Bromhexine

Identification

Summary

Bromhexine is a mucolytic drug used to decrease the viscosity of mucus in the airway, enhancing mucus clearance.

Generic Name

Bromhexine

DrugBank Accession Number

DB09019

Background

Bromhexine is mucolytic agent used for a variety of respiratory conditions associated with increased mucus secretion. It is derived from the Adhatoda vasica plant and aids in the clearance of excess mucus, improving breathing and reducing cough. It was introduced into the market in 1963, and is widely available as an over-the-counter drug in many countries.¹ Recently, bromhexine and its metabolite ambroxol have garnered interest for the potential prevention and treatment of COVID-19 due to their interactions with cell receptors in the lungs.^5,6

Type

Small Molecule

Groups

Approved

Structure

Similar Structures

Weight: Average: 376.13
Monoisotopic: 373.999323944
Chemical Formula: C₁₄H₂₀Br₂N₂

Synonyms

3,5-dibromo-N(alpha)-cyclohexyl-N(alpha)-methyltoluene-alpha-2-diamine
Bromexina
Bromhexina
Bromhexine
Bromhexinum
N-cyclohexyl-N-methyl-(2-amino-3,5-dibrombenzyl)amine

External IDs

NA 274

Pharmacology

Indication

Bromohexine is used alone or with other ingredients such as diphenhydramine, dextromethorphan, and guaifenesin to reduce mucus viscosity and clear mucus in conditions associated with mucus hypersecretion, including the common cold, influenza, respiratory tract infections, or other conditions.¹¹

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Associated Conditions

Associated Therapies

Airway secretion clearance therapy

Contraindications & Blackbox Warnings

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Pharmacodynamics

Bromhexine thins airway secretions, improving breathing and discomfort associated with thick mucus in airways associated with a variety of respiratory conditions.^1,9,11

Mechanism of action

Inflammation of the airways, increased mucus secretion, and altered mucociliary clearance are the hallmarks of various diseases of the respiratory tract. Mucus clearance is necessary for lung health; bromhexine aids in mucus clearance by reducing the viscosity of mucus and activating the ciliary epithelium¹¹, allowing secretions to be expelled from the respiratory tract.¹

Recent have studies have demonstrated that bromhexine inhibits the transmembrane serine protease 2 receptor (TMPRSS2) in humans. Activation of TMPRSS2 plays an important role in viral respiratory diseases such as influenza A and Middle East Respiratory Syndrome (MERS). Inhibition of receptor activation and viral entry by bromhexine may be effective in preventing or treating various respiratory illnesses, including COVID-19.⁵ In vitro studies have suggested the action of ambroxol (a metabolite of bromhexine) on the angiogensin-converting enzyme receptor 2 (ACE2), prevents entry of the viral envelope-anchored spike glycoprotein of SARS-Cov-2 into alveolar cells or increases the secretion of surfactant, preventing viral entry.⁶

Target	Actions	Organism
UTransmembrane protease serine 2	Not Available	Humans
UAngiotensin-converting enzyme 2	binder	Humans

Absorption

After oral administration, bromhexine demonstrates linear pharmacokinetics when given in doses of 8-32 mg. Bromhexine is readily absorbed in the gastrointestinal tract at a rapid rate. This drug undergoes extensive first-pass effect in the range of 75-80%.^3,11 The bioavailability is therefore reduced to approximately 22-27%.¹¹

Volume of distribution

After intravenous administration in a pharmacokinetic study, bromhexine was found to be widely distributed. Bromhexine is known to cross the blood-brain barrier; small concentrations may cross the placenta. The average volume of distribution of bromhexine was 1209 ± 206 L (19 L/kg). Lung tissue concentrations of bromhexine two hours after a dose were 1.5 to 3.2 times higher in bronchial tissues than plasma concentrations. Pulmonary parynchema concentrations were 3.4 to 5.9 times higher when compared to plasma concentrations.¹¹

Protein binding

Bromhexine is approximately 95% bound to plasma proteins.¹¹

Metabolism

Bromhexine is almost completely metabolized to a variety of hydroxylated metabolites in addition to dibromanthranilic acid. Ambroxol is a known metabolite of bromhexine.¹¹ In one study of human plasma, (E)-4-hydroxydemethylbromhexine (E-4-HDMB) and (E)-3-hydroxydemethylbromhexine (E-3-HDMB) were quantified as major metabolites of ambroxol, and (Z)-4-hydroxydemethylbromhexine and (Z)-3-hydroxydemethylbromhexine were quantified as minor metabolites.⁴

