CME INDIA Presentation by Admin.

• A “major scientific discovery,” Colchicine is the first “effective oral drug to treat out-of-hospital patients of COVID-19.”
• This is the first hope for patients who have COVID, who are worried and who hope that they will not have complications
• “Till now, there were no tablets that could be taken by mouth and reduce the risks.”
• This study shows effectiveness of treatment using colchicine to prevent the phenomenon of the major inflammatory storm and reduce complications related to COVID-19

— Dr. Jean-Claude Tardif (Chief Researcher, The ColCorona study)

CME INDIA Breaking news:

(Shared by Dr AK Singh, Kolkata in CME INDIA Group)

• The Montreal Heart Institute (MHI) announced today that the COLCORONA clinical trial has provided clinically persuasive results of colchicine’s efficacy to treat COVID-19.
• The study results have shown that colchicine has reduced by 21% the risk of death or hospitalizations in patients with COVID-19 compared to placebo.
• This result obtained for the global study population of 4488 patients approached statistical significance. The analysis of the 4159 patients in whom the diagnosis of COVID-19 was proven by a naso-pharyngeal PCR test has shown that the use of colchicine was associated with statistically significant reductions in the risk of death or hospitalization compared to placebo.
• In these patients with a proven diagnosis of COVID-19, colchicine reduced hospitalizations by 25%, the need for mechanical ventilation by 50%, and deaths by 44%.
• This major scientific discovery makes colchicine the world’s first oral drug that could be used to treat non-hospitalized patients with COVID-19.
  • COLCORONA trial – in non-hospitals patient – top line results out. Publication in process
  • COLCOVID trial in hospitalized patient – ongoing

Dr H D Sharan, Ranchi:

• The best news since Feb 2020.
• Two medicines that have the approval of clinical trials are Dexamethasone and Colchicine. Both are so cheap. Affordable for all.
• I am really excited.
• Dose 1.2 mg daily. (In some study they used- Colchicine – 0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days. The first dose was 1.0 mg whether body weight was ≥ 80 kg)

Dr Shailesh Trivedi, Chairman Rssdi, Gujrat:

• Great. It’s never too late. We’re going to have COVID-19 19 infection for at least 2 years in the differential diagnosis of fever, cough, ili or unusual symptoms. 

Dr Vijay Arora Physician, Max Hosp., Delhi:

• I have given colchicine in about 830 indoor pts admitted in our unit in last 7 months with excellent results, 0.5 mg 3 stat then one BD for 10 days, only 16/17 pts required Tocilizumab … and most of them (Tocilizumab) patients scumbled to fungemia.

Dr Anil Motta, Max Hosp, Delhi:

• Dr Vijay has corroborated beautifully; the anti-inflammatory effects of Colchicine. First-hand Experience 👍.

Dr H D Sharan, Ranchi: HOW DOES COLCHICINE ACT?

• Tubulin-Colchicine Complex is the game changer
• Colchicine is an inhibitor of mitosis and microtubule assembly.
• Colchicine Interferes with Several Inflammatory Pathways
• Inhibition of Neutrophil Chemotaxis, Adhesion, and Mobilization
• The concentration of colchicine that accumulates in neutrophils may be more than 16 times the peak concentration observed in
• Colchicine dramatically reduces the adhesion of neutrophils to the endothelium.
• By inhibiting microtubule polymerization,
  • Colchicine has been reported to cause a significant decrease in virus replication in flaviviruses, such as dengue and Zika viruses; blocks transport and reduces the replication of recombinant demyelinating strain of the mouse hepatitis virus.
  • Inhibits respiratory syncytial virus (RSV) infection in neonatal rats through regulation of anti-oxidative factor production leading to inhibition of RSV replication, thus, leading to a significant reduction in the levels of IL-6 and TNF-α.
  • Colchicine and colchicine derivatives may influence HIV viral load.

• Coronaviruses moves in the cell in a manner that corresponds to microtubule-associated transport, inducing the formation of double-membrane vesicles in infected cells.
• The infection of cells by coronaviruses involves the interaction of the cytoplasmic tail of the spike protein with cytoskeletal proteins (i.e., tubulin). This interaction leads to viral entry.
• Microtubules are also involved in the transport and assembly of spike proteins into virions during the replication cycle.
• The colchicine-tubulin complex may block viral entry and replication [40]. This hypophysis requires confirmation.

The ColCorona study:

• It involved 4,159 patients whose diagnosis of COVID-19 had been confirmed by a nasopharyngeal test (PCR).
• The randomized, double-blind, placebo-controlled study was deployed in Canada, the United States, Europe, South America and South Africa.
• Analysis of the study found that colchicine resulted in reductions in hospitalizations by 25 per cent, the need for mechanical ventilation by 50 per cent, and deaths by 44 per cent.

