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Abstract

COVID BY VARIANTS OF SARS COV-2: INCLUSION OF NIFUROXAZIDE IN THE FIRST LINE OF THERAPEUTIC ACTION. We report a significant reduction in hospitalizations and the fatality rate with its use associated with Ivermectin. Aguirre-Chang, Gustavo, Córdova M., José Aníbal y Trujillo F., Aurora. ReseachGate. 5 de February 5, 2021. Characteristics of COVID by Variants of SARS CoV-2. Since December 2020 and January 2021, a significant increase in the number of new cases of COVID has begun to appear in several countries, this situation being due in large part to the presence of new variants of the virus. One of the characteristics initially identified in the Variants is a significantly higher contagiousness. For our part, we have observed that, similarly to the fact that it spreads more rapidly in the environment, and generates greater contagiousness, the Variants of SARS CoV-2 affect the intestines more frequently and rapidly, this frequently occurring within the first 4 days from the onset of symptoms, which corresponds to the initial stage, and which in typical COVID-19 the involvement was generally limited to the upper respiratory tract in this initial stage. In addition to the intestines, due to the more frequent presence of tachycardia and chest pain (with normal oxygen saturation), it is understood that there is also a more frequent and rapid involvement of the heart and pericardium. In adults and older adults, it also generates a faster and greater impact on the brain. First international study on the use of Nifuroxazide in COVID. On January 18, 2021, we published the first international study on the use of Nifuroxazide in COVID (1). In the final part of this study, we pointed out that, based on the evidence, we had decided to incorporate Nifuroxazide into the therapeutic plan developed for the COVID produced by the SARS CoV-2 variants. We reaffirm ourselves in this decision. Nifuroxazide, main characteristics. Nifuroxazide is an antibacterial that has been used in humans for more than 50 years, it was patented in 1966. It is used in the treatment of diarrhea and intestinal infections, mainly produced by gram-negative bacteria, such as: E. coli, Salmonella gallinarum, Salmonella pullorum, Salmonella typhimurium, Salmonella cholerasuis, Arizona hinshawii, Vibrio coli, Shigella sp., Haemophilus sp., Klebsiella sp., Citrobacter sp., And Corynebacterium sp. It also acts on Entamoeba histolytica and Giardia lamblia. It is indicated for symptomatic Trichomonas vaginalis infections in women and men. It is mentioned to be an effective anthelmintic, and is used in association with other H. pylori medications. The literature indicates that it is better absorbed when given with food or with agents that delay gastric emptying. When the urine is acidic, a significant reabsorption occurs, therefore, this favors the effectiveness of the drug. It produces a change in the color of the urine to amber or dark yellow, it is observed as darker or loaded urine. This must be informed to the patient. Side and adverse effects Its side effects are mild and infrequent (2), there is good tolerance even given at doses higher than regular ones, and its cost is low. It is noted that it can cause hypersensitivity reactions of various locations, in skin, lung, blood and/or liver. In France, the National Agency for the Safety of Medicines and Health Products (ANSM), through a statement (3) pointed out that, as the vast majority of infectious diarrhea in that country are of viral origin, and Nifuroxazide has not been shown to be of clinical interest in the treatment of this type of conditions, after a review of the benefit-risk ratio, it provides its contraindication in children and adolescents under 18 years of age. As part of the elements that support this decision, they point out that the pharmacovigilance data show a profile of adverse effects marked by very rare but sometimes serious immunoallergic effects, especially in children (anaphylactic shock, Quincke's angioedema), and remember that in the majority of the cases the diarrhea is cured without pharmacological treatment, and that in children it is mainly based on the administration of oral rehydration fluids. Powerful Inhibitory effect of the Transcription Factor STAT3. In 2006, Nelson et al. (4,5) discovered that Nifuroxazide is a potent inhibitor of the Transcription Factor STAT3 (which stands for Signal Transducer and Activator of Transcription-3). In their 2008 study (5) they also reported that Nifuroxazide inhibits tyrosine phosphorylation of the kinase Jak2 and Tyk2. STAT3 is associated with several human cancers and usually indicates a poor prognosis, has both anti-apoptotic and proliferative effects (6,7,8,9). STAT3 inhibition may also be effective in post-graft transplantation (10). In a study by Said et al (11) in 2018 identified a nephroprotective effect of Nifuroxazide in the diabetic kidney, through the effective inhibition of STAT3 activation. Furthermore, Nifuroxazide treatment significantly reduced macrophage infiltration and fibrosis in diabetic kidney tissue and reduced levels of TNF-alpha and IL-18. It induces apoptosis of cancer cells and inhibits tumor growth. Studies have also been published showing that Nifuroxazide induces apoptosis of cancer cells and inhibits tumor growth (9,12,13). Inhibitory effect of ALDH1. In 2016 it was shown that Nifuroxazide is a potent inhibitor of aldehyde dehydrogenase 1 (ALDH1) and that it selectively eliminates cells with a high content of ALDH1 that start cancer (9,14,15). Interrupts the signaling pathway of TLR4/ NLRP3 inflammosome/ IL-1. In a study published by Khodir Samra and Said (16) in September 2020, it was pointed out that Nifuroxazide has a function that generates the attenuation of acute pulmonary and myocardial lesions associated with sepsis; this role could be explained by the interruption of the TLR4/ NLRP3 inflammosome/ IL-1 signaling pathway by Nifuroxazide. TLR stands for Toll-like Receptor, they are Toll-like receptors that are found in cell membranes and serve for the recognition of infectious agents by the body, and induce, as a result of their stimulation, the production of pro-inflammatory cytokines