Route of elimination

After a dose of bromhexine was administered during a pharmacokinetic study, approximately 97% of the radiolabeled dose was detected in the urine; under 1% was detected as the parent drug.¹¹

Half-life

Following single oral doses ranging from 8 and 32 mg, the terminal half-life of bromhexine has been measured between 6.6 and 31.4 hours.¹¹

Clearance

The clearance of bromhexine ranges from 843-1073 mL/min, within the range of the hepatic circulation.¹¹

Adverse Effects

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Toxicity

The oral LD50 of bromhexine in rats is 6 g/kg.¹² The observed symptoms of accidental overdose with bromhexine are consistent with the known adverse effects of bromhexine, including headache, nausea, and vomiting, among other symptoms. Provide symptomatic treatment and contact poison control services if an overdose is confirmed or suspected.¹¹

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions: This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions: No interactions found.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Bromhexine hydrochloride	YC2ZOM3Z8V	611-75-6	UCDKONUHZNTQPY-UHFFFAOYSA-N

International/Other Brands

Amiorel (Boehringer Ingelheim) / Bisolmed (Boehringer Ingelheim) / Bisolvon (Boehringer Ingelheim) / Bisolvon Chesty (Boehringer Ingelheim) / Fluibron

Over the Counter Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
AXCEL BROMHEXINE (CHILDREN) SYRUP	Syrup		Oral	KOTRA PHARMA (M) SDN. BHD.	2020-09-08	Not applicable
AXCEL BROMHEXINE TABLET	Tablet		Oral	KOTRA PHARMA (M) SDN. BHD.	2020-09-08	Not applicable
AXINE SYRUP 4MG/5ML	Syrup		Oral	ROYCE PHARMA MANUFACTURING SDN. BHD.	2020-09-08	Not applicable
AXINE TABLET 8MG	Tablet		Oral	ROYCE PHARMA MANUFACTURING SDN. BHD.	2020-09-08	Not applicable
BEACOLYTIC ELIXIR 4MG/5ML	Elixir		Oral	DUOPHARMA MANUFACTURING (BANGI) SDN BHD	2020-09-08	Not applicable
BEACOLYTIC TABLET 8MG	Tablet		Oral	DUOPHARMA MANUFACTURING (BANGI) SDN BHD	2020-09-08	Not applicable
BISCOMIN SYRUP 4mg/5ml	Syrup		Oral	MALAYSIAN PHARMACEUTICAL INDUSTRIES SDN. BHD.	2020-09-08	Not applicable
BISCOMIN TABLETS 8MG	Tablet		Oral	MALAYSIAN PHARMACEUTICAL INDUSTRIES SDN. BHD.	2020-09-08	Not applicable
BISLAN TABLET 8MG	Tablet		Oral	Y.S.P. INDUSTRIES (M) SDN BHD	2020-09-08	Not applicable
BROMHEXINE ELIXIR	Elixir	4 mg/5ml	Oral	บริษัท พาตาร์แลบ (2517) จำกัด จำกัด	2013-05-08	Not applicable

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End
ATHEN JARABE	Bromhexine hydrochloride (0.08 g) + Guaifenesin (2 g)	Syrup	Oral	COLOMPACK S.A.	2014-04-02	2016-05-06
BREMIEL® JARABE ADULTOS	Bromhexine hydrochloride (0.08 g) + Guaifenesin (2 g)	Syrup	Oral	COASPHARMA S.A.S.	2011-08-23	Not applicable
BREMIEL®JARABE PEDIATRICO	Bromhexine hydrochloride (0.04 g) + Guaifenesin (1 g)	Syrup	Oral	COASPHARMA S.A.S.	2011-08-09	2018-10-11
BRO-GU SOLUCION ORAL	Bromhexine hydrochloride (80 mg) + Guaifenesin (2000 mg)	Solution	Oral	COASPHARMA S.A.S.	2018-06-05	Not applicable
BROMYL	Bromhexine hydrochloride (0.08 g) + Guaifenesin (2 g)	Syrup	Oral	FABRIFARMA S.A.	2018-05-07	2019-01-24
BRONCODEX®	Bromhexine hydrochloride (0.08 g) + Guaifenesin (2 g)	Syrup	Oral	COLOMPACK S.A.	2018-03-23	Not applicable
BRONCODEX® JARABE NIŃOS	Bromhexine hydrochloride (0.04 g) + Guaifenesin (1 g)	Syrup	Oral	COLOMPACK S.A.	2018-03-23	Not applicable
DOSFLEM ® ADULTOS	Bromhexine hydrochloride (0.08 g) + Guaifenesin (2 g)	Syrup	Oral	FABRIFARMA S.A.	2018-01-05	Not applicable
DOSFLEM ® NIŃOS	Bromhexine hydrochloride (40 mg) + Guaifenesin (1000 mg)	Syrup	Oral	FABRIFARMA S.A.	2018-01-05	Not applicable
DURO-TUSS EXPECTORANT COUGH LIQUID	Bromhexine hydrochloride (12 mg/15mL) + Pholcodine (15 mg/15mL)	Elixir	Oral	INOVA PHARMACEUTICALS (SINGAPORE) PTE. LIMITED	1994-02-02	Not applicable

