Journal of Biomedical Research and Clinical Investigation

Research ISSN:2633-8653

Study of the Efficacy and Safety of Topical Ivermectin + Iota-

Carrageenan in the Prophylaxis against COVID-19 in Health
Personnel
Carvallo Héctor1, Hirsch Roberto2*, Alkis Psaltis3, Contreras Veronica4
1
Professor of Internal Medicine,Universities of Buenos Aires and U.A.I., Argentina
2
Professor of Infectology, University of Buenos Aires, Argentina
3
Professor of Otolaryngology Head and Neck Surgery, University of Adelaide, South Australia
4
In Charge of Biosafety, Eurnekian Public Hospital, Argentina

Abstract
The severe acute respiratory syndrome-coronavirus-2 pandemic has had devastating health and socio-economic
implications worldwide. Epidemiologic data indicate that SARS-CoV2 is spread by respiratory droplets and contact.
The lack of acquired human immunity to the virus and the absence of a vaccine, has meant that current management
strategies aimed at virus containment through mask wearing, social distancing and enforced lockdowns. Although
the World Health Organization recommends 1,5 meters distancing to minimize transmission, recent studies have
demonstrated high stability in aerosols and transmission distances up to 10 meters from emission sources .
Health care workers are at particular risk from SARS-CoV-2. At present, no reliable prophylactic therapy exists to
minimize their risk of acquiring SARS-CoV-2, and so they rely solely upon hand hygiene and the wearing of
appropriate personal protective equipment (PPE), which is often in limited supply. Several studies have shown that
the salivary gland and tongue express the ACE2 receptor, suggesting that the oral cavity is a perfect host for the
invasion of COVID. Theoretically, agents that can inhibit viral adhesion and replication within the primary sites of
viral entry (the nasal and oral cavity), may have a role in preventing SARS-CoV-2 transmission. Use of these agents
prophylactically, would be especially beneficial in health care workers, particularly given the delay in results from
viral RNA detection diagnostic test and the fact that many infected patients may have mild or no symptoms of the
virus in the early stages. Two possible substances have been identified as candidate prophylactic agents in the fight
against SARS-CoV-2. Carrageenans are naturally occurring extracts from the Rhodophyceas seaweed. Recently, the
viricidal capacity of carrageenan has been reported, through inhibition of viral- host cell adhesion and early
replication. Iota-carrageenan demonstrates potent antiviral activity in vitro, reducing rhinovirus, herpes simplex
virus and the Japanese encephalitis virus reproduction and their cytopathic effects. Similarly, ivermectin has also
been shown to posess antiviral activity against a whole host of RNA viruses (Zika, dengue, yellow fever, human
immunodeficiency virus type 1). Thus, the combination of both products can provide an extra protection for those at
risk of contagion.
Keywords: COVID-19, Ivermectin, SARS-CoV-2.

Introduction
The severe acute respiratory syndrome-coronavirus-2 (SARS- Corresponding Author: Hirsch Roberto, University
CoV-2) pandemic has had devastating health and socio- of Buenos Aires, Argentina Received date: November
economic implications worldwide. Epidemiologic data indicate 09, 2020; Accepted date: November 16, 2020;
that SARS-CoV is spread by respiratory droplets and contact Published date: November 17, 2020.
[1]. DOI: https://doi.org/10.31546/2633-8653.1007

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 Hirsch Roberto et al.

