European Heart Journal, Volume 41, Issue 32, 21 August 2020, Pages 3038–3044
The vascular endothelium provides the crucial interface between the blood compartment and tissues, and displays a series of remarkable properties that normally maintain homeostasis. This tightly regulated palette of functions includes control of haemostasis, fibrinolysis, vasomotion, inflammation, oxidative stress, vascular permeability, and structure. While these functions participate in the moment-to-moment regulation of the circulation and coordinate many host defence mechanisms, they can also contribute to disease when their usually homeostatic and defensive functions over-reach and turn against the host. SARS-CoV-2, the aetiological agent of COVID-19, causes the current pandemic. It produces protean manifestations ranging from head to toe, wreaking seemingly indiscriminate havoc on multiple organ systems including the lungs, heart, brain, kidney, and vasculature. This essay explores the hypothesis that COVID-19, particularly in the later complicated stages, represents an endothelial disease. Cytokines, protein pro-inflammatory mediators, serve as key danger signals that shift endothelial functions from the homeostatic into the defensive mode. The endgame of COVID-19 usually involves a cytokine storm, a phlogistic phenomenon fed by well-understood positive feedback loops that govern cytokine production and overwhelm counter-regulatory mechanisms. The concept of COVID-19 as an endothelial disease provides a unifying pathophysiological picture of this raging infection, and also provides a framework for a rational treatment strategy at a time when we possess an indeed modest evidence base to guide our therapeutic attempts to confront this novel pandemic.
Free full text.
https://www.thetimes.co.uk/article/spin ... -rc2txfw6g
Swiss Policy Research
On the treatment of Covid-19
Published: July 2, 2020; Updated: September 4, 2020
Languages: DE, EN; Share on: Twitter / Facebook
Immunological and serological studies show that most people develop no symptoms or only mild symptoms when infected with the new
oronavirus, while some people may experience a more pronounced or critical course of the disease.
Based on the available scientific evidence and current clinical experience, the SPR Collaboration recommends that physicians and authorities consider the following Covid-19 treatment protocol for the early treatment of people at high risk or high exposure (see references below).
Note: Patients are asked to consult a doctor.
1. Zinc (50mg to 100mg per day)
2. Quercetin (500mg to 1000mg per day)
3. Bromhexine (25mg to 50mg per day)
4. Vitamins C (1000mg) and D (2000 u/d)
1. Zinc (75mg to 150mg per day)
2. Quercetin (500mg to 1500mg per day)
3. Bromhexine (50mg to 75mg per day)
4. Vitamins C (1000mg) and D (4000 u/d)
Ancillary (prescription only)
1. Hydroxychloroquine (400mg per day)
2. High-dose vitamin D (1x 100,000 IU)
3. Azithromycin (up to 500mg per day)
4. Heparin (usual dosage)
Note: Contraindications for HCQ (e.g. favism or heart disease) must be observed.
Addendum: Other prescription drugs with first reported successes in the early medical treatment of Covid-19 are ivermectin (read more) and favipiravir (read more).
Zinc/HCQ/AZ: US physicians reported an 84% decrease in hospitalization rates, a 50% decrease in mortality rates among already hospitalized patients (if treated early), and an improvement in the condition of patients within 8 to 12 hours. Italian doctors reported a decrease in deaths of 66%.
US physicians also reported a 45% reduction in mortality of hospitalized patients by adding zinc to HCQ/AZ. Another US study reported a rapid resolution of Covid symptoms, such as shortness of breath, based on early outpatient treatment with high-dose zinc.
Bromhexine: Iranian doctors reported in a study with 78 patients a decrease in intensive care treatments of 82%, a decrease in intubations of 89%, and a decrease in deaths of 100%. Chinese doctors reported a 50% reduction in intubations. Bromhexine is a mucolytic cough medication.
Vitamin D: In a Spanish randomized controlled trial (RCT), high-dose vitamine D (100,000 IU) reduced the risk of requiring intensive care by 96%. A large Israeli study found a strong link between vitamin D deficiency and covid-19 severity.
For more results, see the scientific references below.
