PFIZER’S OWN DOCUMENTS STATE BOTH INHALATION AND SKIN CONTACT WILL TRANSMIT WHATEVER IS IN THE VAX FROM THE VACCINATED TO THE UN-VACCINATED

md_a

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Thread starter
Joined
Aug 31, 2015
Messages
297
I think two important methods as prevention / treatment against covid is to block the `virus` from attaching to ACE2 and to reduce the the angiotensin II type 1 receptor (AT1 receptor) in preventing the `virus` from entering the cell.

The most common complication leading to the CoV-induced mortality can be justified through ACE-AngII-AT1-Spike protein overactivation caused by virus / toxin / drugs / nocebo effect induced by media.

The spikes protein have high affinity to ACE2, uses ACE2 to enter a cell.
It is suggested that this “occupation” of the virus of ACE2 might reduce the ability of Ang II to bind to ACE2.

Accumulated Ang II result in an increased activation of AT1.

Activation of AT1 results in vasoconstriction, increased pro-inflammatory response.

If we don-t die from covid plandemic, we have a chance by blocking AT1, to become younger and healthier :).

.........

Ray:
The virus uses ACE2 (angiotensin converting enzyme 2) as receptor and enters cells by the angiotensin receptor. Losartan (recommended in China), an angiotensin blocker, is effective protection, and has many other antiinflammatory effects. The Chinese also have good results with cinanserin, a serotonin blocker. I think cyproheptadine might help, too. Progesterone lowers the angiotensin receptor, but doesn’t act immediately as losartan does.


...the angiotensin converting enzyme is one of the early parts of our immune system that sets up an inflammatory reaction that will set in action a whole chain of events, if the pathogen gets trough and is actually a treat, then you activate this proteolytic protein that create angiotensin witch is like a transmitter of a panic reaction to the organism, and it happens this coronavirus is able to bind to one of this angiotensin converting enzymes, there is one with is only pro-inflammatory and the other one that backs that up, which undoes, inhibits the inflammatory damage done by the first angiotensin producing enzyme, this is called ACE2, and ACE2 happens to be attacked by this particular virus witch binds to that enzyme, and that’s receptor its vulnerable point of organism as far this fire is concern, and binding to that ACE2 means that it leaves the ACE1 which produces angiotensin, it leaves that free to act, and ACE2 is capable in inactivating angiotensin breaking down to the first seven amino acids, they call it angiotensin 1-7, and this is a defensive anti-inflammatory peptide, so if your ACE2 is knocked out, angiotensin has a free range to cause damage, so the virus increases the inflammatory reaction by sticking to the defensive enzyme, and that enzyme combined with the virus, than acts to enter the cell by way of the angiotensin receptor which is called the AT1, that are two known receptors by which angiotensin can do damage. Angiotensin 1 is strictly an inflammation producing system, the angiotensin 2 produces somewhat defensive reactions, but it happens that the virus enzyme combination entering the cell by way of angiotensin receptor 1, AT1, and that turns on a whole range of destructive processes, nitric oxide, serotonin for example. And, so, just looking at the effects, its obvious you can defend by anything that defends you against nitric oxide and serotonin, so anti-inflammatory things are the known treatment for this kind of virus that Chinese for years have been using, cinanserin which is a serotonin blocker for other treatments, and they find that is helpful for people with the established respiratory corona infection, and losartan witch is high blood pressure drug is the most well-known blocker of angiotensin 1 receptor.. losartan is cheap and widely available. - Ray Peat
...........

The mechanistic overview of SARS-CoV-2 using angiotensin-converting enzyme 2 to enter the cell for replication: possible treatment options related to the renin–angiotensin system

Abstract


The SARS-CoV-2 pandemic is a healthcare crisis caused by insufficient knowledge applicable to effectively combat the virus. Therefore, different scientific discovery strategies need to be connected, to generate a rational treatment which can be made available as rapidly as possible. This relies on a solid theoretical understanding of the mechanisms of SARS-CoV-2 infection and host responses, which is coupled to the practical experience of clinicians that are treating patients. Because SARS-CoV-2 enters the cell by binding to angiotensin-converting enzyme 2 (ACE2), targeting ACE2 to prevent such binding seems an obvious strategy to combat infection. However, ACE2 performs its functions outside the cell and was found to enter the cell only by angiotensin II type 1 receptor (AT1R)-induced endocytosis, after which ACE2 is destroyed. This means that preventing uptake of ACE2 into the cell by blocking AT1R would be a more logical approach to limit entry of SARS-CoV-2 into the cell. Since ACE2 plays an important protective role in maintaining key biological processes, treatments should not disrupt the functional capacity of ACE2, to counterbalance the negative effects of the infection. Based on known mechanisms and knowledge of the characteristics of SARS-CoV we propose the hypothesis that the immune system facilitates SARS-CoV-2 replication which disrupts immune regulatory mechanisms. The proposed mechanism by which SARS-CoV-2 causes disease immediately suggests a possible treatment, since the AT1R is a key player in this whole process. AT1R antagonists appear to be the ideal candidate for the treatment of SARS-CoV-2 infection. AT1R antagonists counterbalance the negative consequences of angiotesnin II and, in addition, they might even be involved in preventing the cellular uptake of the virus without interfering with ACE2 function. AT1R antagonists are widely available, cheap, and safe. Therefore, we propose to consider using AT1R antagonists in the treatment of SARS-CoV-2.