Binding of the virus to ACE-2 receptors expressed in the Carrageenans are naturally occurring extracts from the
respiratory tract and eyes, is the proposed mechanisms of entry Rhodophyceas seaweed. They are commonly used as
of SARS-CoV-2 into human cells. The lack of acquired human thickening agents in the food industry with FDA
immunity to the virus and the absence of a vaccine, has meant approval for this indication. Recently, the viricidal
that current management strategies aimed at virus containment capacity of carrageenan has been reported, through
through mask wearing, social distancing and enforced inhibition of viral- host cell adhesion and early
lockdowns. Although the World Health Organization replication. Iota-carrageenan demonstrates potent
recommends 1-5-2 meter distancing to minimize transmission, antiviral activity in vitro, reducing rhinovirus, herpes
recent studies have demonstrated high stability in aerosols and simplex virus and the Japanese encephalitis virus
transmission distances up to 10 meters from emission sources. reproduction and their cytopathic effects. This effect is
Health care workers are at particular risk from SARS-CoV-2. supposed to be mediated by the interaction of sulfated
Their close proximity to infected patients during examination polysaccharides with positively charged domains on
and procedural tasks renders them at increased risk of exposure the glycoprotein envelope involved in binding with
to higher viral loads, which may result in more prolonged and proteinglycans on the surface of the host cell [6].
severe disease. At present, no reliable prophylactic therapy
exists to minimize their risk of acquiring SARS-CoV-2, and so Similarly, ivermectin has also been shown to posess
they rely solely upon hand hygiene and the wearing of antiviral activity against a whole host of RNA viruses
appropriate personal protective equipment (PPE), which is (Zika, dengue, yellow fever, human immunodeficiency
often in limited supply [2-4,10]. virus type 1). Recent in vitro studies have also shown
effect on Covid-19 [7].
The source of contagion is related to Pflügge drops, droplets
and aerosols. All of them are different sizes of salivary Ivermectin mechanisms of action are both extracellular
compounds. Whole saliva is a biomix containing crevicular and intracellular. Outside the host cell, it provokes
fluid, desquamated oral epithelial cells, and microorganisms. ionophores along the virus lipoprotein nocleocapside,
Around 99% of saliva is water and the remaining 1% contains thus allowing the entrance of oxhidril compounds
a large group of components for the purpose of digesting, which damage the virus structure. Despite this, if the
tasting, buffering, balancing remineralization and virus does enter cytosol, ivermectin blocks its
antimicrobials.Several studies have shown that the salivary transportation to the cell nucleus, by keeping the virus
gland and tongue express the ACE2 receptor, suggesting that from using importins alpha and beta1 to do so. In vitro
the oral cavity is a perfect host for the invasion of COVID. sutdies, ivermectin proved to reduce viral load 5000
times in laboratory specimens [5,9,11].
For COVID-19, the salivary gland could be an important room,
generating infectious saliva on a sustained basis.It has been Materials and Method
observed that low levels of COVID-19 RNA could still be This pilot and muti-center clinical trial assesses
excreted in saliva even after clinical recovery. Additionally, whether a combination of topical nasal carageenan and
about half of the patients reported symptoms of dry mouth and oral ivermectin can reduce SARS-CoV-2 infection in
dysgeusia.These symptoms probably stem from dysfunction of Health Care Workers when administered
the tongue expressing ACE2 and furin, and the expression of prophylactically. The safety and efficacy of this
the salivary gland ACE2, apart from SARS COV 2 direct combination therapy will be discussed and compared
neurotropism [19-21]. to the use of standard PPE alone [14].

Theoretically, agents that can inhibit viral adhesion and Methods

replication within the primary sites of viral entry (the nasal and Pilot Study (clinicaltrials.gov NCT 04425850)
oral cavity), may have a role in preventing SARS-CoV-2 Ethics board approval was attained prior to the
transmission. Use of these agents prophylactically, would be commencement of this study and all participants
especially beneficial in health care workers, particularly given provided informed consent prior to study enrollment.
the delay in results from viral RNAdetection diagnostic test Asymptomatic health care workers employed at the
and the fact that many infected patients may have mild or no Alberto Antranik Eurnekian Hospital, Argentina and
symptoms of the virus in the early stages. Two possible involved in the care of and contact of Covid-19
substances have been identified as candidate prophylactic patients were recruited.
agents in the fight against SARS-CoV-2 [8].

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 Hirsch Roberto et al.

All HCW’s were healthy with no Covid-19 symptoms and Statistical Analysis
negative swabs for the virus immediately prior to enrollment in Results
the study. Exclusion criteria included: Children < 18 years old, Pilot Study Demographics
pregnancy, active breast feeding, concurrent autoimmune or
chronic disease, immunosuppression, active infectious diseases A total of 229 health personnel were recruited for this
and a history of previous infection with SARSCoV-2 study; 98 within the control (PPE alone) group and
confirmed by PCR or rapid test. Participants received active 131 received IVECAR treatment in addition to their
treatment with a combination of carrageenan and ivermectin wearing of PPE.
and were compared to a cohort of healthy volunteers who
simply adhered to the use of appropriate personal protective Table 1: summarizes the demographics of each group.
equipment.

Following informed consent eligible patients underwent

standardized symptom questionnaire and physical examination.
Those with negative CoVid-19 (PCR or rapid test) were then
recruited for preventive measures with active combination
treatment (IVERCAR) arm in addition to their wearing of
personal protective equipment (PPE). Acohort of healthy, age
Covid-19 negative health care workers using standard PPE
alone was used as a comparative arm, in a prospective,
observational, not randomized trial. This group was matched
for age, demographics, past medical history, work environment
including hours worked and possible exposure to CoVid 19
positive patients within the hospital [16-18].