Mechanisms of action
Zinc inhibits RNA polymerase activity of coronaviruses and thus blocks virus replication. Hydroxychloroquine and quercetin support the cellular absorption of zinc and have additional anti-viral properties. Bromhexine inhibits the expression of the cellular TMPRSS2 protease and thus the entry of the virus into the cell. Azithromycin prevents bacterial superinfections. Heparin prevents infection-related thromboses and embolisms in patients at risk. (See scientific references below).
See also: Illustration of the mechanisms of action of HCQ, quercetin and bromhexine
The early treatment of patients as soon as the first typical symptoms appear and even without a PCR test is essential to prevent progression of the disease. Zinc, HCQ, quercetin and bromhexin may also be used prophylactically for people at high risk or high exposure (e.g. for health care workers).
In contrast, isolating infected high-risk patients at home and without early treatment until they develop serious respiratory problems, as often happened during lockdowns, may be detrimental.
The alleged or actual negative results with hydroxychloroquine in some studies were based on delayed use (intensive care patients), excessive doses (up to 2400mg per day), manipulated data sets (the Surgisphere scandal), or ignored contraindications (e.g., favism or heart disease).
Early treatment based on the above protocol is intended to avoid hospitalization. If hospitalization nevertheless becomes necessary, experienced ICU doctors recommend avoiding invasive ventilation (intubation) whenever possible and using oxygen therapy (HFNC) instead.
It is conceivable that the above treatment protocol, which is simple, safe and inexpensive, could render more complex medications, vaccinations, and other measures largely obsolete.
The efficacy of HCQ against SARS coronaviruses was established in 2005 in the wake of the SARS-1 epidemic. The efficacy of zinc in blocking RNA replication of coronaviruses was discovered in 2010 by world-leading SARS virologist Ralph Baric. The efficacy of HCQ in supporting the cellular uptake of zinc was discovered in 2014 as part of cancer research. The efficacy of the flavonoid quercetin in supporting the cellular uptake of zinc was also discovered in 2014. The efficacy of bromhexine in blocking cell entry of coronaviruses was established in 2017.
Stages of covid disease (EVMS)
• EVMS Critical Care Covid-19 Management Protocol (Paul Marik, MD, June 2020)
1. Study: Effect of Zinc Salts on Respiratory Syncytial Virus Replication (Suara & Crowe, AAC, 2004)
2. Study: Zinc Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture (Velthuis et al, PLOS Path, 2010)
3. Study: Zinc for the common cold (Cochrane Systematic Review, 2013)
4. Study: Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients (Carlucci et al., MedRxiv, May 2020)
5. Study: Treatment of SARS-CoV-2 with high dose oral zinc salts: A report on four patients (Eric Finzi, International Journal of Infectious Diseases, June 2020)
6. Review: Does zinc supplementation enhance the clinical efficacy of chloroquine/ hydroxychloroquine to win today’s battle against COVID-19? (Derwand & Scholz, MH, 2020)
7. Review: Zinc supplementation to improve treatment outcomes among children diagnosed with respiratory infections (WHO, Technical Report, 2011)
8. Article: Can Zinc Lozenges Help with Coronavirus Infections? (McGill University, March 2020)
1. Study: Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells (Ling Yi et al., Journal of Virology, 2004)
2. Study: Zinc Ionophore Activity of Quercetin and Epigallocatechin-gallate: From Hepa 1-6 Cells to a Liposome Model (Dabbagh et al., JAFC, 2014)
3. Study: Quercetin as an Antiviral Agent Inhibits Influenza A Virus Entry (Wu et al, Viruses, 2016)
4. Study: Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (Biancatelli et al, Front. in Immun., June 2020)
5. Report: EVMS Critical Care Covid-19 Management Protocol (Paul Marik, MD, June 2020)
1. Study: TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections (Wen Shen et al., Biochimie Journal, 2017)
2. Letter: Repurposing the mucolytic cough suppressant and TMPRSS2 protease inhibitor bromhexine for the prevention and management of SARS-CoV-2 infection (Maggio and Corsini, Pharmacological Research, April 2020)
3. Study: Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy? (Depfenhart et al., Internal and Emergency Medicine, May 2020)
4. Study: Bromhexine Hydrochloride: Potential Approach to Prevent or Treat Early Stage COVID-19 (Stepanov and Lierz, Journal of Infectious Diseases and Epidemiology, June 2020)
5. Study: TMPRSS2 inhibitors, Bromhexine, Aprotinin, Camostat and Nafamostat as potential treatments for COVID-19 (Arsalan Azimi, Drug Target Review, June 2020)
6. Trial: Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: A randomized clinical trial (Ansarin et al., BioImpacts, July 2020): “There was a significant reduction in ICU admissions (2 out of 39 vs. 11 out of 39), intubation (1 out of 39 vs. 9 out of 39) and death (0 vs. 5) in the bromhexine treated group compared to the standard group.”