and the expression of molecules costimulatory in mature cells resulting in immune alert signals. The importance of TLR4s in COVID-19 is pointed out in several publications (17 to 24) and clinical trials of TLR4 antagonists for the treatment of COVID-19 are proposed. Taking into account this effect, the use of Nifuroxazide is justified not only in mild and moderate cases of COVID, but also in severe and critical cases, and in the advanced stages of the disease, in which patients present a significant systemic inflammatory reaction. Inhibitory effect of the signaling of the Transcription Factor NF-kB. NF-κB is the Nuclear Factor enhancer of the kappa light chains of activated B cells. It is a transcription factor that regulates multiple aspects of immune function and mediates inflammatory responses, regulates the survival, activation and differentiation of innate immune cells and inflammatory T cells. In a study by Elsherbiny et al (25) published in 2018, it was identified that Nifuroxazide, administered in diabetic rats at a dose of 25 mg/ kg/ day, orally, for 8 weeks, exhibited a renoprotective effect on the kidney diabetic disease through the damping of NF-κB activation, improved oxidative stress and regulated the activity of apoptotic enzymes. In a study by El-Far (26), it was identified that the interaction of the inhibitory effect of Nifuroxazide on NF-kB/ STAT3/ caspase signaling attenuates acetic acid-induced ulcerative colitis, so it can be proposed as a new therapy for ulcerative colitis. In another study, by Hassan, Said and Shehatou (27), it was identified that Nifuroxazide suppresses interstitial fibrosis in kidney tissues, probably via inhibition of STAT-3/ NF-κB signaling and attenuating oxidative stress and inflammation. kidney Recent studies indicate that the inhibition of NF-κB may be a possible mechanism of action with therapeutic potential in patients with severe COVID-19 (28). Other reported effects. A hepatoprotective and ameliortive effect has also been identified in the progression of Hepatic Encephalopathy (98), which was associated with a significant reduction in the liver and brain content of c-june N-terminal kinase (cJNK), so the study concluded that Nifuroxazide would have a modulatory effect on cJNK/ caspase-8/ TRAIL signaling. Our experience of its use in COVID: significant reduction in hospitalizations and the fatality rate with its use associated with Ivermectin. For our part, with the additional experience in the treatment of new patients in the last three weeks, it is evident that the use of Nifuroxazide, together with Iverme ctin,in patients with COVID by the Variants of SARS CoV-2, results in a significant decrease in hospitalizations and the Fatality Rate. Although there are still not many treated cases that we have documented, of the 34 patients that we are treating with Nifuroxazide plus Ivermectin, only one required hospitalization, none required admission to the ICU, or required mechanical ventilation or died. Regarding the clinical response to treatment, we have observed that all the cases in which treatment with Nifuroxazide was started, and who were already receiving high-dose Ivermectin treatment, presented a general clinical improvement of the disease, with resolution of fever and chest pain, in those who presented it, within 12 to 60 hours of starting treatment with Nifuroxazide. Regarding the presence of liquid or semi-liquid stools, these resolved in a period of time of 1 to 3 days. Likewise, an improvement in Oxygen Saturation of 1 to 3% was observed in the first 24 hours after starting treatment with Nifuroxazide, and the patients reached normal levels of Oxygen Saturation, or the levels they had before becoming ill, then 1 to 6 days after starting treatment with Nifuroxazide. It is important to mention that the general clinical improvement, of fever, chest pain and oxygen saturation, indicate that the effect of Nifuroxazide is not limited to the intestines, but that there is an effect at the level of the lungs, of the heart and other organs. On the other hand, we have begun to evaluate the use of higher doses than the regular ones, this mainly for severe and critical cases that present a higher viral load and in which multiple organs and systems are compromised. We are also testing the use of Nifuroxazide together with Ivermectin in patients with Persistent Symptoms of COVID (in Post-Acute and Chronic COVID or Long COVID or Persistent COVID), indicating it in all cases (and not only those with stools semi-liquid or persistent liquid). Very good tolerance is observed, to date treated patients have not manifested any side effects. It is not recommended to give the ground tablets because they have a bitter taste. In case the patient has difficulty taking pills orally, it is recommended to use the syrup presentations that usually contain 200 mg of Nifuroxazide for each teaspoon (for each 5 ml). In critical cases, the drug must be passed through the nasogastric tube. Treatment Scheme Table. In Table 1, the Nifuroxazide Treatment Scheme is presented according to the severity of the disease. In addition to the severity, in adults the doses also vary according to the weight of the patient, establishing cut-off points at 70 and 95 kilos. In children, the doses also vary according to age, establishing cut-off points at 5 and 8 years of age. This Table has been prepared based on the experience of the first 34 cases that we have treated. The use of Nifuroxazide has been done together with Ivermectin at doses of 0.2 to 1.2 mg per kilo of weight per day, and in 70% of the treated cases, ASA (Aspirin) has also been prescribed at doses between 200 to 600 mg a day, which is the Treatment Scheme for Acute COVID that we manage and propose (30). Conclusions Based on what has been evaluated, we conclude that it is advisable to formalize the inclusion of Nifuroxazide in the first line of therapeutic action for COVID due to SARS Cov-2 Variants. In the short term, It is necessary to carry out in the short term clinical studies with a significant number of participants on the use of Nifuroxazide in COVID, its use is recommended in association with Ivermectin, Vitamin C and an antiplatelet such as Acetylsalicylic Acid (ASA).