Combination therapy (IVECAR) consisted of 1 spray of topical

Carrageenan (Cert. No. 57,232, ANMAT (National
Administration for Drugs, Food and Medical Technology) 100
ml, 0.9 g of sodium chloride and 0.17 g of carrageenan) into
each nostril and four sprays of topical Carageenan into the oral
cavity, followed 5 minutes later by 1 drop of ivermectin (Cert.
As far as ethnicity is concerned, all the persons
Nº 58.382, ANMAT 100ml Ivermectin drops (0.6 mg / ml) to
included have latin origin.
the tongue 5 minutes later. This dosage schedule was repeated
5 times a day (every 4 hours) for 14 days with food and liquids
Statistical Analysis
avoided 1 hour before and after treatment [12-15].
COVID-19 transmission rates in both arms were
Patients in the PPE group and IVECAR groups were evaluated
compared by chi squared test. Transmission rate in the
at 7 and 14 days completing symptom questionnaires (
treated group is statistically significantly lower in the
including the reporting of any adverse effects from the
treated group (p < 0.0001). Relative risk reduction was
treatment), physical examinations and CoVid-19 testing of
calculated based on literature, and found to be 15 %
nasopharyngeal secretions (PCR or rapid test) at each time
for the add-on nasal and buccal iota carrageenan +
point. Both groups continued to adhere to standard PPEs and
ivermectin nasal + buccal preventive treatment.
were evaluated at 7, 14, 21 and 28 days from the
commencement of the study. Infection rates were reported for
Infection rates
each group, with 11 contagions among those not treated, and
None of the health personnel treated with IVERCAR
no contagions in the treated group [22-26].
tested positive for CoVid19 during the 14 day
treatment period. Furthermore none returned positive
Outcomes assessed for each of the two groups included:
swabs in the 3 weeks´post completion of their initial
 Incidence of appearance of symptoms related to CoVid-19 treatment. Eleven health personnel (11.1%) in the
infection comparator PPE group yielded positive swabs.
 Incidence of detection of CoVid-19 by PCR
 Incidence of reported adverse events

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 Hirsch Roberto et al.

7 of the 11 patients with positive swabs were nurses. 1 788 participants received IVERCAR and PPEs, while
Intensivist, 1 anesthesiologist, 1 hemotherapeutic technician the remaining 407 simply adhered to standard PPEs.
and 1 laboratory technician also returned positive swabs. (see
Figure 1) Infection Rates - Pooled Results
The overall infection rate in health care workers
recruited for this study was 20% with 237 testing
positive for CoVid 19 during the 3 month study
recruitment. Of those infected, all patients were from
the comparator group of using PPE alone. This
represented an overall infection rate of 58.2% ( 237 of
407) in the PPE group.

No patients of the 788 treated with IVERCAR tested

positive for CoVid 19 during the study.

Infections Rates – Per Hospital

Alberto Antranik Eurnekian Hospital – EZEIZA
Blue: Nurses; Orange: Anesthetiologist; gray: Lab. Personnel; ocre: ICU City:
Personnel; Light Blue: Hemotherapeutic Pnel.
Total participating personnel 730; 600 received
Further Multicenter Study IVERCAR and 130 used PPE alone. 120 of 130 92.3%
Following the promising results of the initial study (see above), personnel in the PPE alone group returned positive
a larger multi-center study was performed with health care CoVid 19 swabs, while 0 of the 600 individuals
personnel recruited from Alberto Antranik Eurnekian Hospital, receiving IVERCAR treatment in addition to PPE
and 3 other hospitals; Hospital Municipal Angel Marzetti ( tested positive for CoVid-19 in the study period.
Canuelas), Cuenca Alta Hospital ( Buenos Aires Province) and
Centro Medico Caseros ( C.A.B.A). The study period was
from June 1 2020 – August 1 2020. A modification of the
initial protocol was performed for ease of medication delivery.
Carageenan application was reduced to 4 x a day at the same
total dose, and Ivermectin was administered as once per week
dose of 12mg. Each of the 4 centers used the same dosing
protocol. Again, two arms were built: those who received the
prophilaxis and standard PPEs, and a cohort who only used
PPEs.