1. Studies: Overview of more than 50 international HCQ studies (C19Study.com)
2. Study: Chloroquine is a potent inhibitor of SARS coronavirus infection and spread (Vincent et al., Virology Journal, 2005)
3. Study: Chloroquine Is a Zinc Ionophore (Xue et al, PLOS One, 2014)
4. Study: Physicians work out treatment guidelines for coronavirus (Korean Biomedical Review, February 2020)
5. Study: Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia (Guangdong Health Commission, February 2020)
6. Study: Clinical Efficacy of Chloroquine derivatives in COVID-19 Infection: Comparative meta-analysis between the Big data and the real world (Million et al, NMNI, June 2020)
7. Study: Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19 (Arshad et al, Int. Journal of Infect. Diseases, July 2020)
8. Study: COVID-19 Outpatients – Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin (Scholz et al., Preprints, July 2020)
9. Study: Effectiveness of HCQ in COVID-19 disease (Monforte et al., IJID, July 2020)
10. Protocol: Advisory on the use of HCQ as prophylaxis for SARS-CoV-2 infection (Indian Council of Medical Research, March 2020)
11. Review: White Paper on Hydroxychloroquine (Dr. Simone Gold, AFD, July 2020)
12. Article: The Key to Defeating COVID-19 Already Exists. We Need to Start Using It. (Professor Harvey A. Risch, Newsweek, July 2020)
1. Commentary: The versatile heparin in COVID‐19 (Thachil, JTH, April 2020)
2. Study: Anticoagulant Treatment Is Associated With Decreased Mortality in Severe Coronavirus Disease 2019 Patients With Coagulopathy (Tang et al, JTH, May 2020)
3. Study: Autopsy Findings and Venous Thromboembolism in Patients With COVID-19 (Wichmann et al., Annals of Internal Medicine, May 2020)
4. Article: Anticoagulation Guidance Emerging for Severe COVID-19 (Medpage Today)
5. Article: Aspirin may prevent blood clots in COVID-19, study shows (Knowridge Science)
• Facts about Covid-19
• On the effectiveness of face masks
• Studies on the lethality of Covid-19
My friend Kathleen wrote she successfully (meaning no adverse effects) received the Russian Covid 19 vaccine at the Santa Rosa Keiser hospital (which isn't publicized for political reasons). If you want the vaccine, contact your hospital. I'm not pro vaccine, but the Russian may be as good as another, maybe better since they have been working on the Cvirus for 20 years? My feeling is that if Fauci and company blocked HCQ therapy in order for Big Pharma to profit from a vaccine, better to get the Russian who hopefully will underprice Big Pharma. Also, consider this. Russian war industry is better and more efficient than the American because their motive is Defense, whereas the American motive is money. Maybe that holds for medical research as well.NHE wrote: ↑Thu Sep 10, 2020 3:58 pmA woman in the Astrazeneca covid19 vaccine trial developed symptoms that resembled transverse myelitis.
https://www.thetimes.co.uk/article/spin ... -rc2txfw6g
https://investor.lilly.com/news-release ... ntibody-ly
INDIANAPOLIS, Sept. 16, 2020 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced proof of concept data from an interim analysis of the BLAZE-1 clinical trial, showing a reduced rate of hospitalization for patients treated with LY-CoV555. The randomized, double-blind, placebo-controlled Phase 2 study evaluated LY-CoV555, a SARS-CoV-2 neutralizing antibody, for the treatment of symptomatic COVID-19 in the outpatient setting. The trial enrolled mild-to-moderate recently diagnosed COVID-19 patients across four groups (placebo, 700 mg, 2800 mg, and 7000 mg).
