Drug Trials for COVID

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• HomeUpCOVID Blood ClottingH1N1 Flu Pandemic 2009How COVID-19 KillsWe’re not going back to normalDrug Trials for COVIDOxygen instead of VentilatorSweden’s GDP reduced by 9.7% and Costa Rica’s by only 3.6% •
• Drugs that may Treat COVID-19 •

VACCINES

July 13th Antibodies to the virus would increase sharply after infection and peak after about two weeks. But then their presence would decline, generally disappearing entirely somewhere between four months and one year.

May 24th the first human trial of a possible vaccine has been found to be safe and may effectively fight the virus. Scientists in China say 108 healthy adults were given a weakened strain of Adenovirus to deliver genetic material which codes for the SARS-CoV-2 spike protein to the cells. These cells then produce the spike protein, and travel to the lymph nodes where the immune system creates antibodies that will recognize that spike protein and fight off SARS-CoV-2.
But 44%-56% of participants in the trial had high
pre-existing immunity to adenovirus type 5, and had a less positive antibody and T-cell  to the vaccine.

Oxford Mar 19: A vaccine against coronavirus could be ready as soon as September !
“80 per cent confident” that the vaccine would work !
---The vaccine being developed at Porton Down is an intramuscular injection that uses a harmless, non-replicating virus to smuggle DNA from the coronavirus into the body’s cells.
---Once inside, the body’s cells use the coronavirus DNA to churn out copies of the “spike proteins” that dot the germ’s surface. It is these that should marshal the immune response against coronavirus infection. Previous studies suggest the vaccine should work with only a single shot.
---Vaccines that operate the same way have been used safely in thousands of people, aged from one week old to 90 years, for diseases ranging from malaria and TB to Mers, (another coronavirus), and Ebola, for which it is now being deployed in Uganda and the Democratic Republic of the Congo.
--The Oxford trial is expected to recruit people from a range of ages, but scientists will be particularly keen to see how it performs in older people. They are most vulnerable to the virus, but tend to respond less well to vaccinations because of their weaker immune systems.

The Oxford vaccine, known as ChAdOx1, is one of five frontrunner vaccines in development around the world.
The US biotech Moderna gave its first vaccine shot to a person in Seattle April. Another US firm, Inovio, will soon start trials on its own coronavirus vaccine, which requires a special device to administer through the skin.
In Germany, CureVac is working on a vaccine, while others are in development in China.

Human testing for Johnson & Johnson coronavirus vaccine this fall

Moderna has already moved into  for its vaccine candidate, as has China's CanSinoBIO.

April 7th STUDY: COVID-19 vaccine candidate shows promise in first peer-reviewed research by University of Pittsburgh

April 7th STUDY:  Trial drug can significantly block early stages of COVID-19 in engineered human tissues -U. British Columbia - Apeiron Biologics

ANTIBODIES

  • Vir Biotechnology (VIR) has partnerships with GlaxoSmithKline (GSK) and Biogen (BIIB). 

  • Amgen (AMGN) and small biotech partner Adaptive Biotechnologies (ADPT) are seeking antibody drugs.

  • Regeneron and Lilly are also testing antibody-based coronavirus treatments.

  • Sorrento Therapeutics (SRNE) preclinical testing"100% inhibition" of Covid-19 — within four days".



               The Chronology of COVID-19 Mutation around the world
The reason we need a new flu vaccine each season is that the flu mutates quickly.
Fortunately, so far the virus that causes COVID-19 mutates more slowly.
But as the above image from Nextstrain.org shows, COVID-19 changes rapidly enough that it’s likely whatever vaccine we develop will need to be updated and readministered periodically.

VIRUS RELATED COMPANIES

Symbol PRICE M
SRNE Sorrento Therapeutics, Inc. 6.96
ABT Abbott Laboratories 91.05
JNJ Johnson & Johnson 150.87
ZM Zoom Video Communications, Inc. 165.5
DHR Danaher Corporation 163.96
TAK Takeda Pharmaceutical Company Limited 18.92
SNY Sanofi 47.50
REGN Regeneron Pharmaceuticals, Inc. 565.55
GILD Gilead Sciences, Inc. 75.02
VIR Vir Biotechnology, Inc. 38.80
MRNA Moderna, Inc. 83.74
HSIC Henry Schein, Inc. 56.60
NVAX Novavax, Inc. 56.37
INO Inovio Pharmaceuticals, Inc. 13.86
AHPI Allied Healthcare Products, Inc. 12.50
NNVC NanoViricides, Inc. 8.90
CODX Co-Diagnostics, Inc. 17.66
APT Alpha Pro Tech, Ltd. 13.52
LAKE Lakeland Industries, Inc. 13.53
 

  July 20th an inhaled formula of the protein interferon beta were at 79 percent lower risk of developing the severe disease.

