China is now using the antibiotic drug Minocycline to treat COVID-19 

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China is now using the antibiotic drug Minocycline to treat COVID-19 cases in various cities across China including Shanghai despite lack of published clinical trial studies showing its efficacy.

Chinese researchers from the Chinese Academy of Medical Sciences & Peking Union Medical College along with scientists from the Inner Mongolia Medical University did published a preprint study a few days ago that only involved a silico and vitro study on the possibility of using Minocycline to treat SARS-CoV-2 infections. 

Minocycline, sold under the brand name Minocin among others, is a tetracycline antibiotic medication used to treat a number of bacterial infections such as pneumonia.

It is also used for the treatment of acne, rheumatoid arthritis, urinary tract infections, various respiratory infections, skin infections, chlamydia, tick fever and others.
 
Minocycline is also known to possesses anti-inflammatory, anti-oxidant, anti-apoptotic and immunomodulatory effects. 

Past studies have shown that minocycline does have antiviral properties against various viruses including retroviruses (HIV), flaviviruses (Japanese encephalitis virus), enteroviruses (EV71) and even prevents respiratory syncytial virus Infections.

The study findings were published in on a preprint server and are currently being peer reviewed for publication into the journal by Springer Group: medicinal Chemistry Research.
https://www.researchsquare.com/article/rs-1528733/v1
 

To explore potential inhibitors of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) for the treatment of novel coronavirus disease (COVID-19), in silico screening of 135 clinical drugs was performed targeting on 3-chymotrypsin-like protease (3CLpro, or Mpro).

Six drugs including anti-HIV drug (raltegravir), antibacterial drugs (cefonicid, cefoperazone, minocycline), and antidiabetic drugs (canaglifozin, glyburide) showed high binding affinities (≤ -8.5 kcal/mol) and interesting binding conformations compared with the designed co-crystal ligand N3 (-7.7 kcal/mol).

In which the antibiotic minocycline, an inhibitor of bacterial ribosomal rRNA, showed the highest binding affinity (-9.6 kcal/mol). Valuable hydrogen bonding and hydrophobic interactions were found between minocycline and Mpro active site.

Beside the hydrogen bond with Cys145, minocycline formed a Pi-Cation with His41, which strongly supported minocycline as a Michael Addition acceptor to bind with the catalytic site of Mpro.

The structure-affinity relationship was studied based on molecular docking of minocycline analogues. Minocycline showed in vitro Mpro inhibitory activity with IC50 of 5 mM. More importantly, the literature review found that minocycline had both in vitro and in vivo broad-spectrum antiviral as well as anti-inflammatory activities.

Minocycline deserves in vivo evaluations as well as randomized controlled trial to investigate the efficacy for the treatment of COVID-19.


A 64-year-old woman had a remote history of generalized fatigue, tightness of the hands, tingling and numbness of the face, joint stiffness, and bluish discoloration of the fingers that worsened with cold weather. Laboratory testing at that time had revealed an antinuclear antibody titer over 1:320 (reference range < 1:10), anti-Scl-70 antibody 100 U/mL (< 32 U/mL), and thyroid-stimulating hormone 10.78 mIU/L (0.4-5.5). Pulmonary function testing showed a pattern of restrictive lung disease. She was diagnosed with hypothyroidism, Raynaud phenomenon, and scleroderma. She was referred to a rheumatologist, who prescribed levothyroxine and penicillamine.

Despite treatment, she continued to feel fatigued, and she requested the addition of minocycline to the scleroderma treatment after seeing a report on television. Minocycline 100 mg twice daily was prescribed. She reported improvement of her symptoms for the next 2 years but was then lost to follow-up with the rheumatologist. She continued to take penicillamine and minocycline as prescribed by her primary care physician.

She presented to our clinic with bluish discoloration (Figure 1) that had started 1 year before as a small area but had spread to involve the entire face, fingers, gums, teeth, and sclera, and included a dark discoloration of the neck and upper chest. She had been taking minocycline for nearly 9 years. We referred her to a dermatologist, who diagnosed minocycline- induced hyperpigmentation. Her minocycline was stopped. Skin biopsy was not done, as the dermatologist was confident making the diagnosis without biopsy. At 1 year later, she continued to have the widespread skin pigmentation with no improvement at all.