Chemical Identifiers

UNII: Q1J152VB1P
CAS number: 3572-43-8
InChI Key: OJGDCBLYJGHCIH-UHFFFAOYSA-N
InChI: InChI=1S/C14H20Br2N2/c1-18(12-5-3-2-4-6-12)9-10-7-11(15)8-13(16)14(10)17/h7-8,12H,2-6,9,17H2,1H3
IUPAC Name: 2,4-dibromo-6-{[cyclohexyl(methyl)amino]methyl}aniline
SMILES: CN(CC1=CC(Br)=CC(Br)=C1N)C1CCCCC1

References

Synthesis Reference

童元峰杨庆云张嵩张对良. (2015). Production method of bromhexine hydrochloride(Worldwide CN2013103399540A ).https://patents.google.com/patent/CN103396323A/en

General References

Zanasi A, Mazzolini M, Kantar A: A reappraisal of the mucoactive activity and clinical efficacy of bromhexine. Multidiscip Respir Med. 2017 Mar 20;12:7. doi: 10.1186/s40248-017-0088-1. eCollection 2017. [Article]
Ansarin K, Tolouian R, Ardalan M, Taghizadieh A, Varshochi M, Teimouri S, Vaezi T, Valizadeh H, Saleh P, Safiri S, Chapman KR: Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: A randomized clinical trial. Bioimpacts. 2020;10(4):209-215. doi: 10.34172/bi.2020.27. Epub 2020 Jul 19. [Article]
Bechgaard E, Nielsen A: Bioavailability of bromhexine tablets and preliminary pharmacokinetics in humans. Biopharm Drug Dispos. 1982 Oct-Dec;3(4):337-44. doi: 10.1002/bdd.2510030407. [Article]
Liu J, Chen X, Hu Y, Cheng G, Zhong D: Quantification of the major metabolites of bromhexine in human plasma using RRLC-MS/MS and its application to pharmacokinetics. J Pharm Biomed Anal. 2010 Apr 6;51(5):1134-41. doi: 10.1016/j.jpba.2009.11.024. Epub 2009 Dec 1. [Article]
Habtemariam S, Nabavi SF, Ghavami S, Cismaru CA, Berindan-Neagoe I, Nabavi SM: Possible use of the mucolytic drug, bromhexine hydrochloride, as a prophylactic agent against SARS-CoV-2 infection based on its action on the Transmembrane Serine Protease 2. Pharmacol Res. 2020 Jul;157:104853. doi: 10.1016/j.phrs.2020.104853. Epub 2020 Apr 30. [Article]
Alkotaji M: Azithromycin and ambroxol as potential pharmacotherapy for SARS-CoV-2. Int J Antimicrob Agents. 2020 Dec;56(6):106192. doi: 10.1016/j.ijantimicag.2020.106192. Epub 2020 Oct 10. [Article]
Gupta PR: Ambroxol - Resurgence of an old molecule as an anti-inflammatory agent in chronic obstructive airway diseases. Lung India. 2010 Apr;27(2):46-8. doi: 10.4103/0970-2113.63603. [Article]
Jauch R, Bozler G, Hammer R, Koss FW, Karlsson M, Vitek E, Haring I, Beschke K, Hadamovsky S, Maass D, Wollmann R: [Ambroxol, studies of biotransformation in man and determination in biological samples (author's transl)]. Arzneimittelforschung. 1978;28(5a):904-11. [Article]
NPRA Product Information: Salmodil (salbutamol sulfate/bromhexine hydrochloride) oral syrup [Link]
NPRA Product Information: Rexom Unizet (diphenhydramine hydrochloride/bromhexine hydrochloride/ammonium chloride) oral syrup [Link]
AUSTRALIAN PRODUCT INFORMATION – BISOLVON® CHESTY (BROMHEXINE HYDROCHLORIDE) for oral use [Link]
Fischer Scientific MSDS: Bromhexine hydrochloride [Link]