Conclusion

Because SARS-CoV-2 enters the cell bound to ACE2, which induces ACE2 deficiency at the cell membrane, AngII is persistently activated. Increased AngII induces activation of AT1R, causing more uptake of SARS-CoV-2 and increasing ACE2 deficiency, thus maintaining and exacerbating a non-specific immune response, consisting of cytokine-induced inflammation.
This non-specific immune response is an attempt to reduce the viral load, while the specific immune response is mounted. Unrestrained AngII eventually causes death by respiratory distress induced by excessive inflammation and its deleterious effects on other organs. Therefore, SARS-CoV-2-induced mortality is promoted by three mechanisms: (i) increased AngII induces endocytosis of ACE2-bound SARS-CoV-2, leading to ACE2 deficiency and viral replication; (ii) ACE2 deficiency prevents the priming of an adaptive immune response by lack of NO; and (iii) Ang II induces an increase in viral load leading to an increased innate immune response and a further increase in AngII levels. Therefore, treatments should aim at preventing the AngII ‘storm’ in an early phase of the infection, restoring the modulation of NO, and preventing the entry of SARS-CoV-2 into the cell. All these mechanisms are targeted by AT1R antagonists. They may reduce morbid inflammatory distress and provide an environment to facilitate an effective, virus-specific adaptive immune response.

The mechanistic overview of SARS-CoV-2 using angiotensin-converting enzyme 2 to enter the cell for replication: possible treatment options related to the renin–angiotensin system



………


[6]-gingerol: a novel AT₁ antagonist for the treatment of cardiovascular disease

Abstract


Considering the prevalence of cardiovascular disease in public health and the limited validated therapeutic options, this study aimed to find novel compounds targeting the angiotensin II type 1 receptor, accepted as a therapeutic target in cardiovascular disease. A small library consisting of 89 compounds from 39 Chinese herbs was profiled using a cell-based calcium mobilization assay which was developed and characterized for high-throughput screening. [6]-Gingerol derived from Zingiber officinale Roscoe (ginger) was identified as a novel angiotensin II type 1 receptor antagonist, with an IC50 value of 8.173 µM. The hit was further tested by a specificity assay indicating that it had no antagonistic effects on other evaluated GPCRs, such as endothelin receptors. The major ingredient of ginger, [6]-gingerol, could inhibit angiotensin II type 1 receptor activation, which partially clarified the mechanism of ginger regulating blood pressure and strengthening heart in the cardiovascular system.

[6]-gingerol: a novel AT₁ antagonist for the treatment of cardiovascular disease - PubMed

……….

Molecular docking study of potential phytochemicals and their effects on the complex of SARS-CoV2 spike protein and human ACE2

Hesperidin is a major flavonoid compound, present in orange and lemon fruits.
470–761 mg/L of Hesperidin is normally present in orange juice31. This phytochemical exhibit various medicinal properties. According to oral toxicity study of hesperidin, it can be concluded that this phytochemical can be safely used in herbal formulations with its LD50 value more than 2000 mg/kg31. This flavanone glycoside, has a long medicinal history in both Indian and Chinese herbal medications32. This phytochemical alone or in combination with other chemicals, is often used to treat various diseases.

Emodin is a polyphenol found in the roots, bark and leaves of several plants including aloe vera, cascara, rhubarb, senna etc. In traditional medicine, emodin has been used for cardiovascular diseases and osteoporosis. It has been suggested earlier that emodin can inhibit influenza A virus replication33 via several cell signaling pathways.

Chrysin a natural flavonoid, is commonly found in propolis and honey. As reported earlier, chrysin can act as an inhibitor during enterovirus 71 (EV71) growth and replication34. Similarly, Song et al.35described antiviral activity of chrysin against coxsackievirus B3 (CVB3).

Considering the results obtained from molecular docking studies, phytochemicals hesperidin, emodin and chrysin can be used for COVID-19 treatment, after in-silico mutagenesis study and experimental verification. These phytochemicals have shown comparable spike protein inhibiting efficacy as that of known inhibitors such as chloroquine and hydroxychloroquine. From the molecular dynamics and QSAR study, it can be concluded that for ACE2 receptor protein, ligand binding activity of spike protein fragment, will be decreased noncompetitively by modulator hesperidin. So, this natural compound can show antiviral activity by destabilizing spike protein binding with human host ACE2 receptor. The modulation of hesperidin of ACE2 protein try to prevent its interaction with spike protein. It has been proved by a simple in silico experiment and the result of this experiment in shown in Supplementary Information S3.

Molecular docking study of potential phytochemicals and their effects on the complex of SARS-CoV2 spike protein and human ACE2

.........

Methylene Blue Inhibits the SARS-CoV-2 Spike–ACE2 Protein-Protein Interaction–a Mechanism that can Contribute to its Antiviral Activity Against COVID-19

As far as clinical applications, one promising indication comes from a report of a cohort of 2,500 French patients treated with MeBlu as part of their cancer care none of whom developed influenza like illness during the COVID-19 epidemics (Henry et al., 2020). MeBlu has also been explored in one Phase one clinical trial (NCT04370288) for treatment of critically ill COVID-19 patients in Iran as part of a three-drug last therapeutic option add-on cocktail (MeBlu 1 mg/kg, vitamin C 1500 mg/kg, and N-acetyl cysteine 2000 mg/kg) based on the hypothesis that this combination could rebalance NO, methemoglobin, and oxidative stress. Four of the five patients responded well to treatment (Alamdari et al., 2020).

In conclusion, screening of our organic dye-based library identified MeBlu as a low-micromolar inhibitor of the interaction between SARS-CoV-2 spike protein and its cognate receptor ACE2, a PPI that is the first critical step initiating the viral entry of this coronavirus. While MeBlu shows strong polypharmacology and might be a somewhat promiscuous PPI inhibitor, its ability to inhibit this PPI could contribute to the antiviral activity of MeBlu against SARS-CoV-2 even in the absence of light making this inexpensive and widely available drug potentially useful in the prevention and treatment of COVID-19 as an oral or inhaled medication.