The Splendid Journey

• Colchicine first received approval from the US Food and Drug Administration in 2009, its modern use dates back two centuries. Indeed, papyri dating from 1500 BC describe the use of colchicine’s source plant—Colchicum autumnale—for pain and inflammation, making colchicine one of the world’s oldest anti-inflammatory therapeutics.
• Currently, colchicine is approved for treating and preventing acute gout and familial Mediterranean fever, and is used off label in Behçet’s disease, pericarditis and other inflammatory conditions.
• Colchicine, one of the oldest known drugs, has been used for over 2000 years ago in the form of preparations of the meadow saffron colchicum autumnale as a remedy for acute gout flares. Colchicine for oral use (capsule/tablet/liquid) is currently FDA approved for prevention and treatment of gout flares in adults and treatment of familial Mediterranean fever (FMF).
•  Off-label uses for colchicine are multiple and include calcium pyrophosphate deposition disease, Behcet’s disease, amyloidosis, primary biliary cirrhosis, and pericarditis. Previous studies provide evidence that cardiovascular events are common in patients with severe COVID-19.
•  Recent colchicine studies showing its efficacy in preventing major cardiovascular adverse events among patients who suffered a recent myocardial infarction compared with placebo is, therefore, of importance

What is the dose schedule in COVID cases?

• Most of physicians have not seen Colchicine tablet and even in Acute flare of Gout, most of us have not used it. It is a well-known fact.
• Colchicine can be administered by mouth as 0.5 or 0.6 mg and up to 1 mg in tablets.
• For the treatment of gout flares, the FDA-approved dose is 1.2 mg (two tablets) at the first sign of a gout flare followed by 0.6 mg (one tablet) 1 h later (total 1.8 mg).
• For gout flare prevention, the FDA-approved dose is 0.6 mg once or twice daily with a maximum dose of 1.2 mg/day.
• For Familial Mediterranean Fever (FMF), the dose is up to 1.2–2.4 mg.
• The oral colchicine dose used in the COVID-19 clinical trials registered on the clinicaltrialsl.gov site varies
  1. 0.5 mg twice daily for the first 3 days and then once daily for the last 27 days; 0.6 mg by mouth twice daily for 30 days; 0.5 mg twice daily with no time limit; or 1 mg daily for 30 days.
  2. Others use a loading dose of 1.2 mg followed by 0.6 mg after 2 h on day 1 (similar to gout flare treatment) followed by 0.6 mg twice a day for 14 days or until discharged or release from the hospital.
  3.  Yet, others load with 1.5 mg (1 mg and 0.5 mg 2 h after), followed by 0.5 mg every 12 h during the next 7 days and 0.5 mg every 24 h after until the completion of 28 days of total treatment.

CME INDIA Learning Points

• The effective COVID-19 management strategies continue to evolve.
• A central role for exaggerated activation of the innate immune system as an important contributor to COVID-19 adverse outcomes.
• This is one of the oldest anti-inflammatory therapeutics, target multiple mechanisms associated with COVID-19 excessive inflammation.
• New study shows that successful outpatient treatment of COVID-19 could greatly reduce morbidity, mortality and the demand for rare or expensive care resources
• The repurposing of colchicine for the treatment of COVID-19 was suggested based in its immunomodulatory, anti-inflammatory, and anti-viral properties.
• Colchicine works by 3 ways:
  1. Colchicine and microtubules: inhibition of neutrophil activity.
  2. Colchicine and the inflammasome: inhibition of IL-1β and prevention of the cytokine storm.
  3. Colchicine and the Inflammation/thrombosis interface.
• Thus, Colchicine has anti-inflammatory and anti-viral properties. The mechanism of action for potential benefit in severe COVID-19 is likely related to an inhibitory effect on the activation, destabilization, and degradation of inflammasomes, which may attenuate cytokine storm.

CME INDIA Tail Piece

• Multiple randomised studies have evaluated the use of colchicine in non-rheumatologic inflammatory conditions.
• In acute pericarditis 2 randomised trials demonstrated lower recurrence rate with colchicine versus conventional or placebo therapy. Colchicine reduced symptom persistence 72 hours after treatment initiation, and colchicine was beneficial even in the setting of recurrent pericarditis.
• Used after cardiac surgery, colchicine appears to prevent the inflammatory post pericardiotomy syndrome.
• Colchicine may reduce risk of acute myocardial infarction (AMI). It has been demonstrated that an association exists between daily colchicine use and decreased prevalence of AMI in patients with gout, a non-traditional cardiovascular risk factor.
• The multicentre, double-blind Colchicine Cardiovascular Outcomes Trial (COLCOT) demonstrated a reduction in the primary composite endpoint of cardiovascular death, resuscitated cardiac arrest, AMI, stroke or urgent revascularisation with colchicine.
• (LoDoCo 2) trial done in stable coronary artery disease demonstrated a reduction in the primary composite endpoint of cardiovascular death, AMI, stroke or urgent revascularisation.
• In cases where the thrombus burden remains refractory to standard antiplatelet and anticoagulant therapies, colchicine has been shown to be associated with thrombus resolution.
• Consistent with a possible preventive role, colchicine is effective to prevent cytokine-based disease flares in gout and familial Mediterranean fever.
• Finally, colchicine has also been shown to dampen the inflammatory response and reduce CRP levels among subjects with metabolic syndrome.

Source:

1. Reyes AZ, et al. Ann Rheum Dis 2020;0:1–8. doi:10.1136/annrheumdis-2020-219174
2. medRxiv preprint doi: https://doi.org/10.1101/2020.08.06.20169573.this version posted August 11, 2020
3. J. Clin. Med. 2020, 9, 2961; doi:10.3390/jcm9092961
4. Schlesinger, N., Firestein, B.L. & Brunetti, L. Colchicine in COVID-19: an Old Drug, New Use. Curr Pharmacol Rep 6, 137–145 (2020). https://doi.org/10.1007/s40495-020-00225-6

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