Both standardized symptom questionnaire and physical

examination were repeated. Those with negative CoVid-19
(PCR or rapid test) were then recruited for preventive
measures with active combination treatment (IVERCAR) arm
in addition to their wearing of personal protective equipment
(PPE). A cohort of healthy, age Covid-19 negative health care Figure 1: Light Blue: Participant Personnel; Orange: Personnel
workers using standard PPE alone was used as a comparative Infected
arm, once again in a prospective, observational, not
randomized trial. No further demographic details were Hospital Municipal Ángel Marzetti – CAÑUELAS
collected, except for successive swabs during the 60 days´ City:
follow-up. Total participating personnel 150; 90 received
A total of 1,195 health care workers were recruited from 4 IVERCAR and 60 used PPE alone.47 health care
major hospitals in Argentina with 730 from Alberto Antranik personnel (78.3%) in the PPE alone group returned
Eurnekian Hospital, 150 from Hospital Municipal Angel positive CoVid 19 swabs, while 0 of the 90 individuals
Marzetti, 150 from Cuenca Alta Hospital and 15 from Centro receiving IVERCAR treatment in addition to PPE
Medico Caseros. tested positive for CoVid-19 in the study period.

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 Hirsch Roberto et al.

Figure 5: Light Blue: Participant Personnel; Orange: Personnel

Infected

Figure 2: Light Blue: Participant Personnel; Orange: Personnel Infected

Discussion
In the present two clinical trias, the ethnic and age
Cuenca Alta Hospital – BUENOS AIRES Province: characteristics, previous health, personal protection
Total participating personnel 300; 90 received IVERCAR and measures, performance areas, work hours, and type of
210 used PPE alone. 65 health care personnel (30.9%) in the patients assisted were the same in each arm.
PPE alone group returned positive CoVid 19 swabs, while 0 of If we consider the following facts:
the 90 individuals receiving IVERCAR treatment in addition to 1) Drops and sprays are a major source of human-to-
PPE tested positive for CoVid-19 in the study period. human transmission.
2) The sources mentioned above depend on different
sizes of saliva droplets.
3) The contagion comes from symptomatic and
asymptomatic patients.
4) The proportion of asymptomatic patients exceeds
30% of all cases.
5) The concentration of ivermectin and carrageenan
is adequate in the nasal mucus and salivary glands.
6) The combined oral solution can offer double
protection: on the one hand, it reduces the spread
and, on the other hand, it reduces the viral load.
Figure 3: Light Blue: Participant Personnel; Orange: Personnel Infected
7) Both (ivermectin and carrageenan) are present in
the international pharmacopoeia, and their use is
Centro Medico Caseros – Buenos Aires City: widely accepted.
Total participating personnel 15; 8 received IVERCAR and 7 8) Their respective "off label" applications do not
used PPE alone.5 health care personnel (71%) in the PPE alone involve any risk.
group returned positive CoVid 19 swabs, while 0 of the 8 9) Health Personnel are constantly at risk of
individuals receiving IVERCAR treatment in addition to PPE contagion, thus locking down all their co-workers,
tested positive for CoVid-19 in the study period. and preventing the community from the access to
appropriate health care.

We conclude that by using ivermectin in oral solution

and carrageenan in nasal spray form, we are providing
an inexpensive, safe and effective means to protect
people from contagion and serious forms of the
disease.

Consent for Publication: Written informed consent

was obtained from the patient for the publication.
Figure 4: Light Blue: Participant Personnel; Orange: Personnel Infected

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 Hirsch Roberto et al.

