WO2022123601A1 - Composition orale à base de plantes pour le sars-cov-2 et son procédé de préparation - Google Patents

Composition orale à base de plantes pour le sars-cov-2 et son procédé de préparation Download PDF

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Publication number
WO2022123601A1
WO2022123601A1 PCT/IN2021/051154 IN2021051154W WO2022123601A1 WO 2022123601 A1 WO2022123601 A1 WO 2022123601A1 IN 2021051154 W IN2021051154 W IN 2021051154W WO 2022123601 A1 WO2022123601 A1 WO 2022123601A1
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extract
treatment
covid
targeting
humans
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PCT/IN2021/051154
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English (en)
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Krishnan PARTHASARATHY
Ramesh K. GOYAL
Mahaveer DHOBI
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Remedium Therapeutics Private Limited
Delhi Pharmaceutical Sciences & Research University
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Publication of WO2022123601A1 publication Critical patent/WO2022123601A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/19—Acanthaceae (Acanthus family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/484—Glycyrrhiza (licorice)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/67—Piperaceae (Pepper family), e.g. Jamaican pepper or kava
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present invention relates to the field of phytopharmaceutical medicine. More particularly, it relates to ayurvedic composition comprising herbal extracts and zinc oxide (Jasad Bhasma).
  • Herbal extracts contain phytochemicals that inhibit SARS-CoV-2 spike (S) protein docking with ACE2 receptor. The phytochemicals also inhibit virus replication by inhibiting RNA-dependent RNA polymerase. Additionally the invention relates to a method of preparation of the oral herbal composition with zinc oxide (Jasad Bhasma).
  • COVID-19 is associated with both pulmonary pathology and extra pulmonary manifestations in multiple vital systems, including hematologic-immune, cardiovascular, renal, gastrointestinal and hepatobiliary, endocrine-neurologic, and ophthalmic dysfunctions.
  • SARS-CoV-2 binds to the angiotensin-converting enzyme-2 (ACE-2) receptors present on the cell surface which undergo endocytosis, and the virus enters inside the cell. Upon entering the cell, it synthesizes RNA using the host metabolic processes in which enzyme RNA dependent RNA polymerase (RdRp) is essential.
  • ACE-2 angiotensin-converting enzyme-2
  • cytokine storm Due to cellular damage caused by the virus, the alveolar macrophages generate various proinflammatory cytokines like interleukin-6 (IL-6), resulting in alterations in the vascular permeability. There is leakage of cytokines, promoting more inflammation with dysfunctional immune responses and infiltration of inflammatory cells like monocytes, macrophages, and T-cells, ultimately producing cytokine storm. Uncontrolled cytokine storm causes lung inflammation and multi organ inflammation leading to respiratory distress and organ failure, resulting in death.
  • IL-6 interleukin-6
  • US8846114B1 discloses a composition for treating herpes and cold sores.
  • a herpes treatment capsule consisting essentially of therapeutically effective amounts of olea europaea leaf extract, olea europaea fruit oil, hypericum performatum extract, propolis extract and maleluca alternifolia extract.
  • US5837257 This invention relates to compositions derived from Chinese herbal medicines, medicinal plants and extracts thereof, and to their use for the treatment of animals infected with viruses, especially with hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV).
  • viruses especially with hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV).
  • a therapeutically effective amount of a composition which comprises at least one herbal medicine selected from the group consisting of: Solani herba, prepared from the whole plant of Solanum nigrum; Lespedezae herba, prepared from the whole plant of Lespedeza cuneata; Senecinis herba, prepared from the whole plant of Senecio scandens; and Ligustri fructus, prepared from the mature fruit of at least one plant selected from the group consisting of Ligustrum lucidum and Ligustrum japonicum.
  • Solani herba prepared from the whole plant of Solanum nigrum
  • Lespedezae herba prepared from the whole plant of Lespedeza cuneata
  • Senecinis herba prepared from the whole plant of Senecio scandens
  • Ligustri fructus prepared from the mature fruit of at least one plant selected from the group consisting of Ligustrum lucidum and Ligustrum japonicum.
  • Zinc oxide (Jasad bhasma) - 3 to 8% w/w; and pharmaceutical excipients - 8 to 16% w/w. It is another aspect of the present invention to provide the herbal composition for the treatment of COVID- 19 by targeting ACE2 receptor and immunity enhancement in humans, wherein the pharmaceutical excipient includes starch.
  • composition for the treatment of COVID- 19 by targeting ACE2 receptor and immunity enhancement in humans, wherein composition preferably comprises extract of Solanum nigrum - 33.33% w/w; Acalypha indica - 33.33% w/w; Ocimum sanctum - 4% w/w; Adathoda vasica - 4% w/w; Withania somnifera - 4% w/w; Glycyrrhiza glabra - 4% w/w; Piper nigrum - 4% w/w; zinc oxide (Jasad bhasma) - 3.33% w/w; and Pharmaceutical excipients - 10% w/w.