1
COVID BY VARIANTS OF SARS COV-2: INCLUSION OF NIFUROXAZIDE
IN THE FIRST LINE OF THERAPEUTIC ACTION.
We report a significant reduction in hospitalizations and the fatality rate with
its use associated with Ivermectin.
Aguirre-Chang, Gustavo, Córdova M., José Aníbal and Trujillo F., Aurora.
ResearchGate. February 5, 2021.
Key Words: COVID 19, Nifuroxazide, Ivermectin, Variants of SARS CoV-2, TLR4.
Characteristics of COVID by Variants of SARS CoV-2.
Since December 2020 and January 2021, a significant increase in the number of new cases
of COVID has begun to appear in several countries, this situation being due in large part to
the presence of new variants of the virus.
One of the characteristics initially identified in the Variants is a significantly higher
contagiousness. For our part, we have observed that, similarly to the fact that it spreads more
rapidly in the environment, and generates greater contagiousness, the Variants of SARS
CoV-2 affect the intestines more frequently and rapidly, this frequently occurring within the
first 4 days from the onset of symptoms, which corresponds to the initial stage, and which in
typical COVID-19 the involvement was generally limited to the upper respiratory tract in this
initial stage. In addition to the intestines, due to the more frequent presence of tachycardia
and chest pain (with normal oxygen saturation), it is understood that there is also a more
frequent and rapid involvement of the heart and pericardium. In adults and older adults, it
also generates a faster and greater impact on the brain.
First international study on the use of Nifuroxazide in COVID.
On January 18, 2021, we published the first international study on the use of Nifuroxazide in
COVID (1). In the final part of this study, we pointed out that, based on the evidence, we had
decided to incorporate Nifuroxazide into the therapeutic plan developed for the COVID
produced by the SARS CoV-2 variants. We reaffirm ourselves in this decision.
Nifuroxazide, main characteristics.
Nifuroxazide is an antibacterial that has been used in humans for more than 50 years, it was
patented in 1966.
It is used regularly for the treatment of diarrhea and intestinal infections, mainly produced by
gram-negative bacteria, such as: E. coli, Salmonella gallinarum, Salmonella pullorum,
Salmonella typhimurium, Salmonella cholerasuis, Arizona hinshawii, Vibrio coli, Shigella sp.,
Haemophilus sp., Klebsiella sp., Citrobacter sp., And Corynebacterium sp.
It also acts on Entamoeba histolytica and Giardia lamblia. It is indicated for symptomatic
Trichomonas vaginalis infections in women and men.
It is mentioned to be an effective anthelmintic, and is used in association with other H. pylori
medications.
The literature indicates that it is better absorbed when given with food or with agents that
delay gastric emptying.
When the urine is acidic, a significant reabsorption occurs, therefore, this favors the
effectiveness of the drug.
It produces a change in the color of the urine to amber or dark yellow, it is observed as darker
or loaded urine. This must be informed to the patient.
COVID by variants of SARS CoV-2: inclusion of Nifuroxazide in the first line of therapeutic action.
Aguirre-Chang G, Córdova M. JA, Trujillo F. A. ResearchGate. February 5, 2021.
2
Side and adverse effects
Its side effects are mild and infrequent (2), there is good tolerance even given at doses higher
than regular ones, and its cost is low. It is noted that it can cause hypersensitivity reactions
of various locations, in skin, lung, blood and/or liver.
