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Study of the Efficacy and Safety of Topical Ivermectin + Iota- Carrageenan in the Prophylaxis against COVID-19 in Health Personnel

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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.
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Journal of Biomedical Research and Clinical Investigation
Journal of Biomedical Research and Clinical Investigation Volume 2 Issue 1.1007
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
Introduction
The severe acute respiratory syndrome-coronavirus-2 (SARS-
CoV-2) pandemic has had devastating health and socio-
economic implications worldwide. Epidemiologic data indicate
that SARS-CoV is spread by respiratory droplets and contact
[1].
Corresponding Author: Hirsch Roberto, University
of Buenos Aires, Argentina Received date: November
09, 2020; Accepted date: November 16, 2020;
Published date: November 17, 2020.
DOI: https://doi.org/10.31546/2633-8653.1007
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.
Hirsch Roberto et al.
Journal of Biomedical Research and Clinical Investigation Volume 2 Issue 1.1007
Binding of the virus to ACE-2 receptors expressed in the
respiratory tract and eyes, is the proposed mechanisms of entry
of SARS-CoV-2 into human cells. 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 1-5-2 meter 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.
Their close proximity to infected patients during examination
and procedural tasks renders them at increased risk of exposure
to higher viral loads, which may result in more prolonged and
severe disease. 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 [2-4,10].
The source of contagion is related to Pflügge drops, droplets
and aerosols. All of them are different sizes of salivary
compounds. Whole saliva is a biomix containing crevicular
fluid, desquamated oral epithelial cells, and microorganisms.
Around 99% of saliva is water and the remaining 1% contains
a large group of components for the purpose of digesting,
tasting, buffering, balancing remineralization and
antimicrobials.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.
For COVID-19, the salivary gland could be an important room,
generating infectious saliva on a sustained basis.It has been
observed that low levels of COVID-19 RNA could still be
excreted in saliva even after clinical recovery. Additionally,
about half of the patients reported symptoms of dry mouth and
dysgeusia.These symptoms probably stem from dysfunction of
the tongue expressing ACE2 and furin, and the expression of
the salivary gland ACE2, apart from SARS COV 2 direct
neurotropism [19-21].
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 RNAdetection 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 [8].
Carrageenans are naturally occurring extracts from the
Rhodophyceas seaweed. They are commonly used as
thickening agents in the food industry with FDA
approval for this indication. 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. This effect is
supposed to be mediated by the interaction of sulfated
polysaccharides with positively charged domains on
the glycoprotein envelope involved in binding with
proteinglycans on the surface of the host cell [6].
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). Recent in vitro studies have also shown
effect on Covid-19 [7].
Ivermectin mechanisms of action are both extracellular
and intracellular. Outside the host cell, it provokes
ionophores along the virus lipoprotein nocleocapside,
thus allowing the entrance of oxhidril compounds
which damage the virus structure. Despite this, if the
virus does enter cytosol, ivermectin blocks its
transportation to the cell nucleus, by keeping the virus
from using importins alpha and beta1 to do so. In vitro
sutdies, ivermectin proved to reduce viral load 5000
times in laboratory specimens [5,9,11].
Materials and Method
This pilot and muti-center clinical trial assesses
whether a combination of topical nasal carageenan and
oral ivermectin can reduce SARS-CoV-2 infection in
Health Care Workers when administered
prophylactically. The safety and efficacy of this
combination therapy will be discussed and compared
to the use of standard PPE alone [14].
Methods
Pilot Study (clinicaltrials.gov NCT 04425850)
Ethics board approval was attained prior to the
commencement of this study and all participants
provided informed consent prior to study enrollment.
Asymptomatic health care workers employed at the
Alberto Antranik Eurnekian Hospital, Argentina and
involved in the care of and contact of Covid-19
patients were recruited.
Hirsch Roberto et al.
Journal of Biomedical Research and Clinical Investigation Volume 2 Issue 1.1007
All HCW’s were healthy with no Covid-19 symptoms and
negative swabs for the virus immediately prior to enrollment in
the study. Exclusion criteria included: Children < 18 years old,
pregnancy, active breast feeding, concurrent autoimmune or
chronic disease, immunosuppression, active infectious diseases
and a history of previous infection with SARSCoV-2
confirmed by PCR or rapid test. Participants received active
treatment with a combination of carrageenan and ivermectin
and were compared to a cohort of healthy volunteers who
simply adhered to the use of appropriate personal protective
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.