July 18th Cholesterol-lowering meds have potential to downgrade COVID-19's threat . By allowing lung cells to burn more fat, Fenofibrate breaks the virus' grip on these cells, and prevents SARS CoV-2's ability to reproduce. In fact, within only five days of treatment, the virus almost completely disappeared.

July 15th NYT Coronavirus Drug and Treatment Tracker

July 6th Excessive production of VWF(Willebrand factor) can lead to the development of thrombosis, including in the capillaries of the lungs and  inflammation of the walls of blood vessels and capillaries.

July 1st attach ACE2 to the end of an synthetic antibody MDR504 and Sars2 attaches to it instead of the ACE2 on our cells. The ACE2 on the synthetic antibody out-competes the ACE2 on our cells for the virus's attention .

June 26th Seem likely to work because they block the chemical signals that activate filopodia production. Among the 7 drugs identified are:

  1. Silmitasertib, a still-experimental drug in early clinical trials as a treatment for bile duct cancer and a form of childhood brain cancer; 
  2. Ralimetinib, a cancer drug developed by Eli Lilly; and 
  3. Gilteritinib (marketed as Xospata), a drug in use already to treat acute myeloid leukemia.

June 16th  2,000 hospital patients were given Dexamethasone and compared with more than 4,000 who were not. For patients on ventilators, it cut the risk of death from 40% to 28%. For patients needing oxygen, it cut the risk of death from 25% to 20%.
It aids acclimatization at high-altitude.
It has saved mountaineers in trouble high on a peak.
It “brings life to a dead person,” said Everest guide


June 10th
Eli Lilly -- 28 days of daily treatment with 4 mg of Baricitinib ( Olumiant) a  rheumatoid arthritis drug. It may inhibit the host cell proteins that assist in viral reproduction, reducing the ability of infected cells to make more of the virus.
--  such as Roche’s 
Actemra and Regeneron and Sanofi’s Kevzara, are also being studied as a potential treatment for the cytokine storms

June 9th The results of clinical trials of the drug, initiated on April 24, demonstrate that Levilimab therapy can significantly reduce mortality. (Russia)

June 5th Acalabrutinib, (FDA-approved for the treatment of several types of B cell cancers), improved the oxygenation levels and decreased molecular markers of inflammation in a majority of 19 patients hospitalized 

June 3rd a newly discovered natural antibiotic, Teixobactin, could be effective in treating bacterial lung conditions such as tuberculosis and those commonly associated with COVID-19.

June 1st Eli Lilly -- Neutralizing Antibodies to lower the virus --  infuse patients with an antibody, giving it over 30 minutes intravenously. It will stay in the body for weeks.

May 28 Already proven safe in Clinical Trial of 700 -- treatment for Blood Clotting AND Inflammation - ARCA Biopharma - AB201 (rNAPc2) 

May 27th An antiviral called EIDD-2801, has shown promise against several RNA viruses, including Ebola, influenza and SARS-CoV-1, in cell and animal studies.
EIDD-2801 targets the same viral enzyme as
remdesivir(which must be given intravenously), EIDD-2801 is an oral medication which could be taken at home rather than in the hospital, allowing treatment earlier.

May 27: Anti-inflammatories may keep coronavirus from replicating
Researchers in Spain using computer techniques have analyzed 6,466 approved drugs and identified seven that might inhibit the main enzyme that helps the coronavirus to replicate, referred to as M-pro.
The approach is already being tested via trials of the HIV antiretroviral medications
lopinavir and ritonavir.
Two of the seven newly identified drugs, both anti-inflammatory medications, have been selected  for early-stage laboratory tests.

  1.  celecoxib, sold by Pfizer Inc for arthritis pain under the brand name Celebrex, and
  2.  carprofen, used for pets under several brand names, including Rimadyl from Zoetis Inc.

 The researchers say the molecular structures of these drugs could be used as starting points for developing derivatives with more potent effects against the coronavirus.

