruses
HRV-1a	Grassauer, 2008; Morokutti-Kurz, 2017; Graf, 2018
HRV-2 (prophylactic)	Grassauer, 2008
HRV-8	Grassauer, 2008; Morokutti-Kurz, 2017
HRV-14	Grassauer, 2008
HRV-16	Grassauer, 2008
HRV-83	Grassauer, 2008
HRV-84	Grassauer, 2008
Human influenza viruses
A/H1N1/PR8/34 (prophylactic)	Leibbrandt, 2010
A/H1N1 A/Hansa Hamburg/01/09	Morokutti-Kurz, 2015, 2017
A/Aichi/2/68 H3N2	Leibbrandt, 2010; Morokutti-Kurz, 2015
A/H5N1/Teal/Germany/Wv632/05	Morokutti-Kurz, 2015
A/H7N7/Türkiye/Germany/R11/01	Morokutti-Kurz, 2015
Endemic coronaviruses
hCoV OC43 (prophylactic)	Morokutti-Kurz, 2017; Graf, 2018
Pandemic coronaviruses
SARS-CoV-2 SPSS 2019	Morokutti-Kurz, 2020
SARS-CoV-2	Varese et al., 2021
SARS-CoV-1	Alsaidi, 2021
SARS-CoV-2 2019 (prophylactic)	Morokutti-Kurz, 2020
SARS-CoV-2 2019	Schütz, 2021
SARS-CoV-2 D614 G, SARS-CoV-2 K1417N/E484K/N501Y	Alsaidi, 2021
SARS-CoV-2 SSPL 2019, SARS-CoV-2 SSPL Alpha, SARS-CoV-2 SSPL Beta, SARS-CoV-2 SSPL Gamma, SARS-CoV-2 SSPL Delta (prophylactic)	Fröba, 2021
Coxsackievirus
Coxsackievirus A10	Morokutti-Kurz, 2017

5. Clinical Trials Demonstrating Efficacy of Iota-Carrageenan

The results of five clinical trials studying the efficacy of intranasal iota-carrageenan for treatment of URTI are summarised in Table 2. Four of the studies used prophylactic treatment starting at the first signs of URTI [31]-[34] and one used prophylactic treatment over a 21-day period [35].

Table 2. Clinical trials using iota-carrageenan as a prophylactic treatment for common cold.

PUBLICATION	PATIENTS	TREATMENT	ANTIVIRAL	SYMPTOMATOLOGY
Eccles et al. (2010) Double blind placebocontrolled trial	n = 35 Adults mean age 19.6 years	0.12% iota-carrageenan nasal spray, 3 times a day for four days	Nasal lavage was analyzed by real time RT-PCR for the presence of viral genomes. Viral load in the respiratory virus positive patients increased by almost sixfold whereas it decreased by 92% in the iota-carrageenan treatment group (p < 0.009).	Carrageenan treated group had a reduction in total symptom scores between days 2 - 4 of trial (p = 0.046)
Fazekas et al. (2012) Double blind placebocontrolled trial	n = 153 children aged between 1 - 18 years, mean age 5 years	0.12% iota-carrageenan nasal spray, 3 times a day for seven days	Topical application of the iota-carrageenan spray reduced viral loads in nasal secretions to a significantly higher degree than placebo after 3 to 5 days of treatment (p = 0.026)	Non significant reduction in total symptom scores between days 2 - 7 of trial
Ludwig et al. (2013) Double blind placebo controlled trial	n = 211 adults mean age 33 years	0.12% iota-carrageenan nasal spray, 3 times a day for seven days	Viral titers in nasal fluids showed a significantly greater decrease in carrageenan treated patients in the intention-to-treat population (p = 0.024) and in the per protocol population (p = 0.018) between days 1 and 3/4.	Significant reduction in total symptom scores in later days of cold (p = 0.048)
Eccles et al. (2015) Double blind placebocontrolled trial	n = 200 adults mean age 20 years	0.12% iota-carrageenan nasal spray, 4 times a day for four days	Non-significant trend for a reduction in viral titres in the iota-carrageenan group compared to the placebo group.	Significant reduction in total symptom scores between days 2 - 4 of trial (p = 0.0364)
Figueroa et al. 2021 Pilot double blind placebo controlled trial	N= 394 hospital workers mean age 38 years	0.17% iota-carrageenan nasal spray, 4 times a day for 21-day	Symptomatic patients had nasophayngeal swab for PCR test for SARS-CoV-2	Significant reduction in incidence of COVID-19 (p = 0.03)

Eccles et al. (2010) [31] conducted a double-blind placebo-controlled pilot study on 35 adults with intranasal treatment with an iota-carrageenan nasal spray given on early symptoms of common cold (<48 hours onset of symptoms) and demonstrated significant reductions in both common cold symptoms and viral load.