58.382, ANMAT 100ml Ivermectin drops (0.6 mg / ml) to
the tongue 5 minutes later. This dosage schedule was repeated
5 times a day (every 4 hours) for 14 days with food and liquids
avoided 1 hour before and after treatment [12-15].
Patients in the PPE group and IVECAR groups were evaluated
at 7 and 14 days completing symptom questionnaires (
including the reporting of any adverse effects from the
treatment), physical examinations and CoVid-19 testing of
nasopharyngeal secretions (PCR or rapid test) at each time
point. Both groups continued to adhere to standard PPEs and
were evaluated at 7, 14, 21 and 28 days from the
commencement of the study. Infection rates were reported for
each group, with 11 contagions among those not treated, and
no contagions in the treated group [22-26].
Outcomes assessed for each of the two groups included:
Incidence of appearance of symptoms related to CoVid-19
infection
Incidence of detection of CoVid-19 by PCR
Incidence of reported adverse events
Statistical Analysis
Results
Pilot Study Demographics
A total of 229 health personnel were recruited for this
study; 98 within the control (PPE alone) group and
131 received IVECAR treatment in addition to their
wearing of PPE.
Table 1: summarizes the demographics of each group.
As far as ethnicity is concerned, all the persons
included have latin origin.
Statistical Analysis
COVID-19 transmission rates in both arms were
compared by chi squared test. Transmission rate in the
treated group is statistically significantly lower in the
treated group (p < 0.0001). Relative risk reduction was
calculated based on literature, and found to be 15 %
for the add-on nasal and buccal iota carrageenan +
ivermectin nasal + buccal preventive treatment.
Infection rates
None of the health personnel treated with IVERCAR
tested positive for CoVid19 during the 14 day
treatment period. Furthermore none returned positive
swabs in the 3 weeks´post completion of their initial
treatment. Eleven health personnel (11.1%) in the
comparator PPE group yielded positive swabs.
Hirsch Roberto et al.
Journal of Biomedical Research and Clinical Investigation Volume 2 Issue 1.1007
7 of the 11 patients with positive swabs were nurses. 1
Intensivist, 1 anesthesiologist, 1 hemotherapeutic technician
and 1 laboratory technician also returned positive swabs. (see
Figure 1)
Blue: Nurses; Orange: Anesthetiologist; gray: Lab. Personnel; ocre: ICU
Personnel; Light Blue: Hemotherapeutic Pnel.
Further Multicenter Study
Following the promising results of the initial study (see above),
a larger multi-center study was performed with health care
personnel recruited from Alberto Antranik Eurnekian Hospital,
and 3 other hospitals; Hospital Municipal Angel Marzetti (
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
workers using standard PPE alone was used as a comparative
arm, once again in a prospective, observational, not
randomized trial. No further demographic details were
collected, except for successive swabs during the 60 days´
follow-up.
A total of 1,195 health care workers were recruited from 4
major hospitals in Argentina with 730 from Alberto Antranik
Eurnekian Hospital, 150 from Hospital Municipal Angel
Marzetti, 150 from Cuenca Alta Hospital and 15 from Centro
Medico Caseros.
788 participants received IVERCAR and PPEs, while
the remaining 407 simply adhered to standard PPEs.
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
City:
Total participating personnel 730; 600 received
IVERCAR and 130 used PPE alone. 120 of 130 92.3%
personnel in the PPE alone group returned positive
CoVid 19 swabs, while 0 of the 600 individuals
receiving IVERCAR treatment in addition to PPE
tested positive for CoVid-19 in the study period.
Figure 1: Light Blue: Participant Personnel; Orange: Personnel
Infected
Hospital Municipal Ángel Marzetti CAÑUELAS
City:
Total participating personnel 150; 90 received
IVERCAR and 60 used PPE alone.47 health care
personnel (78.3%) in the PPE alone group returned
positive CoVid 19 swabs, while 0 of the 90 individuals
receiving IVERCAR treatment in addition to PPE
tested positive for CoVid-19 in the study period.
Hirsch Roberto et al.
Journal of Biomedical Research and Clinical Investigation Volume 2 Issue 1.1007
Figure 2: Light Blue: Participant Personnel; Orange: Personnel Infected
Cuenca Alta Hospital BUENOS AIRES Province:
Total participating personnel 300; 90 received IVERCAR and
210 used PPE alone. 65 health care personnel (30.9%) in the
PPE alone group returned positive CoVid 19 swabs, while 0 of
the 90 individuals receiving IVERCAR treatment in addition to
PPE tested positive for CoVid-19 in the study period.