FIGURE 1

FIGURE 1

DIFFERENTIAL DIAGNOSIS

Hyperpigmentation is the darkening in the natural color of the skin, usually from increased deposition of melanin in the epidermis or dermis, or both. It can occur in different degrees of blue, brown, and black (from lightest to darkest). Less frequently, it may be caused by the deposition in the dermis of an endogenous or exogenous pigment, such as hemosiderin, iron, or heavy metal.1 The hyperpigmentation can be circumscribed or more diffuse.

The differential diagnosis of diffuse skin pigmentation includes Addison disease, hyperthyroidism, hemochromatosis, erythema dyschromicum perstans, cutaneous malignancies, sunburn, and drug-induced hyperpigmentation.1,2 Medications commonly cited as causing hyperpigmentation include minocycline, amiodarone, bleomycin, prostaglandins, oral contraceptives, phenothiazine, and antimalarial drugs.1,3 In Addison disease, the pigmentation is typically diffuse, with accentuation in sun-exposed areas, flexures, palmar and plantar creases, and areas of pressure or friction.2 The bronze discoloration of hemochromatosis is from a combination of hemosiderin deposition and increased melanin production.1 Erythema dyschromicum perstans presents with brownish oval-shaped macules and patches. Early lesions may have thin, raised, erythematous borders that typically involve the trunk, but they may spread to the neck, upper extremities, and face.4

The role of minocycline in the treatment of scleroderma is controversial. Early reports involving a small number of patients showed a benefit of minocycline in decreasing symptoms,5,6 but these findings were not achieved in a larger multicenter trial.7

Types of minocycline-induced hyperpigmentation

Three types of minocycline-induced hyperpigmentation occur3,8:

  • Type 1—blue-grey coloration on the face in areas of inflammation
  • Type 2—blue-grey coloration on normal skin on the skin of the shins and forearms
  • Type 3—the least common, characterized by diffuse muddy brown or blue-grey discoloration in sun-exposed areas, as in our patient.

The prevalence of minocycline-induced hyperpigmentation varies between 2.4% and 41% and is highest in patients with rheumatoid arthritis.3,9 Type 1 pigmentation is not correlated with treatment duration or cumulative dose, while type 2 and 3 are associated with long-term therapy.8 In type 3, changes are nonspecific, consisting of increased melanin in basal keratinocytes and melanin-only staining dermal melanophages. Types 1 and 2 may resolve slowly, whereas type 3 can persist indefinitely.3,8,10

TREATMENT

Treatment involves early recognition, discontinuation of the drug, and avoidance of sun exposure. Treatment with pigment-specific lasers has shown promise.8,10

reference link : https://www.ccjm.org/content/83/12/876


https://pubmed.ncbi.nlm.nih.gov/26177421/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121275/

https://www.sciencedirect.com/science/article/pii/S0753332219324035

https://www.mdpi.com/1999-4915/11/8/739/htm

Minocycline is also known to be able to inhibit West Nile virus infections. https://academic.oup.com/jac/article/60/5/981/2357608

Interestingly, a few study findings have also emerged showing that minocycline is able to improve cognitive deficiencies associate with neuroAIDS. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174065/

https://nn.neurology.org/content/6/3/e551

https://www.medicinabiomolecular.com.br/sdi4/sdi4-arquivos/pdf/mb-0867.pdf

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018688

As early as April 2020, researchers from India had also suggested repurposing Minocycline to treat COVID-19. https://www.tandfonline.com/doi/full/10.1080/14787210.2020.1782190

In June 2020, Italian researchers also proposed repurposing minocycline to treat COVID-19./pmc/articles/PMC7320853/”>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320853/

SARS-CoV-2-Minocycline study published in November 2020 by researchers from Venezuela also suggested that tetracyclines could be used to treat COVID-19. https://link.springer.com/article/10.1007/s00705-020-04860-8

Japanese researchers also propose using minocycline with other existing drugs such as favipiravir to treat COVID-19. https://www.liebertpub.com/doi/10.1089/regen.2021.0037

A study conducted jointly by Indian and Italian researchers showed the merits of using minocycline and other tetracyclines to treat COVID related ARDs (Acute respiratory distress syndrome) and COVID related ALI (Acute lung injury).

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