Fazekas et al. (2012) [32] conducted a double-blind placebo-controlled on 153 children with early symptoms of common cold (<36 hours) and demonstrated significant reduction in viral load on treatment with intranasal iota-carrageenan but there was no significant difference in symptom scores between treatment groups, perhaps because the parents and children had difficulty in assessing symptoms because of the young age of the children (mean age 5 years). The trial did report a reduced time to clearance of common cold symptoms (7.6 in the iota-carrageenan treatment group versus 9.4 days in the placebo group (p = 0.038).

Ludwig et al. (2013) [33] conducted a double blind placebo-controlled trial on 211 adults with early symptoms of common cold (<48 hours) and demonstrated that alleviation of symptoms was 2.1 days faster in the carrageenan group compared to placebo (p = 0.037). Viral titres in nasal fluids showed a significantly greater decrease in carrageenan treated patients in the intention-to-treat population (p = 0.024) and in the per-protocol population (p = 0.018) between days 1 and 3/4.

Eccles et al. (2015) [34] conducted a double-blind placebo-controlled trial on 200 adults with early symptoms of common cold (<48 hours) and demonstrated a significant reduction in symptom scores between treatment groups (p = 0.0364).

Figueroa et al. (2021) [35] conducted a study on 394 adults who treated themselves with an iota-carrageenan nasal spray over a 21-day period and demonstrated a significant reduction in incidence of COVID-19 over the test period (p = 0.03).

Clinical trials on URTI are difficult because of the acute nature of the disease, and the five clinical trials above can be criticised as either being small pilot studies or not achieving all their stated outcome measures. But when the five trials are considered together, they provide evidence that an iota-carrageenan nasal spray can reduce viral titres, and also reduce severity of symptoms of URTI [36] [37].

6. Mechanism of Antiviral Activity of Carrageenans

In order to infect epithelial cells of the respiratory tract, respiratory viruses must travel through a layer of respiratory mucus and then find and interact with surface receptors on the cells. It has been proposed that negatively charged molecules such as heparan sulfate on the surface of epithelial cells are important in attracting positively charged viruses through the mucus layer so that the viruses can reach their specific cell receptors and be absorbed into the cells to replicate [24] [38]-[43]. The virus has been proposed to “surf” along the surface of the epithelial cells as it is attracted to the negatively charged heparan sulfate [41]. Heparan sulfate proteoglycans are long chain branched glycoproteins found on the cell surface that have multiple functions in cell physiology as they interact with numerous ligands such as cytokines, chemokines, proteases and integrin and cell adhesion receptors [44]. The structure of heparan sulfate is illustrated in Figure 2 which illustrates its negatively charged groups.

Figure 2. Structure of heparan sulfate showing the negatively charged sulfate groups.

Several sulfated polysaccharides, such as heparin, dextran sulfate, pentosan polysulfate, mannan sulfate and sulfated cyclodextrins have been shown to exhibit antiviral activity [45]. Iota-carrageenan has similar antiviral properties to other sulfated polysaccharides and it has been proposed that the negatively charged sulfate groups of carrageenan are important for their antiviral activity by giving them a strong anionic charge [46].

The strong anionic charge of carrageenan attracts and traps viruses which have positively charged areas on their surface. The trapped viruses are then unable to infect epithelial cells.

The proposal that negatively charged sulfate groups on polysaccharides such as heparin and carrageenans are responsible for antiviral activity has been put forward many times and is nicely summarised by Nahmias and Kibrick (1964) [11].