Methylene Blue Inhibits the SARS-CoV-2 Spike–ACE2 Protein-Protein Interaction–a Mechanism that can Contribute to its Antiviral Activity Against COVID-19

……

Angiotensin II: A Key Player In Oxidative Stress Toxicity and Aging

We have previously referred to the impact of Ang II in ROS production. In fact, Ang II robustly stimulates the production of molecular oxygen species that trigger mitochondrial dysfunction and cellular injury (de Cavanagh et al, 2007; Wilson, 1990). Ang II via AT1 receptor stimulation can activate NAD(P)H oxidase to produce ROS, resulting in oxidative stress damage (Griendling et al, 1994). Harman has proposed that ROS are the most prominent molecular species involved in the aging process (Harman, 1956). According to his theory, ROS contribute significantly to various age-associated organ failures, including hypertension, cardiovascular diseases and renal damage (de Cavanagh et al, 2007). Hence, Ang II could be involved in organ senescence given its ability to mediate the release of oxidant species. Supporting this hypothesis, Ang II-induced ROS production via AT1 receptor promotes the onset of vascular senescence associated with functional and structural changes of blood vessels that contribute to age-related vascular diseases (Min et al, 2009). Interestingly, homozygous mice deficient for AT1A grow-up normally and outlive their wild-type littermates by 26% (Benigni et al, 2009). These AT1A−/− mice also develop fewer aortic atherosclerotic lesions and less cardiac injury during aging. Oxidative stress is reduced in cardiomyocytes, aortas and kidneys from mice lacking AT1A receptor with respect to aged wild-type mice and ultrastructural analysis of mitochondria in proximal renal tubular cells show that AT1A−/− mice have an increased number of mitochondria (Benigni et al, 2009). Extension of lifespan is associated with upregulation of pro-survival genes including nicotinamide phosphoribosyltransferase (Nampt) and Sirtuin 3 (Sirt3) (but not Sirtuin 1) in the kidney from these mice (Benigni et al, 2009). Importantly, candesartan prevents Ang II-induced Nampt and Sirt3 mRNA down-regulation in cultured tubular epithelial cells indicating a possible molecular link between Ang II, AT1A and these survival genes. The effects in longevity observed in AT1A-deficient mice are likely the consequence of reduced mitochondrial damage due to attenuation of oxidative stress and the increased expression of Nampt and Sirt3 survival genes (Fig 3). Our results shed light on early reports that showed favourable effects of chronic long-term Ang II inhibition by either ACEi or ARBs in protecting rats from the deleterious effects of aging on cardiovascular system and prolonging life span (Basso et al, 2007). Other studies implicate the AT1 receptors in ROS-induced damage and aging; old mice lacking AT1 receptors also do not develop age-related cerebral circulation damage caused by the accumulation of oxygen radicals (Modrick et al, 2009). The inhibition of RAS reverses age-related advanced myocardiac hypertrophy and fibrosis in aged spontaneously hypertensive rats, and the protective effect presumably involves the attenuation of Ang II-mediated oxidative stress, as documented by reduced expression of NAD(P)H oxidative components in the hearts of aged animals (Ito et al, 2007). Chronic treatment with ACEi or ARB reduces kidney damage associated with age, and the beneficial effect of RAS inhibition involves the preservation of renal mitochondria (Ferder et al, 2002). Enalapril and losartan treatments prevent the age-associated decline in the renal mitochondrial capacity for energy production and attenuate the age-associated increase in mitochondrial oxidant production (de Cavanagh et al, 2003). RAS inhibition exerts a similar protective effect in the liver from old rats through the maintenance of an adequate mitochondrial function due to enhanced expression of genes responsible for mitochondrial respiration and biogenesis (de Cavanagh et al, 2008).

Angiotensin II revisited: new roles in inflammation, immunology and aging

....

Serum ACE levels have been found to be significantly elevated in AIDS patients, patients in the intermediate stage of HIV infection, and patients with Pneumocystis carinii pneumonia.

Thiamine attenuates hypertension and metabolic abnormalities in spontaneously hypertensive rats (SHRs). Thiamine repletion downregulates the expression of angiotensinogen (−80%), ACE (−77%), and angiotensin type 1 receptor (−72%) mRNAs in SHRs.34 These observations suggest that thiamine affects ACE activity in HIV-infected patients.


The role of thiamine in HIV infection

..........

Down-regulation of Angiotensin AT1 Receptor by Progesterone in Human Placenta
M K Kalenga et al. J Clin Endocrinol Metab.Mar 1996
Abstract


Regulation of the angiotensin AT1 receptor in human placenta is poorly understood. In this study, we analyzed the time course of angiotensin AT1 receptor expression, internalization, and recycling by human trophoblast cells. We also studied the effects of estradiol, progesterone, and chloroquine on regulation of the angiotensin AT1 receptor in 48-h cell culture. The angiotensin II receptor expression increased with the time of incubation, reaching a level at 48 h of culture that was about 120% above the initial value. A large majority of angiotensin II receptors was of the AT1 subtype, as it was completely inhibited by losartan (1 mumol/L). The internalization of [125]angiotensin II binding and the angiotensin AT1 receptor recycling were also time dependent, with t1/2 values of 12 and 21 min, respectively. In human trophoblast cells exposed to progesterone (10 mumol/L) for 48 h, angiotensin AT1 receptor density was decreased by 49%, whereas estradiol (10 mumol/L) or chloroquine (100 mumol/L) treatment was ineffective. In the freshly isolated trophoblast cells initially treated with unlabeled angiotensin II (200 nmol/L) for 30 min, chloroquine was shown to decrease angiotensin AT1 receptor recycling by 73%, whereas estradiol and progesterone had no effect. These findings indicate that progesterone induces a down-regulation of the angiotensin AT1 receptor in human placenta and that the recycling of this receptor can be delayed by chloroquine.