  • compositions for treatment of COVID- 19 by targeting ACE2 receptor and immunity enhancement comprising the extract of Solanum nigrum, Acalypha indica, Ocimum sanctum, Adathoda vasica, Withania somnifera, Glycyrrhiza glabra, and Piper nigrum; and zinc oxide (Jasad bhasma) is administered at a dosage of 4500 mg per day administered as 1500 mg thrice daily.
  • Figure 1A shows a schematic of the experimental protocol. Viral entry: ACE2 receptor assay.
  • Figure IB shows a representative data of a dose response using different concentrations of CoroQuil-Zn assed to HEK293T cells and SARS-CoV-2 virus Spike (S) protein containing virions; CoroQuil-Zn reduces viral entry.
  • S SARS-CoV-2 virus Spike
  • Figure 2A illustrates graphical representation of relationship between SARS-CoV-2 genome equivalent and CoroQuil-Zn (mg/ml).
  • Figure 2B illustrates graphical representation of relationship between viability of lung cells and CoroQuil-Zn (mg/ml).
  • Figure 3A and 3B illustrates results obtained using the concentration matrix of Remdesivir and CoroQuil-Zn presented as 2D and 3D synergy visual maps.
  • Figure 4A and 4B illustrates results obtained using the concentration matrix of Favipiravir and CoroQuil-Zn presented as 2D and 3D synergy visual maps.
  • Figure 5 illustrates graphical representation of relationship between percentage of control and CoroQuil-Zn (mg/ml).
  • Figure 6 illustrates graphical representation of reduced viral load in the CoroQuil-Zn group suggesting that CoroQuil-Zn may offer protection from SARS-CoV-2 infection.
  • the present invention is an ayurvedic composition (CoroQuil-Zn) containing zinc oxide (Jasad Bhasma) and herbal extracts.
  • Herbal extracts contain phytochemicals that inhibit SARS-CoV-2 Spike (S) protein docking with ACE2 receptor. The phytochemicals also inhibit virus replication by inhibiting RNA-dependent RNA polymerase.
  • the present invention attempted to develop an efficacious prophylactic and therapeutic treatment for COVID- 19.
  • the phytoconstituents present in different plants were identified and selected using in silico molecular docking and cell-based antiviral assays for their ability to interact with the host ACE2 receptor and viral RNA-dependent RNA polymerase (RdRp).
  • the in-silico molecular docking studies revealed that flavonoids that interact with both ACE2 and RdRp proteins.
  • CoroQuil- Zn is formulated based on these molecular docking and cell-based studies of phytochemicals.
  • CoroQuil-Zn contains plant extracts derived from Acalypha indica and Solanum nigrum mainly. In addition, CoroQuil-Zn also contains Zinc oxide (Jasad bhasma), Adathoda vasica, Glycyrrhiza glabra, Ocimum sanctum, Withania somnifera, and Piper nigrum. Phytochemicals in CoroQuil-Zn reduces the entry of virus into the cell by docking at the interface of SARS-CoV-2 and ACE2 interface.
  • CoroQuil-Zn formulation comprises of the following ingredients in percentage by weight basis: Solanum nigrum: 15 to 35% w/w; Acalypha indica: 15 to 35% w/w; Ocimum sanctum: 4 to 15% w/w; Adathoda vasica: 4 to 15% w/w; Withania somnifera: 4 to 15% w/w; Glycyrrhiza glabra: 4 to 15% w/w; Piper nigrum: 4 to 15% w/w; Zinc oxide (Jasad bhasma): 3 to 8% w/w; and pharmaceutical excipients: 8 to 16% w/w.
  • the dried plant material is disintegrated/ powdered by feeding it into a hammer mill or a disc pulverizer which has built-in services.
  • the plant material is reduced to a size between 3 and 4 mm size reduction maximizes the surface area, which in turn enhances the mass transfer of active principle from plant material to the solvent.
  • the powdered material is pelletized to avoid caking.
  • the enriched extract is concentrated in multiple-effect evaporators (in case of extraction with water or the solvent is distilled out to get the concentrate).
  • the concentrated extract is subjected to vacuum drying/spray drying/ freeze drying to get the dry powder.
  • Unload the extract in double lined LDPE poly bags tie with cord and place within HDPE drums.
  • Standard operating procedure for formulation of Coroquil-Zn capsules The following is the SOP for the formulation protocol of 50,000 capsules of 750 mg Coroquil-Zn capsules. Given below is the percentage contribution of each of the ingredients for the formulation.
  • hydroalcoholic extracts of ingredients S.no: 1-7 were weighed in a calibrated electronic weighing balance. They were weighed as follows:
  • the above mixture was mixed in a sigmoidal mixing machine for a period of 15 minutes.