“The inhibitory activity of the heparin was found to be related to the sulfate groupings on the molecule. The effect of heparin appears to be on the virus, rather than on the cell. The virus is not inactivated, however, and the heparin-virus “complex” is readily dissociable on dilution. Heparin was shown to affect viral infection in its earliest phase, probably at the primary electrostatic attachment of virus to cell.” [11].

The electrostatic activity of carrageenan is generally accepted as the explanation for antiviral activity but carrageenan does have other properties that may also contribute to its antiviral efficacy such as modulation of intracellular signalling pathways, antioxidant activity and immunomodulatory properties [46].

7. Prophylaxis

There is still a great need for a safe and effective prophylactic treatment for common cold. The instructions for use of carrageenan nasal sprays are “use at the first signs of symptoms”. A dry, scratchy throat irritation may indicate the onset of a common cold, and similarly, nasal irritation and sneezing may also be early symptoms that a common cold is likely to follow, but these early symptoms are not a “common cold”. The term “common cold” was used to describe a common syndrome of symptoms long before the discovery of the viruses responsible for the disease were discovered. The common cold is therefore self-diagnosed worldwide on the basis of a grouping of familiar symptoms such as sore throat, runny nose, sneezing, and nasal congestion [47] and the presence of a single symptom such as throat irritation or sneezing may indicate that a common cold is likely to follow but these single symptoms would not be deemed by the subject to be a common cold.

Treatment with a carrageenan nasal spray at first signs of symptoms can therefore be considered as a means of preventing the development of a common cold and can be considered as a prophylactic treatment.

8. Safety

Iota-carrageenan is a large polysaccharide molecule that is not absorbed across the respiratory tract when used as a nasal spray. No evidence has been found in the literature for any human metabolism of iota-carrageenan, although it is metabolised by some marine bacteria [48]. Iota-carrageenan exerts its’ antiviral activity by physical means due to its high anionic charge and it does not have any pharmacological properties and therefore does not have any toxicology or known side effects from treatment. The safety of iota-carrageenan when used as a nasal spray is supported by the results of the five clinical trials illustrated in Table 2 which reported that there were no significant differences in adverse events between the verum and placebo-treated groups.

Carrageenan is widely used in the food industry as a thickener and although carrageenan is generally recognised as safe (GRAS), there have been some concerns that intake with food may have adverse effects on gastrointestinal health [49]. The amount of carrageenan ingested in food products is difficult to quantify but it is likely in the order of grams per day in many persons because of the common use of carrageenan as a food additive. David et al. (2018) report intakes of up to 7.7 g per day and that intake of carrageenan from processed food may be up to 2.5 g per day [50]. Other reports quoted by David et al. (2018) have estimated carrageenan intakes between 50 - 100 mg per day [50].

The intranasal daily intake of iota-carrageenan in clinical trials is reported to be 1 mg a day [37] and this intake is much smaller than the grams of carrageenan that can be ingested in foods. The intake of carrageenan when used as a prophylactic treatment for common cold is acute and over a period of a few days, whereas the intake of carrageenan in food is long term over a lifetime. It is therefore not valid to compare any concerns on the safety of carrageenan in food with safety of a nasal spray because of the great differences in dose and the duration of exposure.

9. Tolerability

Iota-carrageenan does not have any taste or smell and when used as a nasal spray does not have any adverse effects apart from those normally associated with the use of any nasal spray. From personal experience in conducting clinical trials on iota-carrageenan nasal sprays as a prophylactic treatment for common cold, participants in the trials comment on the lack of any sensation associated with treatment apart from the sensation of spraying the nose.

Interaction with Other Medicines and Treatments

Iota-carrageenan nasal sprays are licensed by regulators as a medical device that works by the physical properties of carrageenan and therefore do not have any known interactions with any other concomitant treatments for the common cold or any other disease. If patients use concomitant nasal treatments such as saline and corticosteroids, it is recommended to use the carrageenan nasal spray at least an hour before or after the other treatment in order to avoid diluting the treatment or any other interaction.

10. Discussion and Conclusion

Common cold is caused by a wide range of respiratory viruses, and any antiviral treatment for this common disease must work on some properties that are common to all these viruses. All respiratory viruses must pass through the physical barrier of mucus and respiratory fluid lining the respiratory tract to reach the cell surface. There is evidence that the viruses use their positive electrical charge to reach the negatively charged cell surface [41]. Polyanionic molecules such as iota-carrageenan trap viruses as they move towards the epithelial surface, and they also trap viruses that are released from the epithelial cells.