Figure 3: Light Blue: Participant Personnel; Orange: Personnel Infected
Centro Medico Caseros Buenos Aires City:
Total participating personnel 15; 8 received IVERCAR and 7
used PPE alone.5 health care personnel (71%) in the PPE alone
group returned positive CoVid 19 swabs, while 0 of the 8
individuals receiving IVERCAR treatment in addition to PPE
tested positive for CoVid-19 in the study period.
Figure 4: Light Blue: Participant Personnel; Orange: Personnel Infected
Figure 5: Light Blue: Participant Personnel; Orange: Personnel
Infected
Discussion
In the present two clinical trias, the ethnic and age
characteristics, previous health, personal protection
measures, performance areas, work hours, and type of
patients assisted were the same in each arm.
If we consider the following facts:
1) Drops and sprays are a major source of human-to-
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.
7) Both (ivermectin and carrageenan) are present in
the international pharmacopoeia, and their use is
widely accepted.
8) Their respective "off label" applications do not
involve any risk.
9) Health Personnel are constantly at risk of
contagion, thus locking down all their co-workers,
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.
Hirsch Roberto et al.
Journal of Biomedical Research and Clinical Investigation Volume 2 Issue 1.1007
Conflicts of Interest: The authors declare no conflict of
interest.
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... In another study, where the prophylactic capacity of IVM was explored, 131 HCWs were treated with a combination of topical IVM combined with carrageenan (IVER.CAR) compared with 98 subjects without treatment. Over the span of the 28 days of the study, none of the HCWs in the IVER.CAR group tested positive for SARS-CoV-2 according to PCR tests compared to 11.2% of cases in the group treated without IVER.CAR [116]. ...
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Background COVID-19 is an illness caused by severe acute respiratory syndrome coronavirus 2. Due to its rapid spread, in March 2020 the World Health Organization (WHO) declared pandemic. Since the outbreak of pandemic many governments, scientists, and institutions started to work on new vaccines and finding of new and repurposing drugs. Main body of the abstract Drug repurposing is an excellent option for discovery of already used drugs, effective against COVID-19, lowering the cost of production, and shortening the period of delivery, especially when preclinical safety studies have already been performed. There are many approved drugs that showed significant results against COVID-19, like ivermectin and hydrochloroquine, including alternative treatment options against COVID-19, utilizing herbal medicine. Short conclusion This article summarized 11 repurposing drugs, their positive and negative health implications, along with traditional herbal alternatives, that harvest strong potential in efficient treatments options against COVID-19, with small or no significant side effects. Out of 11 repurposing drugs, four drugs are in status of emergency approval, most of them being in phase IV clinical trials. The first repurposing drug approved for clinical usage is remdesivir, whereas chloroquine and hydrochloroquine approval for emergency use was revoked by FDA for COVID-19 treatment in June 2020.
... Yet four times in the text and three times in their Table 3, the Kory review described the intervention only in terms of ivermectin. The RCT (53) and original Carvallo observational study (54) described the intervention as a combination of ivermectin and iotacarrageenan, the latter selected because of its antiviral activity and potential synergistic activity. Neither of these trials studied ivermectin alone and should not have been described as if they did and therefore should not have been included in this review. ...
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The COVID-19 pandemic has been characterized by a lack of clear evidence to guide healthcare professionals, the public and policymakers. The resulting uncertainty, coupled with changing guidelines as additional evidence became available, added to the stress and anxiety reported by decision-makers. Research results are key to providing evidence to guide healthcare decisions. Important questions have arisen about whether various interventions are safe and effective. The evidence found guides those making treatment decisions, and influences those selecting interventions for further evaluation in research studies. As the COVID-19 pandemic intensified, the effectiveness and safety of many pharmaceuticals was queried. Ivermectin will be used to explore the ethics of how healthcare evidence must be critically appraised, even, or especially, during a pandemic. This drug is alleged to be effective in treating COVID-19, with various studies and systematic reviews finding supportive evidence. Some of these have now been linked to concerns about fraud or poor research reporting. This article will focus on the scientific literature and how apparently fraudulent studies were published and influenced treatment decisions, on-going research and public health guidelines. Research evidence is critical during emergencies like pandemics, but urgency should not overtake ethical responsibilities to critically appraise (or evaluate) studies as they become available. These responsibilities apply in various ways to editors, peer-reviewers, news media reporters, and those making treatment decisions, including clinicians, policymakers and the general public. While research article authors have the primary ethical responsibility to reject fraudulent or inaccurate claims, the readers of health research must carefully evaluate all publications. To detect and reject fraudulent healthcare claims, readers need critical appraisal skills that match their level of engagement with those articles. The core principles of critical appraisal will be described in the article, and how they can be adapted for different types of readers. Exemplar tools that develop critical appraisal skills will be noted, with reviews of ivermectin's efficacy explored as examples. As stakeholders in healthcare evidence are increasingly able to identify well-conducted and ethical research they will simultaneously be able to spot and reject fraudulent reports and prevent them from influencing healthcare decisions.