The prespecified primary endpoint, change from baseline in viral load at day 11, was met at the 2800 mg dose level, but not the others. Most patients, including those receiving placebo, demonstrated near complete viral clearance by day 11. Additional analyses of viral data demonstrated that LY-CoV555 improved viral clearance at an earlier time point (day 3) and reduced the proportion of patients with persistently high viral load at later time points.
These biomarker data correlated with LY-CoV555's positive impact on the prespecified endpoint of COVID-19-related hospitalization or ER visit. This endpoint occurred in 1.7 percent (5/302) of LY-CoV555 patients, pooled across dose groups, as compared to 6 percent (9/150) of placebo patients, which corresponds to a 72 percent risk reduction in this limited population. Most study hospitalizations occurred in patients with underlying risk factors (age or BMI), suggesting a more pronounced treatment effect for patients in these higher-risk groups. Ongoing studies will seek to confirm this finding. Across all treatment groups (including placebo), no patients progressed to mechanical ventilation or died. Exploratory analyses indicated a more rapid improvement in symptoms for patients treated with LY-CoV555 versus placebo, supporting the hospitalization effect.
LY-CoV555 was well-tolerated, with no drug-related serious adverse events reported. Treatment emergent adverse events were similar across all dose groups and comparable to placebo. Viral RNA sequencing revealed putative LY-CoV555-resistance variants in placebo and all treatment arms. The rate of resistance variants was numerically higher in treated patients (8 percent) versus placebo (6 percent).
"These interim data from the BLAZE-1 trial suggest that LY-CoV555, an antibody specifically directed against SARS-CoV-2, has a direct antiviral effect and may reduce COVID-related hospitalizations," said Daniel Skovronsky, M.D., Ph.D., Lilly's chief scientific officer and president of Lilly Research Laboratories. "The results reinforce our conviction that neutralizing antibodies can help in the fight against COVID-19."
Lilly intends to quickly publish the results of this interim analysis in a peer-reviewed journal and discuss appropriate next steps with global regulators. The BLAZE-1 clinical trial remains ongoing, testing LY-CoV555 in combination with a second Lilly antibody, LY-CoV016, which binds a different epitope in the SARS-CoV-2 spike region. The trial is currently enrolling a larger, confirmatory cohort of higher risk patients, testing the ability of the antibody combination to reduce the number of patients with persistently high viral load and reduce COVID-related hospitalizations.
"We are grateful to the patients, physicians, and staff that have participated in this trial," Skovronsky continued. "We look forward to continued data generation as this trial proceeds."
BLAZE-1 (NCT04427501) is a randomized, double-blind, placebo-controlled Phase 2 study designed to assess the efficacy and safety of LY-CoV555 and LY-CoV016 for the treatment of symptomatic COVID-19 in the outpatient setting. Across all treatment arms, the trial will enroll an estimated 800 participants.
The monotherapy arms of the trial enrolled mild-to-moderate recently diagnosed COVID-19 patients across four groups (placebo, LY-CoV555 700 mg, LY-CoV555 2800 mg, and LY-CoV555 7000 mg). To be eligible, patients were required to have mild or moderate symptoms of COVID-19 as well as a positive SARS-CoV-2 test based on a sample collected no more than 3 days prior to drug infusion.
The primary outcome measure for the BLAZE-1 monotherapy arms was change from baseline to Day 11 in SARS-CoV-2 viral load. Additional endpoints include the percentage of participants who experience COVID-related hospitalization, ER visit or death from baseline through Day 29, as well as safety.
The study is ongoing with additional treatment arms.
LY-CoV555 is a potent, neutralizing IgG1 monoclonal antibody (mAb) directed against the spike protein of SARS-CoV-2. It is designed to block viral attachment and entry into human cells, thus neutralizing the virus, potentially preventing and treating COVID-19. LY-CoV555 emerged from the collaboration between Lilly and AbCellera to create antibody therapies for the prevention and treatment of COVID-19. Lilly scientists rapidly developed the antibody in less than three months after it was discovered by AbCellera and tested by the scientists at the National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center. It was identified from a blood sample taken from one of the first U.S. patients who recovered from COVID-19.