Iota-carrageenan is an ideal prophylactic treatment for common cold as it does not have any pharmacological or toxicological activity and is safe for use in children. Treatment of common cold with iota-carrageenan has to date been studied in five placebo-controlled clinical trials and these trials support both efficacy as a prophylactic treatment for colds and the safety and tolerability of iota-carrageenan. The information presented in this review provides good clinical evidence for the safety and efficacy of carrageenan as an antiviral therapy, but it is hoped that in the future, larger and robust clinical trials will definitively establish the efficacy and safety of carrageenan.

Acknowledgements

The content of this review article is the independent work of the author. The author will receive payment for any article processing charge and for time spent in preparation of the article from Marinomed Company, which markets iota-carrageenan nasal sprays.

Conflicts of Interest

The author declares no conflicts of interest regarding the publication of this paper.

References

[1]	Johnston, S.L. (2005) Impact of Viruses on Airway Diseases. European Respiratory Review, 14, 57-61. https://doi.org/10.1183/09059180.05.00009503
[2]	Heikkinen, T. and Järvinen, A. (2003) The Common Cold. The Lancet, 361, 51-59. https://doi.org/10.1016/s0140-6736(03)12162-9
[3]	Eccles, R. (2023) Common Cold. Frontiers in Allergy, 4, Article 1224988. https://doi.org/10.3389/falgy.2023.1224988
[4]	Sherman, J.B. (1938) Prophylaxis of Colds. British Medical Journal, 2, 903-904. https://doi.org/10.1136/bmj.2.4060.903
[5]	Rondanelli, M., Miccono, A., Lamburghini, S., Avanzato, I., Riva, A., Allegrini, P., et al. (2018) Self-Care for Common Colds: The Pivotal Role of Vitamin D, Vitamin C, Zinc, and Echinacea in Three Main Immune Interactive Clusters (Physical Barriers, Innate and Adaptive Immunity) Involved during an Episode of Common Colds—Practical Advice on Dosages and on the Time to Take These Nutrients/Botanicals in Order to Prevent or Treat Common Colds. Evidence-Based Complementary and Alternative Medicine, 2018, Article 5813095. https://doi.org/10.1155/2018/5813095
[6]	Merriam Webster (2024) Prophylaxis. https://www.merriam-webster.com/dictionary/prophylaxis
[7]	Usov, A.I. (2011) Polysaccharides of the Red Algae. In: Advances in Carbohydrate Chemistry and Biochemistry, Elsevier, 115-217. https://doi.org/10.1016/b978-0-12-385520-6.00004-2
[8]	Jiang, F., Liu, Y., Xiao, Q., Chen, F., Weng, H., Chen, J., et al. (2022) Eco-Friendly Extraction, Structure, and Gel Properties of Ι-Carrageenan Extracted Using Ca(OH)2. Marine Drugs, 20, Article 419. https://doi.org/10.3390/md20070419
[9]	Necas, J. and Bartosikova, L. (2013) Carrageenan: A Review. Veterinární medicína, 58, 187-205. https://doi.org/10.17221/6758-vetmed
[10]	Gerber, P., Dutcher, J.D., Adams, E.V. and Sherman, J.H. (1958) Protective Effect of Seaweed Extracts for Chicken Embryos Infected with Influenza B or Mumps Virus. Experimental Biology and Medicine, 99, 590-593. https://doi.org/10.3181/00379727-99-24429
[11]	Nahmias, A.J. and Kibrick, S. (1964) Inhibitory Effect of Heparin on Herpes Simplex Virus. Journal of Bacteriology, 87, 1060-1066. https://doi.org/10.1128/jb.87.5.1060-1066.1964