... However, there are concerns about the quality of some of these studies as well. For example, an observational study by Héctor et al., 16 which suggested a 100% benefit for ivermectin in the prevention of COVID-19, has been suggested to be unreliable. Firstly, several discrepancies were identified between the registry, graphs and text in the paper for this trial. ...
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Background Ivermectin is an antiparasitic drug being investigated in clinical trials for the prevention of COVID-19. However, there are concerns about the quality of some of these trials. Objectives To conduct a meta-analysis with randomized controlled trials of ivermectin for the prevention of COVID-19, while controlling for the quality of data. The primary outcome was RT–PCR-confirmed COVID-19 infection. The secondary outcome was rate of symptomatic COVID-19 infection. Methods We conducted a subgroup analysis based on the quality of randomized controlled trials evaluating ivermectin for the prevention of COVID-19. Quality was assessed using the Cochrane risk of bias measures (RoB 2) and additional checks on raw data, where possible. Results Four studies were included in the meta-analysis. One was rated as being potentially fraudulent, two as having a high risk of bias and one as having some concerns for bias. Ivermectin did not have a significant effect on preventing RT–PCR-confirmed COVID-19 infection. Ivermectin had a significant effect on preventing symptomatic COVID-19 infection in one trial with some concerns of bias, but this result was based on post hoc analysis of a multi-arm study. Conclusions In this meta-analysis, the use of ivermectin was not associated with the prevention of RT–PCR-confirmed or symptomatic COVID-19. The currently available randomized trials evaluating ivermectin for the prevention of COVID-19 are insufficient and of poor quality.
... Of the 229 study participants, 131 were treated with 0.2 mg ivermectin drops taken by mouth five times a day. After 28 days, none of the participants receiving ivermectin prophylaxis tested positive for SARS-COV-2, compared to 11.2% of the participants in the control group who tested positive [64]. In line with other prophylaxis reports, a recently published Preprint Matching Case-Control 374 study on medRxiv, which analyzed several drugs experimentally used as COVID-19 375 prophylaxis, showed a 73% reduction in COVID-19 infections in health care workers after two doses of ivermectin (OR 0.27; 95% CI 0.15-0.51) ...
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The global COVID-19 pandemic has affected the world's population by causing changes in behavior, such as social distancing, masking, restricting people's movement, and evaluating existing medication as potential therapies. Many pre-existing medications such as tocilizumab, ivermectin, colchicine, interferon, and steroids have been evaluated for being repurposed to use for the treatment of COVID-19. None of these agents have been effective except for ster-oids and, to a lesser degree, tocilizumab. Ivermectin has been one of the suggested repurposed medications which exhibit an in vitro inhibitory activity on SARS-CoV-2 replication. The most recommended dose of ivermectin for the treatment of COVID-19 is 150-200 µg/kg twice daily. As ivermectin adoption for COVID-19 increased, the Food and Drug Administration (FDA) issued a warning on its use during the pandemic. However, the drug remains of interest to clinicians and has shown some promise in observational studies. This narrative reviews the toxicological profile and some potential therapeutic effects of ivermectin. Based on the current dose recommendation, ivermectin appears to be safe with minimum side effects. However, serious questions remain about the effectiveness of this drug in the treatment of patients with COVID-19.
... p = 1.10 -5 ). A similar multicentric prophylactic study [46] with iota carrageenan nasal spray and IVM oral drops (used as buccal drops, 0.6 mg/ml) was found to be associated with a lower incidence of infection compared to the standard prophylactic measures and PPE only (0% vs. 58.2%). ...