May 24  Injecting neutralising antibodies into infected mice, after five days the viral load was reduced by a factor of 2,500. The drug's antibodies are produced by the human immune system (to prevent the virus infecting cells) — isolated from the blood of 60 recovered patients.
Plasma is limited in supply but these 14 neutralising antibodies could be put into mass production quickly.

May 20th treatment with so-called type-1 interferon “could stop the virus before it could get established,

May 13 Global study using AI to examine COVID-19 patient data from 300 intensive care units (ICU)

May 13 How COVID-19 kills

May 12 STUDY: Treatment with Senicapoc can prevent SARS and the lung damage seen in COVID-19....., we don't treat the viral infection, but we prevent or slow the development of the disease that leads to severe damage to the lungs,

May 12: Lipid Mediators derived from omega-3 fatty acids serve as the body's natural "stop" signals to inflammation. .. already in clinical trials for other inflammation-driven disease ,,,

May 12 CAP-1002, contains cardiosphere-derived cells (CDCs) that are grown in the laboratory from human heart tissues. .... originally created to treat heart failure, can help the whole body.
4 of 6 critically ill ... discharged from the hospital.
5
were on ventilators. Within four days after infusion with CAP-1002, 4 patients were able to breathe without respiratory support

May 8th Of more than 1,600 patients between late February and mid-April., 84 patients received 10–40 mg of intravenous Famotidine (Pepcid Heartburn med.) daily over 6 days.
Those who got
Famotidine fared better.
They were far less likely to die or require a ventilator—a twofold decrease in risk.

May 8th A two-week course of antiviral therapy with

  • interferon beta-1b
  • lopinavir-ritonavir
  • ribavirin,

started within 7 days of showing COVID-19 symptoms, is safe and more effective at reducing the duration of viral shedding than lopinavir-ritonavir alone in patients with mild to moderate illness,

May 7th Lancet:  With ageing, malnutrition, immunosuppression, and co-morbid states, our immune system loses the ability to adapt to novelty.

But the
child's immune system is prepared and fit to react to novelty, a function that might be diminished in adults and ineffective in elderly people aged 70 years or older.

Children have the ability to rapidly produce natural antibodies with broad reactivity that have not yet been selected and shaped by the reaction to common environmental pathogens over time.

In infants and children, crucial parts of the immune system are highly adaptable to new antigens.
In contrast, in the elderly, those parts are replaced with the highly mutated and specific, they recognise their targets but appear incapable of adaptation to new antigens.

The child immune response might have the double function of secreting cytokines. A potent anti-inflammatory cytokine is produced reducing immune-mediated tissue damage, in particular, in the lung.

May 6th baricitinib,  as a possible treatment ?

May 4th: computer-aided drug design to examine the effectiveness of

  1. remdesivir,
  2. 5-fluorouracil,
  3. ribavirin
  4. favipiravir

in treating COVID-19. All four drugs were effective in inhibiting, or blocking, the coronavirus' RNA proteins from making genomic copies of the virus.

May 1st REMDESIVIR Follow-on Study: " suggests it may be possible to develop broad spectrum antiviral inhibitors. ..... theoretical support for the design of more powerful, efficient and specific ..... COVID-19 antiviral drugs.

May 1st "We should pay more attention to T cell counts and their function, rather than respiratory function of patients," ...  identifying drugs that recover T cell numbers and boost function....Tocilizumab is an existing drug that may be effective

May 1 Wean patients from ventilators: A big problem with inflating the lungs using positive pressure to deliver oxygen is that high pressure causes ventilator-induced lung injury, and in COVID-19 patients this may compound the lung damage caused by the virus.

"In contrast, pacing the diaphragm distributes the breathed oxygen more evenly throughout the lungs and this helps protect the tissue from mechanical injury."

A second problem is that mechanical ventilation sidelines the diaphragm muscle and causes it to rapidly atrophy, which is a major reason for failure to wean. "Pacing the diaphragm helps maintain or restore its size, strength and endurance, which is key to enabling successful weaning," he says.

The diaphragm stimulation therapy is delivered through a central venous catheter (CVC), similar to central lines currently placed in mechanically ventilated ICR patients.

The unique central line is used to deliver both fluids and medications, while also incorporating electrodes that activate the diaphragm muscle, via transvenous phrenic-nerve stimulation.

Apr 30 "In addition to pneumonia affecting the small air sacs within the lungs, we are also finding hundreds of small blood clots throughout the lungs. This scenario is not seen with other types of lung infection, and explains why blood oxygen levels fall dramatically in severe COVID-19 infection.