Down-regulation of angiotensin AT1 receptor by progesterone in human placenta - PubMed

..........

Angiotensin II via AT1 receptor accelerates arterial thrombosis in renovascular hypertensive rats​

Abstract​

Although there are some in vitro evidence that angiotensin II (Ang II) may promote thrombosis, there is still no data concerning effect of Ang II on arterial thrombus formation. In the present study we have investigated the influence of Ang II on electrically induced arterial thrombosis in a common carotid artery of renovascular hypertensive rats. Furthermore, we examined if Ang II effect is mediated via AT1 receptor. We measured some coagulation and fibrinolytic parameters at the same time. Since platelets play crucial role in the initiation of arterial thrombosis their contribution in the mode of Ang II action was also determined. Intravenous infusion of Ang II caused significant increase in arterial thrombus weight, which was reversed by losartan, selective AT1 receptor antagonist. The prothrombotic effect of Ang II was accompanied by increase in haemostatic and decrease in fibrinolytic potential of rat plasma. While number of data has clearly demonstrated that Ang II can augment human platelets aggregation, at least in rats, platelets were not involved in the mechanism of Ang II action. Our study shows that Ang II via AT1 receptor accelerates arterial thrombosis in renovascular hypertensive rat, therefore may be considered as a risk factor of myocardial infarction or stroke.
Angiotensin II via AT1 receptor accelerates arterial thrombosis in renovascular hypertensive rats - PubMed

........

Nocebo Effect

The nocebo effect, the opposite of the placebo effect, is a negative reaction caused by a non-medicated control substance, such as a sugar pill. In the placebo effect, a patient experiences the benefits of a medicine under trial, without receiving the medicine. This is thought to be caused by the underlying belief of the patient that the treatment they are receiving will bring beneficial effects. The nocebo effect is similar, in that the patient’s expected outcomes can manifest real symptoms. Often, the nocebo effect is observed when patients are told potential side-effects of a drug, but are only given the placebo, or non-medicated treatment. If patients manifest the side-effects they were told about and never took the drug, this is a clear example of the nocebo effect.

The placebo and nocebo effect have similar causes. In both cases, the body is reacting to what the mind expects. While doctors and scientists first denied the mind’s ability to manifest symptoms or cures, the effect is well documented, as is its counterpart. Apparently, a patient’s expectations can be just as damaging as real chemicals which are introduced to the body. This has been documented in a number of clinical trials, and the nocebo effect itself can introduce a wide array of symptoms, or even increase the symptoms already present.

Nocebo Effect
 

Pina

Member
Joined
Oct 12, 2020
Messages
234
I think two important methods as prevention / treatment against covid is to block the `virus` from attaching to ACE2 and to reduce the the angiotensin II type 1 receptor (AT1 receptor) in preventing the `virus` from entering the cell.

The most common complication leading to the CoV-induced mortality can be justified through ACE-AngII-AT1-Spike protein overactivation caused by virus / toxin / drugs / nocebo effect induced by media.

The spikes protein have high affinity to ACE2, uses ACE2 to enter a cell.
It is suggested that this “occupation” of the virus of ACE2 might reduce the ability of Ang II to bind to ACE2.

Accumulated Ang II result in an increased activation of AT1.

Activation of AT1 results in vasoconstriction, increased pro-inflammatory response.

If we don-t die from covid plandemic, we have a chance by blocking AT1, to become younger and healthier :).

.........

Ray:
The virus uses ACE2 (angiotensin converting enzyme 2) as receptor and enters cells by the angiotensin receptor. Losartan (recommended in China), an angiotensin blocker, is effective protection, and has many other antiinflammatory effects. The Chinese also have good results with cinanserin, a serotonin blocker. I think cyproheptadine might help, too. Progesterone lowers the angiotensin receptor, but doesn’t act immediately as losartan does.


...the angiotensin converting enzyme is one of the early parts of our immune system that sets up an inflammatory reaction that will set in action a whole chain of events, if the pathogen gets trough and is actually a treat, then you activate this proteolytic protein that create angiotensin witch is like a transmitter of a panic reaction to the organism, and it happens this coronavirus is able to bind to one of this angiotensin converting enzymes, there is one with is only pro-inflammatory and the other one that backs that up, which undoes, inhibits the inflammatory damage done by the first angiotensin producing enzyme, this is called ACE2, and ACE2 happens to be attacked by this particular virus witch binds to that enzyme, and that’s receptor its vulnerable point of organism as far this fire is concern, and binding to that ACE2 means that it leaves the ACE1 which produces angiotensin, it leaves that free to act, and ACE2 is capable in inactivating angiotensin breaking down to the first seven amino acids, they call it angiotensin 1-7, and this is a defensive anti-inflammatory peptide, so if your ACE2 is knocked out, angiotensin has a free range to cause damage, so the virus increases the inflammatory reaction by sticking to the defensive enzyme, and that enzyme combined with the virus, than acts to enter the cell by way of the angiotensin receptor which is called the AT1, that are two known receptors by which angiotensin can do damage. Angiotensin 1 is strictly an inflammation producing system, the angiotensin 2 produces somewhat defensive reactions, but it happens that the virus enzyme combination entering the cell by way of angiotensin receptor 1, AT1, and that turns on a whole range of destructive processes, nitric oxide, serotonin for example. And, so, just looking at the effects, its obvious you can defend by anything that defends you against nitric oxide and serotonin, so anti-inflammatory things are the known treatment for this kind of virus that Chinese for years have been using, cinanserin which is a serotonin blocker for other treatments, and they find that is helpful for people with the established respiratory corona infection, and losartan witch is high blood pressure drug is the most well-known blocker of angiotensin 1 receptor.. losartan is cheap and widely available. - Ray Peat
...........