Conflicts of Interest: The authors declare no conflict of as capsule, tablet, and Oral Solution. Eur J Clin
interest. Pharmacol. 1988;35:681-684.
15. Carvallo, H., Hirsch, R, et al. Ivermectin, aspirin,
References: dexametasone and enoxaparin as treatment for
1. Rodríguez MA, Cardona OJ, et al. Clinical, laboratory and COVID 19. J Am Med Assoc. 200.324.
imaging features of COVID-19: A systematic review and 16. Martin K, Thomas L, Angelika B, et al.
meta-analysis. Travel Med Infect Dis. 2020;34:101623. Carrageenan nasal spray in virus confirmed
2. Andersen K, Rambaut A, Lipkin I, et al. The proximal common cold: individual patient data analysis of
origin of SARS-CoV-2. Nat Med. 2020; 26: 450-452. two randomized controlled trials. Multidiscip
3. Recalcati S. Cutaneous manifestations in COVID‐19: a Respir Med. 2014;9:57.
first perspective. J Eur Acad Dermatol Venereol. 17. Mitchell VP, William CS, Douglas GR, et al. West
2020;34:e212-e213. Nile Virus Infection in Reindeer (Rangifer
4. Mehta P, McAuley D, Brown M, et al. COVID-19: Tarandus). J Vet Diagn Invest. 2004;16:219-222.
consider cytokine storm syndromes and 18. TP de Castro, DPF Duarte, DP Carvalho . Estudo
immunosuppression. Lancet. 2020;395(10229):1033-1034. preliminar sobre os efeitos clínicos do tratamento
5. Ordoñez Angulo E. Efficacy of ivermectin in the treatment da Febre Chikungunya aguda usando Ivermectina
of children parasitized by Strongyloides stercoralis. como fármaco antiviral. AMPE. 2017.
Biomedica. 2004;24:33-41. 19. Hamming I, Timens W, Bulthuis MLC, et al.
6. Giovannoni F. Rol antiviral intrinseco de PML en la Tissue distribution of ACE2 protein, the functional
infección con flavivirus.Tesis de doctorado, Universidad receptor for SARS coronavirus. A first step in
de Buenos Aires. Facultad de Ciencias Exactas y understanding SARS pathogenesis. J Pathol. 2004;
Naturales. 2018. 203:631-637.
7. Ruiz Esquide Canale MS, Weil M, Turienzo M. Infección 20. Xu H, Zhong L, Deng J, et al. High expression of
por virus Zika y sus manifestaciones cutáneas. Arch Arg ACE2 receptor of 2019-nCoV on the epithelial
Dermatol. 2019. cells of oral mucosa. Int J Oral Sci. 2020;12:8.
8. Leon C, Julian DD , Mike GC, et al. The FDA-approved 21. Liu L, Wei Q, Alvarez X, et al. Epithelial cells
drug ivermectin inhibits the replication of SARS-CoV-2 in lining salivary gland ducts are early target cells of
vitro. Antiviral Res. 2020;178:104787. severe acute respiratory syndrome coronavirus
9. Cynthia AG, Christine IF, Arturo GP, et al. Safety, infection in the upper respiratory tracts of Rhesus
Tolerability, and Pharmacokinetics of Escalating High macaques. J Virol. 2011;85:4025-4030.
Doses of Ivermectin in Healthy Adult Subjects. J Clin 22. Wang WK, Chen SY, Liu IJ, et al. Detection of
Pharmacol. 2002;42:1122-33. SARS associated coronavirus in throat wash and
10. Guang Chen, Di Wu, Wei Guo, et al. Clinical and saliva in early diagnosis. Emerg Infect Dis.
immunological features of severe and moderate 2004;10:1213-1219.
coronavirus disease 2019. J Clin Invest. 2020;130:2620- 23. Chen L, Jiajia Z, Jinfeng P, et al. Detection of
2629. 2019-nCoV in Saliva and Characterization of Oral
11. Kelvin Kai-Wang T, Owen Tak-Yin T, Wai-Shing L, et al. Symptoms in COVID-19 Patients. Cell Prolif. .
Temporal profiles of viral load in posterior oropharyngeal 2020;00:e12923.
saliva samples and serum antibody responses during 24. Lagerlo F, Dawes C. The volume of saliva in the
infection by SARS-CoV-2: an observational cohort study. mouth before and after swallowing. J Dent Res.
Lancet Infect Dis. 2020;20:565-574. 1984;63:618-621.
12. Sri Santosh T, Parmar R, Anand H, et al. A Review of 25. Eduardo L. Ceccotti: El COVID-19. La Saliva y la
Salivary Diagnostics and Its Potential Implication in Mucosa Lingual. Población y Profesionales en
Detection of Covid-19. Cureus. 2020;12:e7708. Riesgo. ADMIN, MAYO 5, 2020. Academia
13. Baraka OZ, Mahmoud BM, Marschke CK, et al. Nacional de Odontología Argentina.2020.
Ivermectin distribution in the plasma and tissues of 26. Emma AH, Ruth F, Susan MC, et al. Virucidal
patients infected with Onchocerca volvulus. Eur J Clin Activity of Polysaccharide Extracts from Four
Pharmacol. 1996;50:407-410. Algal Species against Herpes Simplex Virus.
14. Edwards G, Dingsdale A, Helsby N, et al. The Relative Antiviral Res. 2009;83:282-289.
Systemic Availability of Ivermectin after Administration

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