[12]	Nahmias, A.J., Kibrick, S. and Bernfeld, P. (1964) Effect of Synthetic and Biological Polyanions on Herpes Simplex Virus. Experimental Biology and Medicine, 115, 993-996. https://doi.org/10.3181/00379727-115-29098
[13]	Colter, J.S., Davies, M.A. and Campbell, J.B. (1964) Studies of Three Variants of Mengo Encephalomyelitis Virus II. Inhibition of Interaction with L Cells by an Agar Inhibitor and by Protamine. Virology, 24, 578-585. https://doi.org/10.1016/0042-6822(64)90210-7
[14]	González, M.E., Alarcón, B. and Carrasco, L. (1987) Polysaccharides as Antiviral Agents: Antiviral Activity of Carrageenan. Antimicrobial Agents and Chemotherapy, 31, 1388-1393. https://doi.org/10.1128/aac.31.9.1388
[15]	Girond, S., Crance, J.M., Van Cuyck-Gandre, H., Renaudet, J. and Deloince, R. (1991) Antiviral Activity of Carrageenan on Hepatitis a Virus Replication in Cell Culture. Research in Virology, 142, 261-270. https://doi.org/10.1016/0923-2516(91)90011-q
[16]	Carlucci, M., Scolaro, L., Noseda, M., Cerezo, A. And Damonte, E. (2004) Protective Effect of a Natural Carrageenan on Genital Herpes Simplex Virus Infection in Mice. Antiviral Research, 64, 137-141. https://doi.org/10.1016/j.antiviral.2004.07.001
[17]	Grassauer, A., Weinmuellner, R., Meier, C., Pretsch, A., Prieschl-Grassauer, E. and Unger, H. (2008) Iota-Carrageenan Is a Potent Inhibitor of Rhinovirus Infection. Virology Journal, 5, 107. https://doi.org/10.1186/1743-422x-5-107
[18]	Buck, C.B., Thompson, C.D., Roberts, J.N., Müller, M., Lowy, D.R. and Schiller, J.T. (2006) Carrageenan Is a Potent Inhibitor of Papillomavirus Infection. PLOS Pathogens, 2, e69. https://doi.org/10.1371/journal.ppat.0020069
[19]	Talarico, L., Pujol, C., Zibetti, R., Faria, P., Noseda, M., Duarte, M., et al. (2005) The Antiviral Activity of Sulfated Polysaccharides against Dengue Virus Is Dependent on Virus Serotype and Host Cell. Antiviral Research, 66, 103-110. https://doi.org/10.1016/j.antiviral.2005.02.001
[20]	Baba, M., Snoeck, R., Pauwels, R. and de Clercq, E. (1988) Sulfated Polysaccharides Are Potent and Selective Inhibitors of Various Enveloped Viruses, Including Herpes Simplex Virus, Cytomegalovirus, Vesicular Stomatitis Virus, and Human Immunodeficiency Virus. Antimicrobial Agents and Chemotherapy, 32, 1742-1745. https://doi.org/10.1128/aac.32.11.1742
[21]	Guo, C., Zhu, Z., Yu, P., Zhang, X., Dong, W., Wang, X., et al. (2018) Inhibitory Effect of Iota-Carrageenan on Porcine Reproductive and Respiratory Syndrome Virus in Vitro. Antiviral Therapy, 24, 261-270. https://doi.org/10.3851/imp3295
[22]	Wang, W., Zhang, P., Hao, C., Zhang, X., Cui, Z. and Guan, H. (2011) In Vitro Inhibitory Effect of Carrageenan Oligosaccharide on Influenza A H1N1 Virus. Antiviral Research, 92, 237-246. https://doi.org/10.1016/j.antiviral.2011.08.010
[23]	Morokutti-Kurz, M., Fröba, M., Graf, P., Große, M., Grassauer, A., Auth, J., et al. (2021) Iota-Carrageenan Neutralizes SARS-CoV-2 and Inhibits Viral Replication in Vitro. PLOS ONE, 16, e0237480. https://doi.org/10.1371/journal.pone.0237480
[24]	Eccles, R. (2020) Iota-Carrageenan as an Antiviral Treatment for the Common Cold. The Open Virology Journal, 14, 9-15. https://doi.org/10.2174/1874357902014010009
[25]	Morokutti-Kurz, M., Graf, C. and Prieschl-Grassauer, E. (2017) Amylmetacresol/2, 4-Dichlorobenzyl Alcohol, Hexylresorcinol, or Carrageenan Lozenges as Active Treatments for Sore Throat. International Journal of General Medicine, 10, 53-60. https://doi.org/10.2147/ijgm.s120665