  • the mixed material was carefully collected and sieved by hand using a 40 mesh sieve. The entire process was completed in 35 minutes.
  • Step 5 The entire lot was weighed again to determine if there was any loss during weighing and sieving.
  • Filled capsules were chosen at random for quality control checks to determine uniformity of weight and pH. Capsules that did not meet the specifications were discarded.
  • capsules were filled in bottles with each bottle containing 60 capsules.
  • CoroQuil-Zn is considered as final finished product (FFP) and is ready for shipping.
  • Remedium therapeutics conducted a detailed literature and in silico molecular docking studies and arrived at a set of phytochemicals that could potentially serve as an entry inhibitor for SARS-CoV-2 with the Spike (S) protein. Based on list of phytochemicals, Remedium did cell culture study to find out which phytochemical had an activity as the entry inhibitor for SARS-CoV-2 Spike protein. After the discovery of a set of phytochemicals through this process, Remedium investigated the plants/herbs that have these phytochemicals in reasonable quantities.
  • Remedium performed the extraction process as prescribed in the Ayurvedic pharmacopeia of India so that the final form can be powder that can be used in the formulation of the drug CoroQuil-Zn.
  • Remedium formulated the drug using the plant extracts as prescribed in the API so that the safety profile is accounted for.
  • Remedium again performed a cell culture assay and animal studies with CoroQuil-Zn formulation to see if the same effect of inhibiting SARS-CoV-2 Spike protein is exhibited in the CoroQuil-Zn formulation. After confirmation from both the cell culture studies and animal studies Remedium concluded with the formulation and froze the specifications to take it to the Clinical trials.
  • SARS-CoV-2 virus binding of Spike (S) protein of SARS-CoV-2 virus to the host cell ACE2 receptors triggers a series of molecular events resulting in the entry of the virus into the host cells. This viral entry activates an immune response in the host for resolving the infection. Depending on the magnitude and duration of the viral load and the activation of immune response, the SARS-CoV-2 infection may result in asymptomatic, mild, moderate, and severe COVID-19 disease and in some critically ill patients may cause death.
  • CoroQuil-Zn was designed mainly to counter the binding of SARS-CoV-2 to ACE2 receptors, thereby blocking the entry of the virus into the host cells.
  • HEK293T cells that express recombinant ACE2 receptors and SARS-CoV-2 virus Spike (S) protein.
  • S SARS-CoV-2 virus Spike
  • a Bright-Glo luciferase reagent (luminescence) was added to the cells, and the luciferase activity was determined using a Veritas microplate luminometer. Luminescence measured in the absence of plant extracts was used as 100% control for quantitation.
  • Figure 1A shows a schematic of the experimental protocol.
  • the virus enters the cells by binding to the ACE2 receptors and the virus is unable to dock to the ACE2 receptor, enter into the cell and replicate. Therefore, the intensity of luminescence “Lights ON” in the Figure 1A schematic corresponds directly to the virus entering the host cells.
  • the experiment was repeated by adding CoroQuil-Zn to the HEK293T cells, there is reduction in the luminescence, which is being depicted in Figure 1A as “Lights OFF”. This confirms a 100% inhibition of viral entry into the HEK293T cells through the ACE2 receptor.
  • Figure IB shows a representative data of a dose response using different concentrations of CoroQuil-Zn added to HEK293T cells and SARS-CoV-2 virus Spike (S) protein containing virions.
  • CoroQuil-Zn produced a concentration-dependent reduction in viral entry with an IC50 of 840 pg/ml.
  • Calu-3 cells a human lung cell line expressing native ACE2 receptors.
  • CoroQuil-Zn reduces the SARS-CoV-2 viral load and increased the viability of lung cells, thereby confirming that CoroQuil-Zn can possibly be used as a therapy for SAR2-CoV-2 infection.
  • Remdesivir and Favipiravir are known to inhibit viral mRNA replication by inducing sequence errors during replication executed at RNA-dependent RNA polymerase (RdRp).
  • RdRp RNA-dependent RNA polymerase
  • ToxGlo was used to measure cell survival. Both Remdesivir (RDV) and Favipiravir (FPV) were tested at 0-5 nM, with CoroQuil-Zn (CQZ) at 0-100 mg/ml in combination with Remdesivir and Favipiravir in two independent experiments. Cell survival was measured and data analyzed using the SynergyFinder software to obtain the Loewe synergy score. A Loewe synergy score of > 10 is considered a significant synergistic effect.
  • Results obtained using the concentration matrix of Remdesivir and CoroQuil-Zn are presented as 2D and 3D synergy visual maps in Figure 3 A and Figure 3B, respectively.
  • the red region depicts the enhanced activity of Remdesivir and CoroQuil-Zn at various concentrations of Remdesivir and CoroQuil-Zn as depicted in the matrix.