Apr 30th Proven cardiovascular anti-inflammatory therapies should be used to treat COVID-19 patients that are at risk of, or have developed, cardiovascular problems, 
 "Inflammation plays an important role in the development and complications of cardiovascular diseases and we have seen that COVID-19 patients with greater signs of an inflammatory response are more likely to suffer
serious cardiovascular events and are at greater risk of dying,"
".... The virus could directly infect and cause
inflammation of the heart's tissues, aggravate existing cardiovascular problems, or trigger an over-excessive immune response in the body, often referred to as a 'cytokine storm', which leads to the body attacking itself."

Apr 30th "ACE2 keeps the substance bradykinin under control. Bradykinin makes blood vessels leak. We have good reason to believe that with COVID-19 infections we see exactly this effect: when the virus is introduced, ACE2 receptors disappear from the lung cells, giving bradykinine free rein in causing the small blood vessels to leak massively at the site of infection."

The problems of vascular leakage can be aggravated by an inflammatory phase. This causes even more leakage and damage to the lungs.
Anti-inflammatory drugs can have a potentially dampening effect here, and doctors and researchers all over the world are doing their best to select the most optimal drugs for this stage. In addition the long lasting vascular leakage and inflammation of the blood vessels will trigger the coagulation cascade leading to thrombosis and eventually scarring of the lungs.
 Interventions that are
started early to treat this leakage have the capacity to prevent these serious complications and might be effective in keeping patients out of the ICU.

Apr 27: People with certain heart diseases may be more susceptible to worse outcomes with COVID-19, but the reason why has remained unknown. Patients with one specific type of heart disease obstructive hypertrophic cardiomyopathy (HCM) the heart increases production of the ACE2 RNA transcript and the translated ACE2 protein.

Normally, this pathological response at the cellular level might be the heart's attempt to compensate for changes caused by disease. Unfortunately, COVID-19, hijacks these ACE2 receptors on the membrane of cells and uses them to get inside the cells. The virus not only gains entry through ACE2, but also it takes this protein with it, removing a protective signaling pathway that normally counters the negative impact of the hormone angiotensin II. This hormone increases blood pressure and leads to fluid retention.

Apr 27: device that does the work of the lungs by removing carbon dioxide from the blood

Apr 24 New research finds a connection between destructive white blood cells and a more severe disease course in patients with COVID-19.

"Patients with COVID-19 infection have higher blood levels of neutrophil extracellular traps, also called NETs, which are a product of an inflammatory type of neutrophil cell death called NETosis," The researchers analyzed blood samples from 50 patients with COVID-19 ....... to better understand what causes the inflammatory storm and blood clots .. They believe NETs may be relevant  given that thrombosis and inflammation are hallmarks .

Apr 23  Recent observations suggest that respiratory failure in COVID-19 is not driven by the development of the acute respiratory distress syndrome alone, but that microvascular thrombotic processes may play a role.
 There is a strong association between D-dimer levels, disease progression and chest CT features suggesting venous thrombosis.
 In addition, various studies in patients with COVID-19 have shown a very strong association between increased D-dimer levels and severe disease/poor prognosis.

Careful attention needs to be paid to the initial diagnosis and treatment of the prothrombotic and thrombotic state that can occur in a substantial percentage of COVID-19 patients.

"Imaging and pathological investigations confirmed the COVID-19 syndrome is a thrombo-inflammatory process that initially affects lung perfusion, but consecutively affects all organs of the body," . "This highly thrombotic syndrome leads to macro-thrombosis and embolism. Therefore, strict thrombosis prophylaxis, close laboratory and appropriate imaging monitoring with early anti-coagulant therapy in case of suspected venous thromboembolism are indicated."

Recommendations:

  • prophylactic-dose heparin,

  • chest CT,

  • CT pulmonary angiography and

  • routine D-dimer testing.

Findings have also emerged linking COVID-19 more specifically with pulmonary embolism

"See:- "Why Some Doctors Are Now Moving Away From Ventilator Treatments"

April 21: More deaths, no benefit from malaria drug hydroxychloroquine in VA coronavirus study

April 16" Proteins may halt the severe cytokine storms seen in COVID-19 patients

April 15: New mask material can remove virus-size nanoparticles

April 13: Virology lab finds drug Remdesivir  originally meant for Ebola is effective against a key enzyme of coronavirus that causes COVID-19

 

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