In France, the National Agency for the Safety of Medicines and Health Products (ANSM),
through a statement (3) pointed out that, as the vast majority of infectious diarrhea in that
country are of viral origin, and Nifuroxazide has not been shown to be of clinical interest in
the treatment of this type of conditions, after a review of the benefit-risk ratio, it provides its
contraindication in children and adolescents under 18 years of age. As part of the elements
that support this decision, they point out that the pharmacovigilance data show a profile of
adverse effects marked by very rare but sometimes serious immunoallergic effects,
especially in children (anaphylactic shock, Quincke's angioedema), and remember that in the
majority of the cases the diarrhea is cured without pharmacological treatment, and that in
children it is mainly based on the administration of oral rehydration fluids.
Powerful Inhibitory effect of the Transcription Factor STAT3.
In 2006, Nelson et al. (4,5) discovered that Nifuroxazide is a potent inhibitor of the
Transcription Factor STAT3 (which stands for Signal Transducer and Activator of
Transcription-3). In their 2008 study (5) they also reported that Nifuroxazide inhibits tyrosine
phosphorylation of the kinase Jak2 and Tyk2.
STAT3 is associated with several human cancers and usually indicates a poor prognosis,
has both anti-apoptotic and proliferative effects (6,7,8,9). STAT3 inhibition may also be
effective in post-graft transplantation (10).
In a study by Said et al (11) in 2018 identified a nephroprotective effect of Nifuroxazide in the
diabetic kidney, through the effective inhibition of STAT3 activation. Furthermore,
Nifuroxazide treatment significantly reduced macrophage infiltration and fibrosis in diabetic
kidney tissue and reduced levels of TNF-alpha and IL-18.
It induces apoptosis of cancer cells and inhibits tumor growth.
Studies have also been published showing that Nifuroxazide induces apoptosis of cancer
cells and inhibits tumor growth (9,12,13).
Inhibitory effect of ALDH1.
In 2016 it was shown that Nifuroxazide is a potent inhibitor of aldehyde dehydrogenase 1
(ALDH1) and that it selectively eliminates cells with a high content of ALDH1 that start cancer
(9,14,15).
Interrupts the signaling pathway of TLR4/ NLRP3 inflammosome/ IL-1.
In a study published by Khodir Samra and Said (16) in September 2020, it was pointed out
that Nifuroxazide has a function that generates the attenuation of acute pulmonary and
myocardial lesions associated with sepsis; this role could be explained by the interruption of
the TLR4/ NLRP3 inflammosome/ IL-1 signaling pathway by Nifuroxazide. TLR stands for
Toll-like Receptor, they are Toll-like receptors that are found in cell membranes and serve for
the recognition of infectious agents by the body, and induce, as a result of their stimulation,
the production of pro-inflammatory cytokines and the expression of molecules costimulatory
in mature cells resulting in immune alert signals. The importance of TLR4s in COVID-19 is
pointed out in several publications (17 to 24) and clinical trials of TLR4 antagonists for the
treatment of COVID-19 are proposed. Taking into account this effect, the use of Nifuroxazide
COVID by variants of SARS CoV-2: inclusion of Nifuroxazide in the first line of therapeutic action.
Aguirre-Chang G, Córdova M. JA, Trujillo F. A. ResearchGate. February 5, 2021.
3
is justified not only in mild and moderate cases of COVID, but also in severe and critical
cases, and in the advanced stages of the disease, in which patients present a significant
systemic inflammatory reaction.
Inhibitory effect of the signaling of the Transcription Factor NF-kB.
NF-κB is the Nuclear Factor enhancer of the kappa light chains of activated B cells. It is a
transcription factor that regulates multiple aspects of immune function and mediates
inflammatory responses, regulates the survival, activation and differentiation of innate
immune cells and inflammatory T cells.
In a study by Elsherbiny et al (25) published in 2018, it was identified that Nifuroxazide,
administered in diabetic rats at a dose of 25 mg/ kg/ day, orally, for 8 weeks, exhibited a
renoprotective effect on the kidney diabetic disease through the damping of NF-κB activation,
improved oxidative stress and regulated the activity of apoptotic enzymes.
In a study by El-Far (26), it was identified that the interaction of the inhibitory effect of
Nifuroxazide on NF-kB/ STAT3/ caspase signaling attenuates acetic acid-induced ulcerative
colitis, so it can be proposed as a new therapy for ulcerative colitis.
In another study, by Hassan, Said and Shehatou (27), it was identified that Nifuroxazide
suppresses interstitial fibrosis in kidney tissues, probably via inhibition of STAT-3/ NF-κB
signaling and attenuating oxidative stress and inflammation. kidney
Recent studies indicate that the inhibition of NF-κB may be a possible mechanism of action
with therapeutic potential in patients with severe COVID-19 (28).
Other reported effects.