  • the composite Loewe synergy score for the combination treatment was 14.93. Favipiravir and CoroQuil-Zn
  • Results obtained using the concentration matrix of Favipiravir and CoroQuil-Zn are presented as 2D and 3D synergy visual maps in Figure 4A and Figure 4B, respectively.
  • the red region depicts the enhanced activity of Favipiravir and CoroQuil-Zn at various concentrations of Favipiravir and CoroQuil-Zn as depicted in the matrix.
  • the composite Loewe synergy score for the combination treatment was 20.48.
  • the first dose of CoroQuil-Zn (300 mg/kg of CoroQuil-Zn) was administered via oral gavage 2.5 hours prior to infecting the hamster with SARS-CoV-2.
  • the Control group was given a placebo. Treatment continued in both groups every 12 hours for 4 consecutive days. Animals were euthanized on day 4, and lungs were harvested. The viral load was determined by RT-qPCR. The initial viral load on Day 1 was determined using oral swab samples.
  • the study drug was well-tolerated by the subjects and no adverse drug reactions were observed.
  • Baseline IL-6 levels compared to Day 7 and Day 14 visit There is a statistically significant reduction in IL-6 levels at day 7 (p-value: ⁇ 0.0001) and Day 14 (p-value: ⁇ 0.0001) in the CoroQuil-Zn group which is not seen in the standard of cure group when compared to the baseline visit. There is statistically significant change seen between the two treatment groups at day 7 (p-value: 0.002) and day 14 visit (p-value: 0.0046) when compared to the baseline visit.

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  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Alternative & Traditional Medicine (AREA)
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  • Mycology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne un procédé de découverte, de développement et de formulation du médicament CoroQuil-Zn pour combattre le COVID-19 en ciblant l'enzyme de conversion de l'angiotensine 2 (ACE2) et aider les gens à se remettre de la maladie hautement transmissible. La formulation à base de plantes comprend des extraits de plantes/herbes choisis parmi Solanum nigrum, Acalypha indica, Ocimum sanctum, Adathoda vasica, Withania somnifera, Glycyrrhiza glabra et Piper nigrum ; de l'oxyde de zinc (Jasad bhasma) et des excipients pharmaceutiques.
PCT/IN2021/051154 2020-12-10 2021-12-09 Composition orale à base de plantes pour le sars-cov-2 et son procédé de préparation WO2022123601A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN2012MU01517A (fr) * 2012-05-18 2014-05-16 Manish A. Rachchh Dr.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN2012MU01517A (fr) * 2012-05-18 2014-05-16 Manish A. Rachchh Dr.

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BM01/15 ; THOOTHU KANDAN KIRUTHAM; KNOWLEDGE KNOWN SINCE: 1000 YEARS *
GR 06/129 ; KAALA KANDA MEGANARAYANA CHENDURAM-2 ; KNOWLEDGE KNOWN SINCE: 200 YEARS *
KHANNA KANIKA; KOHLI SUKHMEEN KAUR; KAUR RAVDEEP; BHARDWAJ ABHAY; BHARDWAJ VINAY; OHRI PUJA; SHARMA ANKET; AHMAD AJAZ; BHARDWAJ RE: "Herbal immune-boosters: Substantial warriors of pandemic Covid-19 battle", PHYTOMEDICINE, ELSEVIER, AMSTERDAM, NL, vol. 85, 3 October 2020 (2020-10-03), AMSTERDAM, NL , XP086537990, ISSN: 0944-7113, DOI: 10.1016/j.phymed.2020.153361 *
MAURYA DHARMENDRA KUMAR, SHARMA DEEPAK: "Evaluation of traditional ayurvedic Kadha for prevention and management of the novel Coronavirus (SARS-CoV-2) using in silico approach", JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, ADENINE PRESS, NEW YORK, NY, US, vol. 40, no. 9, 13 June 2022 (2022-06-13), US , pages 3949 - 3964, XP055944908, ISSN: 0739-1102, DOI: 10.1080/07391102.2020.1852119 *
RAMESH K. GOYAL ET AL.: "Current targets and drug candidates for prevention and treatment of SARS-CoV-2 (COVID-19) infection", REVIEWS IN CARDIOVASCULAR MEDICINE, vol. 21, no. 3, - 30 September 2020 (2020-09-30), pages 365 - 384, XP055944903 *
WESSELS INGA, ROLLES BENJAMIN, RINK LOTHAR: "The Potential Impact of Zinc Supplementation on COVID-19 Pathogenesis", FRONTIERS IN IMMUNOLOGY, FRONTIERS MEDIA, LAUSANNE, CH, vol. 11, 10 July 2020 (2020-07-10), Lausanne, CH , XP055852400, ISSN: 1664-3224, DOI: 10.3389/fimmu.2020.01712 *

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