The mechanistic overview of SARS-CoV-2 using angiotensin-converting enzyme 2 to enter the cell for replication: possible treatment options related to the renin–angiotensin system

Abstract


The SARS-CoV-2 pandemic is a healthcare crisis caused by insufficient knowledge applicable to effectively combat the virus. Therefore, different scientific discovery strategies need to be connected, to generate a rational treatment which can be made available as rapidly as possible. This relies on a solid theoretical understanding of the mechanisms of SARS-CoV-2 infection and host responses, which is coupled to the practical experience of clinicians that are treating patients. Because SARS-CoV-2 enters the cell by binding to angiotensin-converting enzyme 2 (ACE2), targeting ACE2 to prevent such binding seems an obvious strategy to combat infection. However, ACE2 performs its functions outside the cell and was found to enter the cell only by angiotensin II type 1 receptor (AT1R)-induced endocytosis, after which ACE2 is destroyed. This means that preventing uptake of ACE2 into the cell by blocking AT1R would be a more logical approach to limit entry of SARS-CoV-2 into the cell. Since ACE2 plays an important protective role in maintaining key biological processes, treatments should not disrupt the functional capacity of ACE2, to counterbalance the negative effects of the infection. Based on known mechanisms and knowledge of the characteristics of SARS-CoV we propose the hypothesis that the immune system facilitates SARS-CoV-2 replication which disrupts immune regulatory mechanisms. The proposed mechanism by which SARS-CoV-2 causes disease immediately suggests a possible treatment, since the AT1R is a key player in this whole process. AT1R antagonists appear to be the ideal candidate for the treatment of SARS-CoV-2 infection. AT1R antagonists counterbalance the negative consequences of angiotesnin II and, in addition, they might even be involved in preventing the cellular uptake of the virus without interfering with ACE2 function. AT1R antagonists are widely available, cheap, and safe. Therefore, we propose to consider using AT1R antagonists in the treatment of SARS-CoV-2.

Conclusion

Because SARS-CoV-2 enters the cell bound to ACE2, which induces ACE2 deficiency at the cell membrane, AngII is persistently activated. Increased AngII induces activation of AT1R, causing more uptake of SARS-CoV-2 and increasing ACE2 deficiency, thus maintaining and exacerbating a non-specific immune response, consisting of cytokine-induced inflammation.
This non-specific immune response is an attempt to reduce the viral load, while the specific immune response is mounted. Unrestrained AngII eventually causes death by respiratory distress induced by excessive inflammation and its deleterious effects on other organs. Therefore, SARS-CoV-2-induced mortality is promoted by three mechanisms: (i) increased AngII induces endocytosis of ACE2-bound SARS-CoV-2, leading to ACE2 deficiency and viral replication; (ii) ACE2 deficiency prevents the priming of an adaptive immune response by lack of NO; and (iii) Ang II induces an increase in viral load leading to an increased innate immune response and a further increase in AngII levels. Therefore, treatments should aim at preventing the AngII ‘storm’ in an early phase of the infection, restoring the modulation of NO, and preventing the entry of SARS-CoV-2 into the cell. All these mechanisms are targeted by AT1R antagonists. They may reduce morbid inflammatory distress and provide an environment to facilitate an effective, virus-specific adaptive immune response.

The mechanistic overview of SARS-CoV-2 using angiotensin-converting enzyme 2 to enter the cell for replication: possible treatment options related to the renin–angiotensin system



………


[6]-gingerol: a novel AT₁ antagonist for the treatment of cardiovascular disease

Abstract


Considering the prevalence of cardiovascular disease in public health and the limited validated therapeutic options, this study aimed to find novel compounds targeting the angiotensin II type 1 receptor, accepted as a therapeutic target in cardiovascular disease. A small library consisting of 89 compounds from 39 Chinese herbs was profiled using a cell-based calcium mobilization assay which was developed and characterized for high-throughput screening. [6]-Gingerol derived from Zingiber officinale Roscoe (ginger) was identified as a novel angiotensin II type 1 receptor antagonist, with an IC50 value of 8.173 µM. The hit was further tested by a specificity assay indicating that it had no antagonistic effects on other evaluated GPCRs, such as endothelin receptors. The major ingredient of ginger, [6]-gingerol, could inhibit angiotensin II type 1 receptor activation, which partially clarified the mechanism of ginger regulating blood pressure and strengthening heart in the cardiovascular system.

[6]-gingerol: a novel AT₁ antagonist for the treatment of cardiovascular disease - PubMed

……….

Molecular docking study of potential phytochemicals and their effects on the complex of SARS-CoV2 spike protein and human ACE2

Hesperidin is a major flavonoid compound, present in orange and lemon fruits.
470–761 mg/L of Hesperidin is normally present in orange juice31. This phytochemical exhibit various medicinal properties. According to oral toxicity study of hesperidin, it can be concluded that this phytochemical can be safely used in herbal formulations with its LD50 value more than 2000 mg/kg31. This flavanone glycoside, has a long medicinal history in both Indian and Chinese herbal medications32. This phytochemical alone or in combination with other chemicals, is often used to treat various diseases.

Emodin is a polyphenol found in the roots, bark and leaves of several plants including aloe vera, cascara, rhubarb, senna etc. In traditional medicine, emodin has been used for cardiovascular diseases and osteoporosis. It has been suggested earlier that emodin can inhibit influenza A virus replication33 via several cell signaling pathways.