A hepatoprotective and ameliortive effect has also been identified in the progression of
Hepatic Encephalopathy (98), which was associated with a significant reduction in the liver
and brain content of c-june N-terminal kinase (cJNK), so the study concluded that
Nifuroxazide would have a modulatory effect on cJNK/ caspase-8/ TRAIL signaling.
Our experience of its use in COVID: significant reduction in hospitalizations and the
fatality rate with its use associated with Ivermectin.
For our part, with the additional experience in the treatment of new patients in the last three
weeks, it is evident that the use of Nifuroxazide, together with Iverme ctin,in patients with
COVID by the Variants of SARS CoV-2, results in a significant decrease in hospitalizations
and the Fatality Rate. Although there are still not many treated cases that we have
documented, of the 34 patients that we are treating with Nifuroxazide plus Ivermectin, only
one required hospitalization, none required admission to the ICU, or required mechanical
ventilation or died.
Regarding the clinical response to treatment, we have observed that all the cases in which
treatment with Nifuroxazide was started, and who were already receiving high-dose
Ivermectin treatment, presented a general clinical improvement of the disease, with
resolution of fever and chest pain, in those who presented it, within 12 to 60 hours of starting
treatment with Nifuroxazide. Regarding the presence of liquid or semi-liquid stools, these
resolved in a period of time of 1 to 3 days.
Likewise, an improvement in Oxygen Saturation of 1 to 3% was observed in the first 24 hours
after starting treatment with Nifuroxazide, and the patients reached normal levels of Oxygen
Saturation, or the levels they had before becoming ill, then 1 to 6 days after starting treatment
with Nifuroxazide.
COVID by variants of SARS CoV-2: inclusion of Nifuroxazide in the first line of therapeutic action.
Aguirre-Chang G, Córdova M. JA, Trujillo F. A. ResearchGate. February 5, 2021.
4
It is important to mention that the general clinical improvement, of fever, chest pain and
oxygen saturation, indicate that the effect of Nifuroxazide is not limited to the intestines, but
that there is an effect at the level of the lungs, of the heart and other organs.
On the other hand, we have begun to evaluate the use of higher doses than the regular ones,
this mainly for severe and critical cases that present a higher viral load and in which multiple
organs and systems are compromised.
We are also testing the use of Nifuroxazide together with Ivermectin in patients with
Persistent Symptoms of COVID (in Post-Acute and Chronic COVID or Long COVID or
Persistent COVID), indicating it in all cases (and not only those with stools semi-liquid or
persistent liquid).
Very good tolerance is observed, to date treated patients have not manifested any side
effects.
It is not recommended to give the ground tablets because they have a bitter taste. In case
the patient has difficulty taking pills orally, it is recommended to use the syrup presentations
that usually contain 200 mg of Nifuroxazide for each teaspoon (for each 5 ml). In critical
cases, the drug must be passed through the nasogastric tube.
Treatment Scheme Table.
In Table 1, the Nifuroxazide Treatment Scheme is presented according to the severity of the
disease. In addition to the severity, in adults the doses also vary according to the weight of
the patient, establishing cut-off points at 70 and 95 kilos. In children, the doses also vary
according to age, establishing cut-off points at 5 and 8 years of age.
This Table has been prepared based on the experience of the first 34 cases that we have
treated.
COVID by variants of SARS CoV-2: inclusion of Nifuroxazide in the first line of therapeutic action.
Aguirre-Chang G, Córdova M. JA, Trujillo F. A. ResearchGate. February 5, 2021.
5
The use of Nifuroxazide has been done together with Ivermectin at doses of 0.2 to 1.2 mg
per kilo of weight per day, and in 70% of the treated cases, ASA (Aspirin) has also been
prescribed at doses between 200 to 600 mg a day, which is the Treatment Scheme for Acute
COVID that we manage and propose (30).
Nifurtimox, another Nitrofuran with antitumor effects.
Nifurtimox is another Nitrofuran which has been reported since 2006 to have antitumor
activity in pediatric patients with Neuroblastoma (31,32,33,34,35), Medulloblastoma (36),
other neural tumors (37) and Astroglioma (38).
In another study (39), it was identified that Nifurtimox is useful for the eradication of hypoxic
tumor cells. It can function as a hypoxia-activated cytotoxin that preferentially inhibits
clonogenic tumor cells under severely hypoxic conditions.
A study reported a better effect of Nifurtimox when used in conjunction with ASA, which is
Aspirin (40,41), this for the treatment of Chagas disease, which is an intracellular infectious
pathology.
Nifuratel and other Nitrofurans.
Nifuratel is a little known Nitrofuran, a study by Zheng et al. (42) found it to be a STAT3
inhibitor with potent activity against human gastric cancer cells. That is, he identified that it
has properties similar to those found in Nifuroxazide.