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Ivermectin (IVM), an approved anthelminthic drug, has been reported to have antiviral, antibacterial, and anticancer activities. Antiviral activity is due to the inhibition of nuclear cargo importin (IMP) protein. The anti-SARS CoV-2 activity through in vitro study was first reported by an Australian team. Later, many studies were conducted, and most of the study results were available as non-peer reviewed preprints. In this narrative review, literature on the clinical studies conducted with ivermectin from published articles, preprints, and unpublished evidence are collected till 13th June 2021 and they are discussed based on the severity of COVID-19 disease. Out of the 23 peer-reviewed published articles, 13 studies were randomized controlled trials and the remaining were either prospective interventional, prospective observational, retrospective cohort, cross-sectional, or case series type of studies; additionally, there were 10 randomized controlled trials available as preprints. In most of the studies, ivermectin was used in combination with doxycycline, azithromycin or other drugs. Some of the studies suggested either higher dose and/ or increased duration of ivermectin use to achieve favorable effects. In this review, articles on the prophylactic role of ivermectin in COVID-19 are also discussed – wherein the results are more promising. Despite accumulating evidence suggest the possible use of ivermectin, the final call to incorporate ivermectin in the management of COVID-19 is still inconclusive.
Preprint
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Ivermectin reduces risk for COVID-19 with very high confidence for mortality, ventilation, ICU admission, hospitalization, progression, recovery, cases, viral clearance, and in pooled analysis. We show traditional outcome specific analyses and combined evidence from all studies, incorporating treatment delay, a primary confounding factor in COVID-19 studies. Real-time updates and corrections, transparent analysis with all results in the same format, consistent protocol for 42 treatments. 83 ivermectin COVID-19 controlled studies, 34 RCTs 63% improvement for early treatment, R 0.37 (0.29-0.48] Probability results from ineffective treatment (since 25 Mar 2021): under 1 in 1 billion @ME: Licensing & copy-editing suggestions, RG u/l. @CA: Everything else.
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Coronavirus disease-2019 (COVID-19) is a novel viral infectious disease that the World Health Organization (WHO) has announced to be a pandemic. This meta-analysis was aimed at providing evidence for the use of ivermectin to prevent COVID-19 among hospital workers in low-resource countries. Medical databases including African Journals online, Google Scholar, PubMed, Cochrane library, EMBASE, COVID-19 research database (WHO), Clinicaltrials.gov, and SCOPUS were searched for studies on Ivermectin as a chemoprophylactic drug against COVID-19 among hospital personnel in settings with limited resources. Preprint servers such as bioRxiv and medRxiv as well as the gray literature were also searched. Studies adjudged to be eligible were identified using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses algorithm. Statistical analyses were done using Stata version 14.3. Seven studies were selected for the meta-analysis. The total sample size was 2652. There were two randomized controlled trials and five nonrandomized studies. Some studies dosed Ivermectin daily while some dosed it weekly. However, one of the studies dosed it monthly. The studies reported variable clinical benefits. I2 statistic was 92%, and random effect model was used. The pooled odd ratio was 0.11 (95% confidence interval 0.09-0.13). This implies that 89% of the participants benefited from taking Ivermectin as a form of preexposure chemoprophylaxis. Ivermectin has a significant clinical benefit as a preventive drug against COVID-19 for hospital personnel in settings with limited resources.
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Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 hours post infection with SARS-CoV-2 able to effect ∼5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.
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Introduction An epidemic of Coronavirus Disease 2019 (COVID-19) began in December 2019 in China leading to a Public Health Emergency of International Concern (PHEIC). Clinical, laboratory, and imaging features have been partially characterized in some observational studies. No systematic reviews on COVID-19 have been published to date. Methods We performed a systematic literature review with meta-analysis, using three databases to assess clinical, laboratory, imaging features, and outcomes of COVID-19 confirmed cases. Observational studies and also case reports, were included, and analyzed separately. We performed a random-effects model meta-analysis to calculate the pooled prevalence and 95% confidence interval (95%CI). Results 660 articles were retrieved for the time frame (1/1/2020-2/23/2020). After screening, 27 articles were selected for full-text assessment, 19 being finally included for qualitative and quantitative analyses. Additionally, 39 case report articles were included and analyzed separately. For 656 patients, fever (88.7%, 95%CI 84.5–92.9%), cough (57.6%, 40.8–74.4%) and dyspnea (45.6%, 10.9–80.4%) were the most prevalent manifestations. Among the patients, 20.3% (95%CI 10.0–30.6%) required intensive care unit (ICU), 32.8% presented with acute respiratory distress syndrome (ARDS) (95%CI 13.7–51.8), 6.2% (95%CI 3.1–9.3) with shock. Some 13.9% (95%CI 6.2–21.5%) of hospitalized patients had fatal outcomes (case fatality rate, CFR). Conclusion COVID-19 brings a huge burden to healthcare facilities, especially in patients with comorbidities. ICU was required for approximately 20% of polymorbid, COVID-19 infected patients and hospitalization was associated with a CFR of over 13%. As this virus spreads globally, countries need to urgently prepare human resources, infrastructure and facilities to treat severe COVID-19.