[26]	Graf, C., Bernkop-Schnürch, A., Egyed, A., Koller, C., Prieschl-Grassauer, E. and Morokutti-Kurz, M. (2018) Development of a Nasal Spray Containing Xylometazoline Hydrochloride and Iota-Carrageenan for the Symptomatic Relief of Nasal Congestion Caused by Rhinitis and Sinusitis. International Journal of General Medicine, 11, 275-283. https://doi.org/10.2147/ijgm.s167123
[27]	Leibbrandt, A., Meier, C., König-Schuster, M., Weinmüllner, R., Kalthoff, D., Pflugfelder, B., et al. (2010) Iota-Carrageenan Is a Potent Inhibitor of Influenza a Virus Infection. PLOS ONE, 5, e14320. https://doi.org/10.1371/journal.pone.0014320
[28]	Morokutti-Kurz, M., König-Schuster, M., Koller, C., Graf, C., Graf, P., Kirchoff, N., et al. (2015) The Intranasal Application of Zanamivir and Carrageenan Is Synergistically Active against Influenza a Virus in the Murine Model. PLOS ONE, 10, e0128794. https://doi.org/10.1371/journal.pone.0128794
[29]	Varese, A., Paletta, A., Ceballos, A., Palacios, C.A., Figueroa, J.M. and Dugour, A.V. (2021) Iota-Carrageenan Prevents the Replication of SARS-CoV-2 in a Human Respiratory Epithelium Cell Line in Vitro. Frontiers in Virology, 1, Article 746824. https://doi.org/10.3389/fviro.2021.746824
[30]	Alsaidi, S., Cornejal, N., Mahoney, O., Melo, C., Verma, N., Bonnaire, T., et al. (2021) Griffithsin and Carrageenan Combination Results in Antiviral Synergy against SARS-CoV-1 and 2 in a Pseudoviral Model. Marine Drugs, 19, Article 418. https://doi.org/10.3390/md19080418
[31]	Eccles, R., Meier, C., Jawad, M., Weinmüllner, R., Grassauer, A. and Prieschl-Grassauer, E. (2010) Efficacy and Safety of an Antiviral Iota-Carrageenan Nasal Spray: A Randomized, Double-Blind, Placebo-Controlled Exploratory Study in Volunteers with Early Symptoms of the Common Cold. Respiratory Research, 11, Article No. 108. https://doi.org/10.1186/1465-9921-11-108
[32]	Fazekas, T., Eickhoff, P., Pruckner, N., Vollnhofer, G., Fischmeister, G., Diakos, C., et al. (2012) 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. BMC Complementary and Alternative Medicine, 12, Article No. 147. https://doi.org/10.1186/1472-6882-12-147
[33]	Ludwig, M., Enzenhofer, E., Schneider, S., Rauch, M., Bodenteich, A., Neumann, K., et al. (2013) Efficacy of a Carrageenan Nasal Spray in Patients with Common Cold: A Randomized Controlled Trial. Respiratory Research, 14, Article No. 124. https://doi.org/10.1186/1465-9921-14-124
[34]	Eccles, R., Winther, B., Johnston, S.L., Robinson, P., Trampisch, M. and Koelsch, S. (2015) Efficacy and Safety of Iota-Carrageenan Nasal Spray versus Placebo in Early Treatment of the Common Cold in Adults: The ICICC Trial. Respiratory Research, 16, Article No. 121. https://doi.org/10.1186/s12931-015-0281-8
[35]	Figueroa, J.M., Lombardo, M.E., Dogliotti, A., Flynn, L.P., Giugliano, R., Simonelli, G., et al. (2021) Efficacy of a Nasal Spray Containing Iota-Carrageenan in the Postexposure Prophylaxis of COVID-19 in Hospital Personnel Dedicated to Patients Care with COVID-19 Disease. International Journal of General Medicine, 14, 6277-6286. https://doi.org/10.2147/ijgm.s328486
[36]	Koenighofer, M., Lion, T., Bodenteich, A., Prieschl-Grassauer, E., Grassauer, A., Unger, H., et al. (2014) Carrageenan Nasal Spray in Virus Confirmed Common Cold: Individual Patient Data Analysis of Two Randomized Controlled Trials. Multidisciplinary Respiratory Medicine, 9, Article No. 57. https://doi.org/10.1186/2049-6958-9-57