Another Nitrofuran of known use in medicine is Furazolidone, which is used like Nifuroxazide
for the treatment of traveler's diarrhea, against Trichomona and Giardia, therefore, it could
be considered as an alternative to be used in cases where Nifuroxazide is not available.
Nitrofurantoin is another Nitrofuran, but its use is specifically aimed at treating urinary
infections.
Other lesser known Nitrofurans are Nifuraldezone, Nifupirazine, Nitrovine, Nifuresterinate.
Nitrofurazone, Furaltadone.
Conclusions
Based on what has been evaluated, we conclude that it is advisable to formalize the inclusion
of Nifuroxazide in the first line of therapeutic action for COVID due to SARS Cov-2 Variants.
In the short term,
It is necessary to carry out in the short term clinical studies with a significant number of
participants on the use of Nifuroxazide in COVID, its use is recommended in association with
Ivermectin, Vitamin C and an antiplatelet such as Acetylsalicylic Acid (ASA).
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6
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Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has now spread globally. Some patients develop severe complications including multiple organ failure. It has been suggested that excessive inflammation associated with the disease plays major role in the severity and mortality of COVID-19. To elucidate the inflammatory mechanisms involved in COVID-19, we examined the effects of SARS-CoV-2 spike protein S1 subunit (hereafter S1) on the pro-inflammatory responses in murine and human macrophages. Murine peritoneal exudate macrophages produced pro-inflammatory mediators in response to S1 exposure. Exposure to S1 also activated nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) signaling pathways. Pro-inflammatory cytokine induction by S1 was suppressed by selective inhibitors of NF-κB and JNK pathways. Treatment of murine peritoneal exudate macrophages and human THP-1 cell-derived macrophages with a toll-like receptor 4 (TLR4) antagonist attenuated pro-inflammatory cytokine induction and the activation of intracellular signaling by S1 and lipopolysaccharide. Similar results were obtained in experiments using TLR4 siRNA-transfected murine RAW264.7 macrophages. In contrast, TLR2 neutralizing antibodies could not abrogate the S1-induced pro-inflammatory cytokine induction in either RAW264.7 or THP-1 cell-derived macrophages. These results suggest that SARS-CoV-2 spike protein S1 subunit activates TLR4 signaling to induce pro-inflammatory responses in murine and human macrophages. Therefore, TLR4 signaling in macrophages may be a potential target for regulating excessive inflammation in COVID-19 patients.
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The occurrence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVD-19), represents a catastrophic threat to global health. Protruding from the viral surface is a densely glycosylated spike (S) protein, which engages angiotensin-converting enzyme 2 (ACE2) to mediate host cell entry. However, studies have reported viral susceptibility in intra- and extrapulmonary immune and non-immune cells lacking ACE2, suggesting that the S protein may exploit additional receptors for infection. Studies have demonstrated interactions between S protein and innate immune system, including C-lectin type receptors (CLR), toll-like receptors (TLR) and neuropilin-1 (NRP1), and the non-immune receptor glucose regulated protein 78 (GRP78). Recognition of carbohydrate moieties clustered on the surface of the S protein may drive receptor-dependent internalization, accentuate severe immunopathological inflammation, and allow for systemic spread of infection, independent of ACE2. Furthermore, targeting TLRs, CLRs, and other receptors (Ezrin and dipeptidyl peptidase-4) that do not directly engage SARS-CoV-2 S protein, but may contribute to augmented anti-viral immunity and viral clearance, may represent therapeutic targets against COVID-19.
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SUMMARY: As of December 2020, a very significant number of new cases have begun to appear worldwide, identifying that this situation is due in large part to the presence of new variants of the SARS CoV-2 virus, which initially have the characteristic identified as significantly more contagious. With the experience in the treatment of these patients since the last week of December 2020, a greater number of cases with intestinal compromise have been observed since the first days that patients start the symptoms of COVID, with the presence of semi-liquid stools or diarrhea, sometimes preceded by constipation the first 2 to 4 days, and the presence of persistent fever for more than 2 days, and whose symptoms do not show improvement with the application of the treatment regimens that we had previously established for COVID-19, therefore which has been necessary to evaluate new drugs and therapeutic schemes to provide an effective and timely solution to these cases with new characteristics and that would correspond to COVID by Variants of SARS CoV-2. MATERIAL Y METHODS: This is a cases report, which includes 10 adult patients with a diagnosis of SARS CoV-2 infection, and COVID, with the presence of fever with a temperature greater than 37.8°C for more than 2 days in a row and intestinal symptoms characterized with more often, by semi-liquid stools or diarrheal, in 2 cases preceded by constipation the first 2 to 3 days. All patients were within first 10 days counting from the date of onset of symptoms and undergoing home treatment. They had general malaise, chest pain, and respiratory symptoms of varying degrees. The levels of Oxygen