Lilly has successfully completed enrollment and primary safety assessments of LY-CoV555 in a Phase 1 study of hospitalized patients with COVID-19 (NCT04411628) and long-term follow-up is ongoing. A Phase 2 study in people recently diagnosed with COVID-19 in the ambulatory setting (NCT04427501) is ongoing. Lilly recently initiated a Phase 3 study for the prevention of COVID-19 in residents and staff at long-term care facilities (NCT04497987). In addition, LY-CoV555 is being tested in the National Institutes of Health-led ACTIV-2 and ACTIV-3 studies of ambulatory and hospitalized COVID-19 patients.
September 2, 2020 5:21 PM ET
https://www.npr.org/sections/health-sho ... 9-patients
Three new studies strongly support using inexpensive and widely available drugs to treat people who are seriously ill with COVID-19. The drugs are steroids, and the research published Wednesday confirms they are proving to be the most effective treatment found to date.
Initially, the use of these drugs in COVID-19 was controversial. Some doctors have long used steroids to treat conditions related to COVID-19, namely sepsis and acute respiratory distress syndrome.
Steroids help tamp down the immune system's potentially deadly overreaction to an infection. But some doctors worried that steroids could also prevent the body from fighting off the coronavirus effectively.
"Giving steroids to COVID-19 could have been quite scary," says Dr. Derek Angus, a critical care specialist at the University of Pittsburgh Medical Center.
In June, a major study from the U.K. found that the steroid dexamethasone was a big help. It reduced deaths significantly among the most serious cases of COVID-19 — notably people who needed ventilators or supplemental oxygen.
That advance was great news, but those findings created a conundrum for Angus and other researchers who were running their own studies of steroids in COVID-19 patients. It no longer felt appropriate to be giving some people steroids and others a placebo.
"Essentially overnight, because these findings were so striking, there was this sense among clinicians participating in other clinical trials [that] ... we have to stop our trials."
So those studies all ended prematurely. Researchers from three research groups have now published the findings they had gathered in the journal JAMA. One group is from France, one is from Brazil, and the third is an international team that includes the University of Pittsburgh's Angus.
Taken together, the publication of these studies "represents an important step forward in the treatment of patients with COVID-19," Drs. Hallie Prescott and Todd Rice wrote in a JAMA editorial. The results not only provide further support for the use of dexamethasone, they also back the use of another widely used steroid, hydrocortisone.
"I think it's good news to have a strong, clear signal on what is a widely available, inexpensive class of therapies," Angus says. He also contrasts these studies with a lot of other research on COVID-19. Many other studies, such as those involving much-hyped anti-malaria drugs, did not randomize their participants or include a comparison group. Such measures — randomized controlled trials — are the gold standard for medical research.
"It is reassuring that we can get randomized trials executed successfully and rapidly in the face of a pandemic," Angus says, "and it definitely puts us on a surer footing."
Based on these new results and related analysis, the World Health Organization on Wednesday updated its guidelines for steroids. It now recommends them for severely or critically ill COVID-19 patients, such as those on a ventilator, but not for patients with milder disease.
Universidad del Desarrollo-Clínica Alemana, Santiago, Chile
COVID-19 in a multiple sclerosis (MS) patient treated with alemtuzumab: Insight to the immune response after COVID
Background: The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a novel disease that has spread abruptly over the world, allowing the development of countermeasures an urgent global priority. It has been speculated that elder people and patient with comorbidities may be at risk of developing complication. On the other hand, it has been seen that immunosuppressed patients could develop a mild presentation of the disease. Based on this hypothesis, several immunosuppressant agents are currently being tested as potential treatment for coronavirus 2019 (COVID-19).
Methods: report a patient treated with alemtuzumab (Humanized monoclonal antibody against the lymphocyte and monocyte surface antigen CD52, which depletes B and T cells) (Thompson et al., 2018) for recurrent remittent multiple sclerosis (RRMS) who developed mild COVID-19.
Results: Despite complete B and T cell depletion, patient symptoms abated few days with no need for hospitalization due to COVID-19 and no clinical evidence of disease activation regarding her MS.
Discussion: This report shows that MS patients with mild depletion of B and T cells can mount an antiviral response against COVID-19 and produce IgG.
- Similar Topics
- Last post