Chrysin a natural flavonoid, is commonly found in propolis and honey. As reported earlier, chrysin can act as an inhibitor during enterovirus 71 (EV71) growth and replication34. Similarly, Song et al.35described antiviral activity of chrysin against coxsackievirus B3 (CVB3).

Considering the results obtained from molecular docking studies, phytochemicals hesperidin, emodin and chrysin can be used for COVID-19 treatment, after in-silico mutagenesis study and experimental verification. These phytochemicals have shown comparable spike protein inhibiting efficacy as that of known inhibitors such as chloroquine and hydroxychloroquine. From the molecular dynamics and QSAR study, it can be concluded that for ACE2 receptor protein, ligand binding activity of spike protein fragment, will be decreased noncompetitively by modulator hesperidin. So, this natural compound can show antiviral activity by destabilizing spike protein binding with human host ACE2 receptor. The modulation of hesperidin of ACE2 protein try to prevent its interaction with spike protein. It has been proved by a simple in silico experiment and the result of this experiment in shown in Supplementary Information S3.

Molecular docking study of potential phytochemicals and their effects on the complex of SARS-CoV2 spike protein and human ACE2

.........

Methylene Blue Inhibits the SARS-CoV-2 Spike–ACE2 Protein-Protein Interaction–a Mechanism that can Contribute to its Antiviral Activity Against COVID-19

As far as clinical applications, one promising indication comes from a report of a cohort of 2,500 French patients treated with MeBlu as part of their cancer care none of whom developed influenza like illness during the COVID-19 epidemics (Henry et al., 2020). MeBlu has also been explored in one Phase one clinical trial (NCT04370288) for treatment of critically ill COVID-19 patients in Iran as part of a three-drug last therapeutic option add-on cocktail (MeBlu 1 mg/kg, vitamin C 1500 mg/kg, and N-acetyl cysteine 2000 mg/kg) based on the hypothesis that this combination could rebalance NO, methemoglobin, and oxidative stress. Four of the five patients responded well to treatment (Alamdari et al., 2020).

In conclusion, screening of our organic dye-based library identified MeBlu as a low-micromolar inhibitor of the interaction between SARS-CoV-2 spike protein and its cognate receptor ACE2, a PPI that is the first critical step initiating the viral entry of this coronavirus. While MeBlu shows strong polypharmacology and might be a somewhat promiscuous PPI inhibitor, its ability to inhibit this PPI could contribute to the antiviral activity of MeBlu against SARS-CoV-2 even in the absence of light making this inexpensive and widely available drug potentially useful in the prevention and treatment of COVID-19 as an oral or inhaled medication.

Methylene Blue Inhibits the SARS-CoV-2 Spike–ACE2 Protein-Protein Interaction–a Mechanism that can Contribute to its Antiviral Activity Against COVID-19

……

Angiotensin II: A Key Player In Oxidative Stress Toxicity and Aging

We have previously referred to the impact of Ang II in ROS production. In fact, Ang II robustly stimulates the production of molecular oxygen species that trigger mitochondrial dysfunction and cellular injury (de Cavanagh et al, 2007; Wilson, 1990). Ang II via AT1 receptor stimulation can activate NAD(P)H oxidase to produce ROS, resulting in oxidative stress damage (Griendling et al, 1994). Harman has proposed that ROS are the most prominent molecular species involved in the aging process (Harman, 1956). According to his theory, ROS contribute significantly to various age-associated organ failures, including hypertension, cardiovascular diseases and renal damage (de Cavanagh et al, 2007). Hence, Ang II could be involved in organ senescence given its ability to mediate the release of oxidant species. Supporting this hypothesis, Ang II-induced ROS production via AT1 receptor promotes the onset of vascular senescence associated with functional and structural changes of blood vessels that contribute to age-related vascular diseases (Min et al, 2009). Interestingly, homozygous mice deficient for AT1A grow-up normally and outlive their wild-type littermates by 26% (Benigni et al, 2009). These AT1A−/− mice also develop fewer aortic atherosclerotic lesions and less cardiac injury during aging. Oxidative stress is reduced in cardiomyocytes, aortas and kidneys from mice lacking AT1A receptor with respect to aged wild-type mice and ultrastructural analysis of mitochondria in proximal renal tubular cells show that AT1A−/− mice have an increased number of mitochondria (Benigni et al, 2009). Extension of lifespan is associated with upregulation of pro-survival genes including nicotinamide phosphoribosyltransferase (Nampt) and Sirtuin 3 (Sirt3) (but not Sirtuin 1) in the kidney from these mice (Benigni et al, 2009). Importantly, candesartan prevents Ang II-induced Nampt and Sirt3 mRNA down-regulation in cultured tubular epithelial cells indicating a possible molecular link between Ang II, AT1A and these survival genes. The effects in longevity observed in AT1A-deficient mice are likely the consequence of reduced mitochondrial damage due to attenuation of oxidative stress and the increased expression of Nampt and Sirt3 survival genes (Fig 3). Our results shed light on early reports that showed favourable effects of chronic long-term Ang II inhibition by either ACEi or ARBs in protecting rats from the deleterious effects of aging on cardiovascular system and prolonging life span (Basso et al, 2007). Other studies implicate the AT1 receptors in ROS-induced damage and aging; old mice lacking AT1 receptors also do not develop age-related cerebral circulation damage caused by the accumulation of oxygen radicals (Modrick et al, 2009). The inhibition of RAS reverses age-related advanced myocardiac hypertrophy and fibrosis in aged spontaneously hypertensive rats, and the protective effect presumably involves the attenuation of Ang II-mediated oxidative stress, as documented by reduced expression of NAD(P)H oxidative components in the hearts of aged animals (Ito et al, 2007). Chronic treatment with ACEi or ARB reduces kidney damage associated with age, and the beneficial effect of RAS inhibition involves the preservation of renal mitochondria (Ferder et al, 2002). Enalapril and losartan treatments prevent the age-associated decline in the renal mitochondrial capacity for energy production and attenuate the age-associated increase in mitochondrial oxidant production (de Cavanagh et al, 2003). RAS inhibition exerts a similar protective effect in the liver from old rats through the maintenance of an adequate mitochondrial function due to enhanced expression of genes responsible for mitochondrial respiration and biogenesis (de Cavanagh et al, 2008).

