Zinc

Monica V. Mahoney, PharmD, BCPS AQ-ID, BCIDPClinical Pharmacy Specialist, Beth Israel Deaconess Medical Center

mmahoney@bidmc.harvard.edu@mmPharmD

A Review of Pertinent Drug Information for SARS-CoV-2

Data as of May 3, 2020

Zinc Chemistry & Metabol ism• Trace element

• Cellular metabolism:• Required for catalytic activity of ~100 enzymes• Immune function• Protein synthesis• Wound healing• DNA synthesis• Cell division

National Institutes of Health. Zinc Fact Sheet. https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/

https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/

Zinc

National Institutes of Health. Zinc Fact Sheet. https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/

Doses & Toxicity

Age Male Female

0-6 months 2 mg 2 mg

7-12 months 3 mg 3 mg

1-3 years 3 mg 3 mg

4-8 years 5 mg 5 mg

9-13 years 8 mg 8 mg

14-18 years 11 mg 9 mg

19+ years 11 mg 8 mg

Recommended Daily Intake:Age Male Female

0-6 months 4 mg 4 mg

7-12 months 5 mg 5 mg

1-3 years 7 mg 7 mg

4-8 years 12 mg 12 mg

9-13 years 23 mg 23 mg

14-18 years 34 mg 34 mg

19+ years 40 mg 40 mg

Tolerable Upper Intake Levels:

• N / V / D• ↓ appetite• Abdominal cramping• Headaches• ↓ copper levels• Altered iron function• ↓ immune function

https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/

Zinc Salts

Zinc acetate … 2.8 mgZinc gluconate … 7.14 mg

Zinc sulfate ….4.4 mg

Equivalent to 1 mg elemental zinc …

Common Zinc Salt Products• Zinc gluconate lozenge … 13.3 mg elemental zinc• Zinc sulfate 220 mg … 50 mg elemental zinc

www.pdr.net/drug-summary/Galzin-zinc-acetate-3863 Accessed 5/5/20

http://www.pdr.net/drug-summary/Galzin-zinc-acetate-3863

Population Intervention Infection Types

49 elderly

patients

45 mg zinc/day

vs.Placebo

Results

Prasad AS, et al. Am J Cin Nutr 2007;85:837-44

Zinc & Infectious Diseases

Infection rate:

29% vs. 88%

• Cold• URI• Fever• Flu

12-month placebo-controlled trial:

Zinc & the Common Cold

Hemila H. J Royal Society Med Open. 2017;8:1-7. https://doi.org/10.1177/2054270417694291

Meta-analysis comparing zinc lozenges ≥75 mg/day to treat cold symptoms

SALT :acetate = gluconate

DAILY DOSE :100 mg

LOZENGE DOSE & FREQUENCY:Too heterogeneous

Reduction in duration by 33%

https://doi.org/10.1177/2054270417694291

Rhinovirus

Influenza

Adenovirus

Parainfluenza

RSV

Enterovirus

Coronavirus

The Common Cold

Makela MJ et al. J Clin Microbiol. 1998;36:539-42

Zinc & SARS-CoV

te Velthuis AJW, et al. PLoS Pathogens. 2010;6:e1001176. https://doi.org/10.1371/journal.ppat.1001176

• Pyrithione (PT): zinc ionophore• Transports zinc intracellularly

• ↑ zinc via ↑ PT = Ø replication of SARS-CoV• RNA synthesis catalyzed by an RNA-dependent

RNA polymerase (RdRp)• Ø RdRp elongation• ↓ template binding

↑ PT ↓ green-fluorescent protein-marked SARS-CoV. Blue = 0 µM; green = 1 µM; black = 2 µM ZnOAC2

https://doi.org/10.1371/journal.ppat.1001176

Zinc & Chloroquine

Xue J, et al. PLoS ONE. 2014;9:e109180. https://doi.org/10.1371/journal.pone.0109180

• Chloroquine enhanced intracellular zinc uptake

• Zinc enhanced cytotoxic activity of chloroquine

https://doi.org/10.1371/journal.pone.0109180

Proposed Mechanisms of Action

Skalny AV, et al. Intern J Molecular Med. 2020. https://doi.org/10.3892/ijmm.2020.4575

https://doi.org/10.3892/ijmm.2020.4575

www.clinicaltrials.gov Accessed: 5/3/20

Tr e a t m e n t : P r o p h y l a x i s :

Current Zinc-COVID-19 Trials

NCT04370782• HCQ• Azithromycin• Zinc

• HCQ• Doxycycline• Zinc

NCT04342728• Zinc

• Zinc• Vitamin C

• Vitamin C

• SOC

NCT04351490• Zinc• Vitamin D3

• SOC

NCT04334512• HCQ• Azithromycin• Vitamin C• Vitamin D• Zinc

NCT04335084• HCQ• Vitamin C• Vitamin D• Zinc

NCT04326725• HCQ• Vitamin C• Zinc

http://www.clinicaltrials.gov/

Zinc: COVID-19 Treatment

NCT04370782• HCQ 400mg BID x 2 then 200mg BID days 2-5• Azithromycin 500mg x1 then 250mg days 2-5• Zinc sulfate 220mg daily x 5 days