[37]	Hemilä, H. and Chalker, E. (2021) Carrageenan Nasal Spray May Double the Rate of Recovery from Coronavirus and Influenza Virus Infections: Re-Analysis of Randomized Trial Data. Pharmacology Research & Perspectives, 9, e00810. https://doi.org/10.1002/prp2.810
[38]	Bergström, T., Trybala, E. and Spillmann, D. (1997) Heparan Sulfate and Viral Tropism. Nature Medicine, 3, 1177-1177. https://doi.org/10.1038/nm1197-1177b
[39]	Li, J. and Spillmann, D. (2011) Heparan Sulfate Proteoglycans as Multifunctional Cell Regulators: Cell Surface Receptors. In: Methods in Molecular Biology, Humana Press, 239-255. https://doi.org/10.1007/978-1-61779-498-8_16
[40]	Liu, J. and Thorp, S.C. (2001) Cell Surface Heparan Sulfate and Its Roles in Assisting Viral Infections. Medicinal Research Reviews, 22, 1-25. https://doi.org/10.1002/med.1026
[41]	Oh, M., Akhtar, J., Desai, P. and Shukla, D. (2010) A Role for Heparan Sulfate in Viral Surfing. Biochemical and Biophysical Research Communications, 391, 176-181. https://doi.org/10.1016/j.bbrc.2009.11.027
[42]	Zhang, X., Shi, J., Ye, X., Ku, Z., Zhang, C., Liu, Q., et al. (2017) Coxsackievirus A16 Utilizes Cell Surface Heparan Sulfate Glycosaminoglycans as Its Attachment Receptor. Emerging Microbes & Infections, 6, 1-7. https://doi.org/10.1038/emi.2017.55
[43]	Cagno, V., Tseligka, E.D., Jones, S.T. and Tapparel, C. (2019) Heparan Sulfate Proteoglycans and Viral Attachment: True Receptors or Adaptation Bias? Viruses, 11, Article 596. https://doi.org/10.3390/v11070596
[44]	Sarrazin, S., Lamanna, W.C. and Esko, J.D. (2011) Heparan Sulfate Proteoglycans. Cold Spring Harbor Perspectives in Biology, 3, a004952. https://doi.org/10.1101/cshperspect.a004952
[45]	Carlucci, M.J., Ciancia, M., Matulewicz, M.C., Cerezo, A.S. and Damonte, E.B. (1999) Antiherpetic Activity and Mode of Action of Natural Carrageenans of Diverse Structural Types. Antiviral Research, 43, 93-102. https://doi.org/10.1016/s0166-3542(99)00038-8
[46]	Pradhan, B. and Ki, J. (2023) Biological Activity of Algal Derived Carrageenan: A Comprehensive Review in Light of Human Health and Disease. International Journal of Biological Macromolecules, 238, Article 124085. https://doi.org/10.1016/j.ijbiomac.2023.124085
[47]	Eccles, R. (2013) Is the Common Cold a Clinical Entity or a Cultural Concept? Rhinology Journal, 51, 3-8. https://doi.org/10.4193/rhino12.123
[48]	Ficko-Blean, E., Préchoux, A., Thomas, F., Rochat, T., Larocque, R., Zhu, Y., et al. (2017) Carrageenan Catabolism Is Encoded by a Complex Regulon in Marine Heterotrophic Bacteria. Nature Communications, 8, Article No. 1685. https://doi.org/10.1038/s41467-017-01832-6
[49]	Liu, F., Hou, P., Zhang, H., Tang, Q., Xue, C. and Li, R.W. (2021) Food-Grade Carrageenans and Their Implications in Health and Disease. Comprehensive Reviews in Food Science and Food Safety, 20, 3918-3936. https://doi.org/10.1111/1541-4337.12790
[50]	David, S., Shani Levi, C., Fahoum, L., Ungar, Y., Meyron-Holtz, E.G., Shpigelman, A., et al. (2018) Revisiting the Carrageenan Controversy: Do We Really Understand the Digestive Fate and Safety of Carrageenan in Our Foods? Food & Function, 9, 1344-1352. https://doi.org/10.1039/c7fo01721a