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It has been reported that ACE2 is the main host cell receptor of 2019-nCoV and plays a crucial role in the entry of virus into the cell to cause the final infection. To investigate the potential route of 2019-nCov infection on the mucosa of oral cavity, bulk RNA-seq profiles from two public databases including The Cancer Genome Atlas (TCGA) and Functional Annotation of The Mammalian Genome Cap Analysis of Gene Expression (FANTOM5 CAGE) dataset were collected. RNA-seq profiling data of 13 organ types with para-carcinoma normal tissues from TCGA and 14 organ types with normal tissues from FANTOM5 CAGE were analyzed in order to explore and validate the expression of ACE2 on the mucosa of oral cavity. Further, single-cell transcriptomes from an independent data generated in-house were used to identify and confirm the ACE2-expressing cell composition and proportion in oral cavity. The results demonstrated that the ACE2 expressed on the mucosa of oral cavity. Interestingly, this receptor was highly enriched in epithelial cells of tongue. Preliminarily, those findings have explained the basic mechanism that the oral cavity is a potentially high risk for 2019-nCoV infectious susceptibility and provided a piece of evidence for the future prevention strategy in dental clinical practice as well as daily life.
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The shedding of severe acute respiratory syndrome coronavirus (SARS-CoV) into saliva droplets plays a critical role in viral transmission. The source of high viral loads in saliva, however, remains elusive. Here we investigate the early target cells of infection in the entire array of respiratory tissues in Chinese macaques after intranasal inoculations with a single-cycle pseudotyped virus and a pathogenic SARS-CoV. We found that angiotensin-converting enzyme 2-positive (ACE2+) cells were widely distributed in the upper respiratory tract, and ACE2+ epithelial cells lining salivary gland ducts were the early target cells productively infected. Our findings also have implications for SARS-CoV early diagnosis and prevention.
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Saliva is an exocrine secretion produced from the salivary glands and has numerous functions, such as cleansing and protection of the oral cavity, antimicrobial effects and aids in digestion. Due to the speedy development in the field of salivaomics, saliva is now well accepted as a pool of biological markers that vary from changes in biochemicals, nucleic acids and proteins to the microflora. Saliva has an immense potential as a diagnostic fluid and offers an edge over other biological fluids as its collection method does not require invasive procedure, economical and is useful for monitoring systemic health. Development of sensitive and precise salivary diagnostic tools and the formulation of defined guidelines following meticulous testing will allow salivary diagnostics to be utilised as chair side tests for various oral and systemic diseases in the near future. The coronavirus disease (Covid-19) pandemic is the biggest challenge and global health crisis for the world since World War Two. Rapid and accurate diagnosis of Covid-19 is crucial in controlling the outbreak in the community and in hospitals. Nasopharyngeal and oropharyngeal swabs are the recommended specimen types for Covid-19 diagnostic testing. The collection of these specimen types requires close contact between healthcare workers and patients and poses a risk of transmission of the virus, causes discomfort and may cause bleeding, especially in patients with condition such as thrombocytopenia. Hence, nasopharyngeal or oropharyngeal swabs are not desirable for sequential monitoring of viral load. Saliva specimens can be obtained easily as the patient is asked to spit into a sterile bottle. The collection of saliva is non-invasive and greatly minimizes the exposure of healthcare workers to Covid-19. Saliva has a high consistency rate of greater than 90% with nasopharyngeal specimens in the detection of respiratory viruses, including coronaviruses. Saliva has also been used in screening respiratory viruses among hospitalized patients without pyrexia or respiratory symptoms. SARS-CoV can be detected in saliva at high titers. Salivary diagnostics is a dynamic field that is being incorporated as part of disease diagnosis, clinical monitoring of systemic health and to make significant clinical decisions for patient care. More research is required to analyze the potential diagnostic of Covid-19 in saliva to develop rapid chair side tests for the detection of Covid-19 and it is also pivotal to improve and develop successful strategies for prevention, especially for dentists and healthcare professionals who are involved in performing aerosol-generating procedures.