Saturation were between 90 and 96%, none were with medicinal oxygen treatment or even required it. In all cases, the patients were already taking Ivermectin plus Azithromycin and/ or Levofloxacin from 3 to 6 days before starting with Nifuroxazide and Atapulgite. They also took Metamizole conditionally on the presentation of a fever greater than 38.2 °C. The following treatment protocol was indicated: - NIFUROXAZIDE 200 mg + Activated ATAPULGITE 350 mg: a drug containing Nifuroxazide and Atapulgite (Cortafan, Nifloral, Diaren, Nifurat) was prescribed. The indicated doses in adult patients were between 12 to 25 mg per kilo of weight per day, this total dose per day was divided into 2 to 4 doses during the day. In the first treated patients, doses of 400 mg were indicated. of Nifuroxazide + Atapulgite every 12 hours or 200 mg every 8 hours. In the last patients treated, a dose of 400 mg has been indicated. every 6 or every 8 hours (3 to 4 doses a day of 400 mg), with good response and tolerance. In all cases, it was indicated to take it for 4 to 6 days. From 2 days after no longer present liquid or semi-liquid stool, the indication was to give Nifuroxazide alone, without Atapulgita. These medications can be taken before or after food. - IVERMECTIN: It was indicated to continue with the 2 to 3 doses a day of 0.2 mg per kilo of body weight that they had been receiving, they completed 8 to 14 days with treatment with ivermectin, it was indicated to take the drug after meals. The variation in the number of doses per day and days of treatment is given according to the clinical response to treatment. - METAMIZOL 500 mg 1 tablet every 8 hours and conditional on the presence of fever greater than 38.2 °C. When the fever was above 39.5 °C, the indication was to resort to presentation in injectable ampoules, intramuscularly. Before starting with Nifuroxazide, 9 of the 10 patients received treatment with Azithromycin, 1 TB of 500 mg dayly for 3 a 4 days, without clinical improvement, and the fever persisted. 1 of the patients received only Levofloxaxin previously, and 3 patients first received Azithromycin and then Levofloxaxin, 1 TB of 500 or 750 mg daily for 3 to 4 days, without clinical improvement, with persistence of fever. In 6 of the 10 patients, who had diarrhea, the probiotic Enterogermina was additionally prescribed, 1 to 2 5 ml vials. orally every 12 hours for 2 to 3 days. In 5 patients, Acetyl salicylic Acid (ASA or Aspirin) in Tablets of 81 or 100 mg, 2 doses a day, after meals) were indicated for 7 to 14 days. RESULTS The 10 cases that had already been treated with Ivermectin and Metamizole and Azithromycin and/ or Levofloxacin, when given Nifuroxazide with Atapulgite, presented a significant clinical improvement, with resolution of fever and semi-liquid or liquid stools within 24 to 48 hours after starting treatment with Nifuroxazide and Atapulgita. In addition to rapid resolution of fever and intestinal symptoms, clinical improvement in general malaise, chest pain and respiratory symptoms was observed. Likewise, an improvement in Oxygen Saturation of 2 to 3% at 24 hours was observed, counting from the start of treatment with Nifuroxazide, reaching normal levels of Oxygen Saturation between 1 to 5 days after starting treatment. DISCUSSION AND CONCLUSIONS In the present cases report, a total clinical improvement of the symptoms of fever and semi-liquid or liquid stools was observed within 24 to 48 hours in the 10 patients treated with Nifuroxazide, Atapulgite, and that from 3 to 6 days before they had already been receiving treatment with Ivermectin, Metamizole and Azithromycin and/ or Levofloxacin. The fact that all cases responded favorably after a very few days with the established treatment scheme, would indicate that Nifuroxazide is an effective drug against the microorganisms that cause persistent fever and intestinal compromise in patients with COVID due to variants of the SARS CoV-2. The general improvement in all symptoms, including fever and oxygen saturation, indicates that the effect of Nifuroxazide is not limited to the intestinal level, but rather has an effect at the level of multiple organs. The results of this report support the conduct of studies with a greater number of participants. For our part, our working group has proceeded to incorporate Nifuroxazide into potential therapies in the therapeutic plan developed for COVID produced by Variants of SARS CoV-2.
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Coronavirus disease 2019 (COVID-19) pandemic has affected health care systems worldwide. Severe presentations of COVID-19 such as severe pneumonia and acute respiratory distress syndrome (ARDS) have been associated with the post-viral activation and release of cytokine/chemokines which leads to a “cytokine storm” causing inflammatory response and destruction, mainly affecting the lungs. COVID-19 activation of transcription factor, NF-kappa B (NF-κB) in various cells such as macrophages of lung, liver, kidney, central nervous system, gastrointestinal system and cardiovascular system leads to production of IL-1, IL-2, IL-6, IL-12, TNF-α, LT-α, LT-β, GM-CSF, and various chemokines. The sensitised NF-κB in elderly and in patients with metabolic syndrome makes this set of population susceptible to COVID-19 and their worse complications, including higher mortality. Immunomodulation at the level of NF-κB activation and inhibitors of NF-κB (IκB) degradation along with TNF-α inhibition will potentially result in a reduction in the cytokine storm and alleviate the severity of COVID-19. Inhibition of NF-κB pathway has a potential therapeutic role in alleviating the severe form of COVID-19.