External Links

KEGG Drug: D07542
PubChem Compound: 2442
PubChem Substance: 310264976
ChemSpider: 2348
BindingDB: 50239965
RxNav: 1753
ChEBI: 77032
ChEMBL: CHEMBL253376
ZINC: ZINC000000608220
Drugs.com: Drugs.com Drug Page
Wikipedia: Bromhexine

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Prevention	Coronavirus Disease 2019 (COVID‑19) / Increased Risk of SARS-CoV-2 Infection	1
4	Recruiting	Treatment	Coronavirus Disease 2019 (COVID‑19)	1
4	Recruiting	Treatment	Coronavirus Disease 2019 (COVID‑19) / Treatment Efficacy	1
3	Completed	Treatment	Abnormal Mucus Secretions / Respiratory Tract Diseases	1
3	Not Yet Recruiting	Treatment	Coronavirus Disease 2019 (COVID‑19)	1
3	Recruiting	Treatment	Coronavirus Disease 2019 (COVID‑19)	1
1	Not Yet Recruiting	Treatment	Pharmacokinetics	1
0	Enrolling by Invitation	Prevention	Antimalarials / Antirheumatic Agents / Coronavirus Disease 2019 (COVID‑19) / Enzyme Inhibitors / Hydroxychloroquine	1
Not Available	Active Not Recruiting	Treatment	Coronavirus Disease 2019 (COVID‑19) / Novel Coronavirus Pneumonia	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Granule		8 MG
Injection	Intramuscular; Intravenous
Injection, solution		4 MG/2ML
Solution	Oral	2 MG/ML
Suppository	Rectal	16 MG
Suppository	Rectal	8 MG
Solution	Oral
Solution	Oral	8 MG/5ML
Tablet	Oral	8 mg/1
Solution	Respiratory (inhalation)	0.2 g
Tablet, soluble	Oral	8 mg
Tablet	Oral	8 mg
Tablet, sugar coated	Oral	8 mg/1
Solution	Oral	8 MG/10ML
Tablet	Oral	12 MG
Solution	Oral	12 MG/ML
Solution	Oral	8 MG/ML
Powder	Not applicable	1000 g/1000g
Tablet	Oral
Syrup	Oral	0.16 g
Cream	Oral; Vaginal
Syrup	Oral	50 mg
Syrup	Oral	0.08 g
Powder
Solution	Oral	12 mg/15ml
Elixir	Oral	12 mg/15mL
Solution	Oral
Solution	Oral	80 mg
Tablet
Elixir	Oral
Tablet	Oral	8.00 mg
Syrup	Oral
Elixir	Oral
Solution	Oral	0.08 g
Solution	Oral	160 mg
Syrup	Oral
Capsule, liquid filled	Oral	8 mg
Syrup	Oral	80 mg
Solution	Oral	0.16 g
Syrup	Oral	160 mg
Syrup	Oral	8 mg/10ml
Syrup	Oral	40 mg
Elixir	Oral	4 mg/5ml
Syrup	Oral	0.08 g
Tablet, film coated	Oral
Solution
Tablet, sugar coated	Oral
Capsule
Capsule		8 mg
Solution	Oral	4 mg/5ml
Solution		4 mg/5ml
Syrup
Elixir	Oral	4 mg/5ml
Syrup	Oral	4 mg/5ml
Solution		2 mg/1ml
Syrup	Oral	8 mg/5ml
Tablet, film coated

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	232-235	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB3249453.htm
boiling point (°C)	413.8	https://www.guidechem.com/dictionary/en/3572-43-8.html
water solubility	<1 mg/mL	https://www.scbt.com/p/bromhexine-hydrochloride-611-75-6https://www.scbt.com/p/bromhexine-hydrochloride-611-75-6
logP	5.14	https://www.guidechem.com/dictionary/en/3572-43-8.html
pKa	8.69	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB92617054.htm

Predicted Properties

Property	Value	Source
Water Solubility	0.00362 mg/mL	ALOGPS
logP	4.08	ALOGPS
logP	4.42	ChemAxon
logS	-5	ALOGPS
pKa (Strongest Acidic)	19.89	ChemAxon
pKa (Strongest Basic)	9.32	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	2	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	29.26 Å²	ChemAxon
Rotatable Bond Count	3	ChemAxon
Refractivity	85.56 m³·mol^-1	ChemAxon
Polarizability	32.98 Å³	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
LC-MS/MS Spectrum - LC-ESI-QTOF , positive	LC-MS/MS	splash10-03di-0095000000-2c4f15e31beb22fd1178
LC-MS/MS Spectrum - LC-ESI-QTOF , positive	LC-MS/MS	splash10-03di-0090000000-4d3be1605bfa79609959
LC-MS/MS Spectrum - LC-ESI-QTOF , positive	LC-MS/MS	splash10-03di-0090000000-428c05c13a2a9e326945
LC-MS/MS Spectrum - LC-ESI-QTOF , positive	LC-MS/MS	splash10-03di-0390000000-b0ece5d5d6f8b78af198