Angiotensin II revisited: new roles in inflammation, immunology and aging

....

Serum ACE levels have been found to be significantly elevated in AIDS patients, patients in the intermediate stage of HIV infection, and patients with Pneumocystis carinii pneumonia.

Thiamine attenuates hypertension and metabolic abnormalities in spontaneously hypertensive rats (SHRs). Thiamine repletion downregulates the expression of angiotensinogen (−80%), ACE (−77%), and angiotensin type 1 receptor (−72%) mRNAs in SHRs.34 These observations suggest that thiamine affects ACE activity in HIV-infected patients.


The role of thiamine in HIV infection

..........

Down-regulation of Angiotensin AT1 Receptor by Progesterone in Human Placenta
M K Kalenga et al. J Clin Endocrinol Metab.Mar 1996
Abstract


Regulation of the angiotensin AT1 receptor in human placenta is poorly understood. In this study, we analyzed the time course of angiotensin AT1 receptor expression, internalization, and recycling by human trophoblast cells. We also studied the effects of estradiol, progesterone, and chloroquine on regulation of the angiotensin AT1 receptor in 48-h cell culture. The angiotensin II receptor expression increased with the time of incubation, reaching a level at 48 h of culture that was about 120% above the initial value. A large majority of angiotensin II receptors was of the AT1 subtype, as it was completely inhibited by losartan (1 mumol/L). The internalization of [125]angiotensin II binding and the angiotensin AT1 receptor recycling were also time dependent, with t1/2 values of 12 and 21 min, respectively. In human trophoblast cells exposed to progesterone (10 mumol/L) for 48 h, angiotensin AT1 receptor density was decreased by 49%, whereas estradiol (10 mumol/L) or chloroquine (100 mumol/L) treatment was ineffective. In the freshly isolated trophoblast cells initially treated with unlabeled angiotensin II (200 nmol/L) for 30 min, chloroquine was shown to decrease angiotensin AT1 receptor recycling by 73%, whereas estradiol and progesterone had no effect. These findings indicate that progesterone induces a down-regulation of the angiotensin AT1 receptor in human placenta and that the recycling of this receptor can be delayed by chloroquine.

Down-regulation of angiotensin AT1 receptor by progesterone in human placenta - PubMed

..........

Angiotensin II via AT1 receptor accelerates arterial thrombosis in renovascular hypertensive rats​

Abstract​

Although there are some in vitro evidence that angiotensin II (Ang II) may promote thrombosis, there is still no data concerning effect of Ang II on arterial thrombus formation. In the present study we have investigated the influence of Ang II on electrically induced arterial thrombosis in a common carotid artery of renovascular hypertensive rats. Furthermore, we examined if Ang II effect is mediated via AT1 receptor. We measured some coagulation and fibrinolytic parameters at the same time. Since platelets play crucial role in the initiation of arterial thrombosis their contribution in the mode of Ang II action was also determined. Intravenous infusion of Ang II caused significant increase in arterial thrombus weight, which was reversed by losartan, selective AT1 receptor antagonist. The prothrombotic effect of Ang II was accompanied by increase in haemostatic and decrease in fibrinolytic potential of rat plasma. While number of data has clearly demonstrated that Ang II can augment human platelets aggregation, at least in rats, platelets were not involved in the mechanism of Ang II action. Our study shows that Ang II via AT1 receptor accelerates arterial thrombosis in renovascular hypertensive rat, therefore may be considered as a risk factor of myocardial infarction or stroke.
Angiotensin II via AT1 receptor accelerates arterial thrombosis in renovascular hypertensive rats - PubMed

........

Nocebo Effect

The nocebo effect, the opposite of the placebo effect, is a negative reaction caused by a non-medicated control substance, such as a sugar pill. In the placebo effect, a patient experiences the benefits of a medicine under trial, without receiving the medicine. This is thought to be caused by the underlying belief of the patient that the treatment they are receiving will bring beneficial effects. The nocebo effect is similar, in that the patient’s expected outcomes can manifest real symptoms. Often, the nocebo effect is observed when patients are told potential side-effects of a drug, but are only given the placebo, or non-medicated treatment. If patients manifest the side-effects they were told about and never took the drug, this is a clear example of the nocebo effect.

The placebo and nocebo effect have similar causes. In both cases, the body is reacting to what the mind expects. While doctors and scientists first denied the mind’s ability to manifest symptoms or cures, the effect is well documented, as is its counterpart. Apparently, a patient’s expectations can be just as damaging as real chemicals which are introduced to the body. This has been documented in a number of clinical trials, and the nocebo effect itself can introduce a wide array of symptoms, or even increase the symptoms already present.

Nocebo Effect
Do you think Losartan is superior for achieving this than Telmisartan? Dr Peat seems to mention Losartan more than Telmisartan.
 

Nemo

Member
Joined
Jul 8, 2019
Messages
675
Wrong, so very wrong.