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The current work explored the influences of nifuroxazide, an in vivo inhibitor of signal transducer and activator of transcription-3 (STAT-3) activation, on tubulointerstitial fibrosis in rats with obstructive nephropathy using unilateral ureteral obstruction (UUO) model. Thirty-two male Sprague Dawley rats were assigned into 4 groups (n = 8/group) at random. Sham and UUO groups were orally administered 0.5% carboxymethyl cellulose (CMC) (2.5 mL/kg/day), while Sham-NIF and UUO-NIF groups were treated with 20 mg/kg/day of NIF (suspended in 0.5% CMC, orally). NIF or vehicle treatments were started 2 weeks after surgery and continued for further 2 weeks. NIF treatment ameliorated kidney function in UUO rats, where it restored serum creatinine, blood urea, serum uric acid and urinary protein and albumin to near-normal levels. NIF also markedly reduced histopathological changes in tubules and glomeruli and attenuated interstitial fibrosis in UUO-ligated kidneys. Mechanistically, NIF markedly attenuated renal immunoexpression of E-cadherin and α-smooth muscle actin (α-SMA), diminished renal oxidative stress (↓ malondialdehyde (MDA) levels and ↑ superoxide dismutase (SOD) activity), lessened renal protein expression of phosphorylated-STAT3 (p-STAT-3), phosphorylated-Src (p-Src) kinase, the Abelson tyrosine kinase (c-Abl), phosphorylated nuclear factor-kappaB p65 (pNF-κB p65), decreased renal cytokine levels of transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and monocyte chemoattractant protein-1 (MCP-1) and reduced number of cluster of differentiation 68 (CD68) immunolabeled macrophages in UUO renal tissues, compared to levels in untreated UUO kidneys. Taken together, NIF treatment suppressed interstitial fibrosis in UUO renal tissues, probably via inhibiting STAT-3/NF-κB signaling and attenuating renal oxidative stress and inflammation.
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Coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has led to a pandemic since March 2020. The exact pathogenesis of SARS‐CoV‐2 and role of each component of innate and adaptive immune system is still unknown. However, available data from other corona virus families, such as SARS‐CoV and Middle East respiratory syndrome (MERS) and also new findings could be useful for better understanding of SARS‐CoV‐2. Toll‐like receptors (TLR) play an important role in recognition of viral particles and activation of innate immune system. Activation of TLR pathways lead to secretion of pro‐inflammatory cytokines, such as IL‐1, IL‐6, and TNF‐α, as well as type 1 interferon. Different TLRs, like TLR2, TLR3, TLR4, TLR6, TLR7, TLR8, and TLR9 are potentially important in COVID‐19 infection. It is also worth mentioning that we should not forget both beneficial and harmful effects of TLR in confronting COVID‐19 infection. TLRs could be a potential target in controlling the infection in early stages of disease and production of vaccine against SARS‐CoV‐2. This article is protected by copyright. All rights reserved.
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Background: Observational studies of the ongoing coronavirus disease 2019 (COVID-19) outbreak suggest that a 'cytokine storm' is involved in the pathogenesis of severe illness. However, the molecular mechanisms underlying the altered pathological inflammation in COVID-19 are largely unknown. We report here that toll-like receptor (TLR) 4-mediated inflammatory signaling molecules are upregulated in peripheral blood mononuclear cells (PBMCs) from COVID-19 patients, compared with healthy controls (HC). Methods: A total of 48 subjects including 28 COVID-19 patients (8 severe/critical vs. 20 mild/moderate cases) admitted to Chungnam National University Hospital, and age/sex-matched 20 HC were enrolled in this study. PBMCs from the subjects were processed for nCounter Human Immunology gene expression assay to analyze the immune related transcriptome profiles. Recombinant proteins of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were used to stimulate the PBMCs and monocyte-derived macrophages, and real-time polymerase chain reaction was performed to quantify the mRNA expressions of the pro-inflammatory cytokines/chemokines. Results: Among the most highly increased inflammatory mediators in severe/critically ill patients, S100A9, an alarmin and TLR4 ligand, was found as a noteworthy biomarker, because it inversely correlated with the serum albumin levels. We also observed that recombinant S2 and nucleocapsid proteins of SARS-CoV-2 significantly increased pro-inflammatory cytokines/chemokines and S100A9 in human primary PBMCs. Conclusion: These data support a link between TLR4 signaling and pathological inflammation during COVID-19 and contribute to develop therapeutic approaches through targeting TLR4-mediated inflammation.