• HCQ 400mg BID x 2 then 200mg BID days 2-5• Doxycycline 200mg daily x 5 days• Zinc sulfate 220mg daily x 5 days

• Randomized, open-label, outpatient treatment. 1˚ outcome = time to symptom resolution

NCT04334512 (HAZDpaC)• HCQ dose unknown• Azithromycin dose unknown• Vitamin C dose unknown• Vitamin D dose unknown• Zinc salt and dose unknown

• Open-label, single arm treatment. 1˚ outcome = successful treatment at 24 weeks

www.clinicaltrials.gov Accessed: 5/3/20

http://www.clinicaltrials.gov/

Zinc: COVID-19 Treatment

NCT04351490 (ZnD3-CoVici)• Zinc gluconate 15 mg BID x 2 months• Vitamin D3 2000 IU daily x 2 months

• SOC

• Randomized, open-label inpatient treatment ≥60 years. 1˚ outcome = survival rate in asymptomaticpatients at inclusion

NCT04342728 (COVIDAtoZ)• Zinc gluconate 50 mg qHS x 10 days

• Zinc gluconate 50 mg qHS x 10 days• Vitamin C 8000 mg/day ÷ 2-3 doses with food x 10d

• Vitamin C 8000 mg/day ÷ 2-3 doses with food x 10d

• SOC

• Open-label treatment. 1˚ outcome = time to symptom resolution

www.clinicaltrials.gov Accessed: 5/3/20

http://www.clinicaltrials.gov/

Zinc: COVID-19 Prophylaxis

NCT04335084 (HELPCOVID-19)• HCQ dose unknown• Vitamin C dose unknown• Vitamin D dose unknown• Zinc salt and dose unknown

• Open-label prophylaxis of healthcare workers at risk for COVID-19. 1˚ outcome = prevention of COVID-19 at 24 weeks via diary symptom tracking.

NCT04326725• HCQ 200 mg x1, every 3 weeks• Vitamin C dose unknown daily• Zinc salt and dose unknown daily

• Case-control prophylaxis of healthcare workers. 1˚ outcome = protection against COVID-19 at 4 months.

www.clinicaltrials.gov Accessed: 5/3/20

http://www.clinicaltrials.gov/

Zinc

National Institutes of Health. Zinc Fact Sheet. https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/

Doses & Toxicity

Age Male Female

0-6 months 2 mg 2 mg

7-12 months 3 mg 3 mg

1-3 years 3 mg 3 mg

4-8 years 5 mg 5 mg

9-13 years 8 mg 8 mg

14-18 years 11 mg 9 mg

19+ years 11 mg 8 mg

Recommended Daily Intake:Age Male Female

0-6 months 4 mg 4 mg

7-12 months 5 mg 5 mg

1-3 years 7 mg 7 mg

4-8 years 12 mg 12 mg

9-13 years 23 mg 23 mg

14-18 years 34 mg 34 mg

19+ years 40 mg 40 mg

Tolerable Upper Intake Levels:

• N / V / D• ↓ appetite• Abdominal cramping• Headaches• ↓ copper levels• Altered iron function• ↓ immune function

https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/

• Zinc is a polyvalent cation – caution with oral co-administration

• HIV medications: bictegravir, dolutegravir, elvitegravir, raltegravir• Antibiotics: quinolones, tetracyclines

• Diuretics: (chlorthalidone, hydrochlorothiazide) may ↑ urinary zinc excretion

• ↑ iron may ↓ zinc• ↑ zinc may ↓ copper

National Institutes of Health. Zinc Fact Sheet. https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/

Zinc Drug Interactions

https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/

COVID-19 Guidel ines

Accessed: 5/3/20

Guideline Zinc CitationIDSA (Infectious Diseases Society of America)

No mention https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/

NIH (National Institutes of Health) No mention https://covid19treatmentguidelines.nih.gov/introduction/

WHO (World Health Organization) No mention https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected

SCCM (Society of Critical Care Medicine – Surviving Sepsis Campaign)

No mention https://www.sccm.org/getattachment/Disaster/SSC-COVID19-Critical-Care-Guidelines.pdf?lang=en-US

NICE (National Institute for Health and Care Excellence)

No mention https://www.nice.org.uk/covid-19

https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/https://covid19treatmentguidelines.nih.gov/introduction/https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspectedhttps://www.sccm.org/getattachment/Disaster/SSC-COVID19-Critical-Care-Guidelines.pdf?lang=en-UShttps://www.nice.org.uk/covid-19

Summary• Data support zinc treatment of the common cold

• Data currently lacking in zinc for COVID-19

• Ongoing trials:• Treatment: most studying in combination therapy• Prophylaxis: only studying in combination therapy

• Not mentioned in national treatment guidelines

Zinc

Monica V. Mahoney, PharmD, BCPS AQ-ID, BCIDPClinical Pharmacy Specialist, Beth Israel Deaconess Medical Center

mmahoney@bidmc.harvard.edu@mmPharmD

A Review of Pertinent Drug Information for SARS-CoV-2

Data as of May 3, 2020

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