"Study Intervention" refers to the vaccine itself, not the test subjects. It's spelled out clearly on Page 45-



That is clearly NOT the test subject. You also changed the text of 8.3.5.3. in regards to occupational exposure (page 69)-



That clearly says "study intervention," not "vaccine test subject." And I posted the definition of "Study Intervention" above.

That means unplanned direct contact with the investigational interventions (the vaccine), marketed products, placebo, or medical devices (say, a needle or syringe). Certainly NOT an unplanned handshake, or simply breathing the air of someone who walks by. No mention of "super spreaders."

It would also make sense why this would need to be reported.

Is this whole freakout related to the fact that people didn't actually look up the definition of "study intervention" in the document?

The document clearly says they collected evidence of environmental transmission.

The question is whether the document can be trusted.

If you go there, I can go with you.
 

tankasnowgod

Member
Joined
Jan 25, 2014
Messages
5,498
The document clearly says they collected evidence of environmental transmission.

The question is whether the document can be trusted.

If you go there, I can go with you.

Where in the document does it say this? Do you have a section or page number? Can you post the paragraph here?

It's not in the section mentioned in the OP, as the OP changed "study intervention" to "vaccine test subject," which is not how the document defined "study intervention."

I'd be happy to discuss if you can reference the section you are referring to.
 

mayku-T-meelo

Member
Joined
Sep 24, 2016
Messages
44
I doubt Pfizer would just self-sabotage itself like that, but it's more to protect itself. And I'm not saying such shedding transmission is not possible, because I don't know, but the capslock title is in fact misleading and equating participants by OP with vaccines even more (participants are participants in the text). I also don't clearly understand the motivations of the OP saying SAE is an event when someone has had adverse reactions from being exposed to a vaccinated person, when in fact the definition in the document is death from adverse events - reactions. It could be either death from AE from participant or the personnel that administers the vaccines (or some third person for that matter if the shedding is happening).

However again, the text in the document itself could be read as it is suggested from the OP, but with a lot of a stretch and it's definitely not specific enough to meet the criteria and to accuse Pfizer directly this way. It's just a note on how to report adverse reactions, if they happen. You could start reading in between the lines, but formally those are just legal notes that are there to protect Pfizer from responsibility, if such second hand exposures happen (from staff mishandling the vaccine, breaking the vial, squrting "the juice" or something else, I guess shedding included). This way nobody can accuse them that they didn't consider such scenario. The more potentially concerning part is "however, a copy of the completed VaccineSAE Report Form is maintained in the investigator site file." They keep those records separate from the case, which makes sense, but they don't include them in the report? They are only reported to Pfizer? What is investigator site file?

Also for me more concerning lines are in fact those about exposure during pregnancy, which seem to suggest that close contact between a vaccinated spouse and the pregnant wife is not at all safe and in that light the previous paragraphs - where those kind of adverse reactions are not necessarily reported and if they are, they are saved separately - could be read retroactively very differently.
 

tankasnowgod

Member
Joined
Jan 25, 2014
Messages
5,498
However again, the text in the document itself could be read as it is suggested from the OP,

It actually can't. Section 8.3.5.3 was talking about unplanned contact with the "Study Intervention,"which means the vaccine or placebo. Like if a nurse got an accidental needle stick, or a vial broke and the liquid came into direct contact with the skin. The OP misquotes the document, and gives a different definition to "Study Intervention." It's a deliberate misrepresentation of what the Pfizer document clearly states.
 

mayku-T-meelo

Member
Joined
Sep 24, 2016
Messages
44
It actually can't. Section 8.3.5.3 was talking about unplanned contact with the "Study Intervention,"which means the vaccine or placebo. Like if a nurse got an accidental needle stick, or a vial broke and the liquid came into direct contact with the skin. The OP misquotes the document, and gives a different definition to "Study Intervention." It's a deliberate misrepresentation of what the Pfizer document clearly states.
True. I can't argue, because formally study intervention means that and misrepresenting by the OP is definitely causing confusion and I'm amused he doesn't chime in to comment on his reasons.

Although, looking at the document, next paragraphs mention a possibility of exposure during pregnancy and occupational exposure and that in those cases that should be reported to Pfizer, but it should not be included in the CRF (case report form), just as in the case of those accidental exposures to "study interventions" during the vaccination process. Which again makes sense, but leaves me with an open question on where are those reports published. What's that "investigator site file"?

"When exposure during breastfeeding occurs in the setting of environmental exposure, the exposure information does not pertain to the participant enrolled in the study, so the information is not recorded on a CRF. However, a copy of the completed Vaccine SAE Report Form is maintained in the investigator site file."
 

sun-maid

Member
Joined
Sep 19, 2019
Messages
92
I think the pdf document OP link is just to protect Pfizer from potential lawsuit if something go wrong and to give clear instruction to people in case of a pregnancy or wtv. It really doesnt say anything as a fact. I'm sure you would find similar sentence in a study for a skin care product.
 

StephanF

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Jul 8, 2014
Messages
270
Location
Reno
A Quick search and you will fund it on their page. But i dont know about the interpretation. But clearly they count on people transmitting via breathing or skin contact.
Hi Canti, I finally got to read through the whole document. This is really concerning! But I wonder if this is ‘just some lawyer language’, so they include this to avert legal issues. Did Pfizer or other vaccine manufacturers add similar language for ‘normal’ vaccines, for example the yearly flu vaccines? It would be interesting to see if this statement of shedding and infecting other non-vaccinated is completely new and solely for the mRNA vaccines.

On one of the last the Corona-Ausschuss sessions, they went over other vaccines that seem to be in the pipeline. Self-amplifying vaccines or purposely shedding vaccines. My god, what else will they come up with?
 
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