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Background: Since December 2019, an outbreak of Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, and is now becoming a global threat. We aimed to delineate and compare the immunologic features of severe and moderate COVID-19. Methods: In this retrospective study, the clinical and immunologic characteristics of 21 patients (17 male and 4 female) with COVID-19 were analyzed. These patients were classified as severe (11 cases) and moderate (10 cases) according to the Guidelines released by the National Health Commission of China. Results: The median age of severe and moderate cases was 61.0 and 52.0 years, respectively. Common clinical manifestations included fever, cough and fatigue. Compared to moderate cases, severe cases more frequently had dyspnea, lymphopenia, and hypoalbuminemia, with higher levels of alanine aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin and D-dimer as well as markedly higher levels of IL-2R, IL-6, IL-10, and TNF-α. Absolute number of T lymphocytes, CD4+T and CD8+T cells decreased in nearly all the patients, and were markedly lower in severe cases (294.0, 177.5 and 89.0 × 106/L) than moderate cases (640.5, 381.5 and 254.0 × 106/L). The expressions of IFN-γ by CD4+T cells tended to be lower in severe cases (14.1%) than moderate cases (22.8%). Conclusion: The SARS-CoV-2 infection may affect primarily T lymphocytes particularly CD4+T and CD8+ T cells, resulting in decrease in numbers as well as IFN-γ production. These potential immunological markers may be of importance due to their correlation with disease severity in COVID-19.
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Background Coronavirus disease 2019 (COVID-19) causes severe community and nosocomial outbreaks. Comprehensive data for serial respiratory viral load and serum antibody responses from patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not yet available. Nasopharyngeal and throat swabs are usually obtained for serial viral load monitoring of respiratory infections but gathering these specimens can cause discomfort for patients and put health-care workers at risk. We aimed to ascertain the serial respiratory viral load of SARS-CoV-2 in posterior oropharyngeal (deep throat) saliva samples from patients with COVID-19, and serum antibody responses. Methods We did a cohort study at two hospitals in Hong Kong. We included patients with laboratory-confirmed COVID-19. We obtained samples of blood, urine, posterior oropharyngeal saliva, and rectal swabs. Serial viral load was ascertained by reverse transcriptase quantitative PCR (RT-qPCR). Antibody levels against the SARS-CoV-2 internal nucleoprotein (NP) and surface spike protein receptor binding domain (RBD) were measured using EIA. Whole-genome sequencing was done to identify possible mutations arising during infection. Findings Between Jan 22, 2020, and Feb 12, 2020, 30 patients were screened for inclusion, of whom 23 were included (median age 62 years [range 37–75]). The median viral load in posterior oropharyngeal saliva or other respiratory specimens at presentation was 5·2 log10 copies per mL (IQR 4·1–7·0). Salivary viral load was highest during the first week after symptom onset and subsequently declined with time (slope −0·15, 95% CI −0·19 to −0·11; R²=0·71). In one patient, viral RNA was detected 25 days after symptom onset. Older age was correlated with higher viral load (Spearman's ρ=0·48, 95% CI 0·074–0·75; p=0·020). For 16 patients with serum samples available 14 days or longer after symptom onset, rates of seropositivity were 94% for anti-NP IgG (n=15), 88% for anti-NP IgM (n=14), 100% for anti-RBD IgG (n=16), and 94% for anti-RBD IgM (n=15). Anti-SARS-CoV-2-NP or anti-SARS-CoV-2-RBD IgG levels correlated with virus neutralisation titre (R²>0·9). No genome mutations were detected on serial samples. Interpretation Posterior oropharyngeal saliva samples are a non-invasive specimen more acceptable to patients and health-care workers. Unlike severe acute respiratory syndrome, patients with COVID-19 had the highest viral load near presentation, which could account for the fast-spreading nature of this epidemic. This finding emphasises the importance of stringent infection control and early use of potent antiviral agents, alone or in combination, for high-risk individuals. Serological assay can complement RT-qPCR for diagnosis. Funding Richard and Carol Yu, May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Michael Tong, Marina Lee, Government Consultancy Service, and Sanming Project of Medicine.