Targets

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Details1. Transmembrane protease serine 2

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Plasma membrane-anchored serine protease that participates in proteolytic cascades of relevance for the normal physiologic function of the prostate (PubMed:25122198). Androgen-induced TMPRSS2 activates several substrates that include pro-hepatocyte growth factor/HGF, the protease activated receptor-2/F2RL1 or matriptase/ST14 leading to extracellular matrix disruption and metastasis of prostate cancer cells (PubMed:15537383, PubMed:26018085, PubMed:25122198). In addition, activates trigeminal neurons and contribute to both spontaneous pain and mechanical allodynia (By similarity).
Specific Function: Scavenger receptor activity
Gene Name: TMPRSS2
Uniprot ID: O15393
Uniprot Name: Transmembrane protease serine 2
Molecular Weight: 53858.845 Da

References

Habtemariam S, Nabavi SF, Ghavami S, Cismaru CA, Berindan-Neagoe I, Nabavi SM: Possible use of the mucolytic drug, bromhexine hydrochloride, as a prophylactic agent against SARS-CoV-2 infection based on its action on the Transmembrane Serine Protease 2. Pharmacol Res. 2020 Jul;157:104853. doi: 10.1016/j.phrs.2020.104853. Epub 2020 Apr 30. [Article]
Maggio R, Corsini GU: Repurposing the mucolytic cough suppressant and TMPRSS2 protease inhibitor bromhexine for the prevention and management of SARS-CoV-2 infection. Pharmacol Res. 2020 Jul;157:104837. doi: 10.1016/j.phrs.2020.104837. Epub 2020 Apr 22. [Article]
Depfenhart M, de Villiers D, Lemperle G, Meyer M, Di Somma S: Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy? Intern Emerg Med. 2020 Aug;15(5):801-812. doi: 10.1007/s11739-020-02383-3. Epub 2020 May 26. [Article]

Details2. Angiotensin-converting enzyme 2

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Binder
Curator comments: Ambroxol is a major metabolite of bromhexine.

General Function: Zinc ion binding
Specific Function: Carboxypeptidase which converts angiotensin I to angiotensin 1-9, a peptide of unknown function, and angiotensin II to angiotensin 1-7, a vasodilator. Also able to hydrolyze apelin-13 and dynorphin...
Gene Name: ACE2
Uniprot ID: Q9BYF1
Uniprot Name: Angiotensin-converting enzyme 2
Molecular Weight: 92462.4 Da

References

Olaleye OA, Kaur M, Onyenaka CC: Ambroxol Hydrochloride Inhibits the Interaction between Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein's Receptor Binding Domain and Recombinant Human ACE2. bioRxiv. 2020 Sep 14. doi: 10.1101/2020.09.13.295691. [Article]
Alkotaji M: Azithromycin and ambroxol as potential pharmacotherapy for SARS-CoV-2. Int J Antimicrob Agents. 2020 Dec;56(6):106192. doi: 10.1016/j.ijantimicag.2020.106192. Epub 2020 Oct 10. [Article]

Enzymes

Details1. Angiotensin-converting enzyme 2

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Binder

General Function: Zinc ion binding
Specific Function: Carboxypeptidase which converts angiotensin I to angiotensin 1-9, a peptide of unknown function, and angiotensin II to angiotensin 1-7, a vasodilator. Also able to hydrolyze apelin-13 and dynorphin...
Gene Name: ACE2
Uniprot ID: Q9BYF1
Uniprot Name: Angiotensin-converting enzyme 2
Molecular Weight: 92462.4 Da

References

Olaleye OA, Kaur M, Onyenaka CC: Ambroxol Hydrochloride Inhibits the Interaction between Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein's Receptor Binding Domain and Recombinant Human ACE2. bioRxiv. 2020 Sep 14. doi: 10.1101/2020.09.13.295691. [Article]

Drug created at June 24, 2014 16:22 / Updated at May 07, 2021 21:33

Bromhexine

Identification

Structure for Bromhexine (DB09019)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Targets

References

References

Enzymes

References