Status: FDA approved; not manufactured or marketed

Organizations involved:

Parke-Davis Div. – Manuf.; R&D; Tech.; Former inv.

Fujisawa USA, Inc. – USA mark.; Former inv.

Warner-Lambert Co. – Parent co..; Former inv.

Cross ref.: See the entry for recombinant DNase (Pulmo-zyme) (#126) in the Recombinant DNA Products section. See the Fibrinolytic and Thrombolytic Enzymes entry (#613)

Description: Fibrinolysin and Deoxyribonuclease Combined (Bovine) is a topical ointment formulation containing fibrinolysin enzyme protein derived from bovine (cow) plasma and deoxyribonuclease (DNase) enzyme protein derived from bovine pancreas.

This entry actually covers two distinct products – Fibrinolysin and Desoxyribonuclease Combined (Bovine); and Fibrinolysin, and Desoxyribonuclease Combined (Bovine) with Chloramphenicol (an antibiotic). Both of these are currently approved. However, these products are no longer manufactured or marketed in the U.S.

Elase was used for enzymatic debridement (clearing/cleaning) of necrotic (decayed) tissue by-products in a variety of inflammatory skin wounds, and intravaginally for vaginitis and cervicitis. Purulent wound exudates (pus) consists largely of cellular debris, particularly partially broken down fibrous proteins and nucleic acids. The DNase in Elase ointment breaks down the DNA in the exudate which acts as a thickener, leading to a significant reduction in purulent exudate (pus) viscosity. The fibrinolysin breaks down fibrin (the structural component of blood clots) and fibrinous exudates in the pus, further reducing this exudate viscosity. The fibrinoly-sin is active against denatured proteins, such as those in devitalized (dead) tissue, generally leaving healthy cellular fibrin and healthy tissues unaffected.

Elase ointment was packaged in 10 and 30 gram tubes. Disposable applicators were available for vaginal application. The 30 gram tube contained 30 units (Loomis units) of fibrinolysin and 20,000 units of DNase with 0.12 mg thimerosal (mercury derivative; entry #939) as an antimicrobial preservative, in an inert ointment base of liquid petrolatum (petroleum gelly) and polyethylene glycol (PEG) polymer. Other excipients were sodium chloride and sucrose. The 10 gram tube of Elase contained 10 units of fibrinolysin and 6,666 units of DNase, and included an elongated nozzle to aid in application to surface lesions. Elase was originally available as a lyophilized powder.

Biological.: DNase from bovine pancreas is a type I deoxyribonuclease (DNase I) with a molecular weight of ~31,000 dalton (31 kDa) and an optimum pH of 7.8. DNase I is an endonuclease enzyme that splits phosphodiester linkages linking the nucleotides within polynucleotides, acting primarily on single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), and chromatin. DNase I is activated by bivalent metal ions, such as Mg2+ and Ca2+. Bovine pancreatic DNase selectively splits phospho-diester bonds of DNA, preferentially adjacent to a pyrimidine nucleotide, yielding polynucleotides with a free hydroxyl at the 3’-position and a phosphate group at the 5’-position. The average nucleotide chain length of a limit digest is a tetranu-cleo-tide. See the recombinant DNase (Dornase alfa) entry (#126) for further DNase information.

DNase is generally assayed according to the photometric method developed by Kunitz (see Kunitz, M., Journal of General Physiology, vol. 33, p. 349 and 363, 1950). One DNase unit results in an increase in absorbance at 260 nm of 0.001/minute at 25˚C when acting upon highly polymerized DNA at pH of 5.0. Also, 0.005 Kunitz unit digests 1 µg of lambda bacteriophage DNA in ten minutes at 37% in 50 mM Tris, 1 mM Mg2+, pH of 7.8 in a 50 µl reaction.

Fibrinolysin is a protease enzyme formed by the enzymatic action of streptokinase on profibrinolysin. Fibrinolysin is normally present in human and bovine plasma and serum in the form of profibrinolysin. Fibrinolysin (bovine) is a water-insoluble, saline soluble, nondia-lyz-able, euglobulin with an isolectric point of pH 5.5. The Loomis unit of fibrinolysin activity is defined as that quantity which will liquify 1 mL of a 0.3% fibrin clot in 120 seconds at 45˚C in an imidazole buffered system at pH 7.2. The use of 0.3% fibrin clot was chosen because it is comparable in fibrin content to human blood clots. The proteolytic activity of fibrinolysin, compared to trypsin and other proteinases, is marked by primary production of relatively large, soluble products, which are further hydrolyzed at a slower rate. This is desirable since diffusion of smaller breakdown molecules, such as result from use of bacterial enzymes for wound debridement, can cause systemic adverse effects (e.g., chills). Fibrinolysin breaks down purified blood products in vitro and ex vivo but not in the blood (in vivo) where it is neutralized by the action of fibrinolysin antibodies. Note, Merck & Co., Inc. was approved for manufacture of Fibrinolysin (Human) from April 1960-Nov. 1985.

Nomenclature: Fibrinolysin & DNase [BIO]; Elase [TR held by Warner-Lambert Co.]; Fibrinolysin and Deoxyribonuclease Combined (Bovine) [FDA]; Fibrinolysin, Human [INN]; Plasmin [BAN]; 9004-09-5 [CAS RN]

Companies.: Elase products were manufactured by Parke-Davis, Div., Warner-Lambert Co. (now merged into Pfizer), CBER/FDA est. no. 0001. The products were marketed in the U.S. by Parke-Davis/Warner-Lambert; and since 1990 by Fujisawa USA, Inc. The product was returned to Parke-Davis by Fujisawa, and subsequently discontinued (no longer manufactured or marketed).

Manufacture: Fibrinolysin was manufactured using the method developed by Loomis, et al., for activation of profibrinolysin with chloroform. See Lommis, E.C. et al, Fibrinolysin: Nomenclature, Unit, Assay, Preparation and Properties, Archives of Biochemistry, vol. 12, p. 1, 1947. Thimerosal is used as an antimicrobial preservative during the manufacture of fibrinolysin.

The DNase was isolated from bovine (cow) pancreas. See, Kunitz, M., Crystalline Desoxyribonuclease I. Isolation and General Properties, Journal of General Physiology, vol 33, p. 348, 1950.

FDA class: Biologic PLA

CBER class: Blood And Blood Derivatives

Approvals: Date = 19600419; first approval, PLA, granted to Parke-Davis Div., Warner-Lambert Co. for Fibrinolysin and Deoxyribonuclease

Date = 19630924; PLA; Indication = new formulation, Fibrinolysin and Deoxyribonuclease Combined (Bovine) with Chloramphinicol (an antibacterial agent added)

Indications: [from 1994 FDA product insert review]:

as a debriding agent in a variety of inflammatory and infected wounds. These include: (1) general surgical wounds, (2) ulcerative lesions - trophic, decubitus, stasis, arteriosclerotic, (3) second- and third-degree burns, (4) circumcision and episotomy. Elase is used intravaginally in: (1) cervicitis - benign, postpartum, and postconization and (2) vaginitis.

Status: The approvals for both Fibrinolysin and Desoxyribo-nuclease Combined (Bovine) with Chloramphenicol and Fibrinolysin and Desoxyribonuclease remain valid (4/2005). However, the product is no longer manufactured or marketed.

Medical: The product was primarily used for wound debridement (wound clearing and cleaning), involving removal of necrotic (dead) debris and purulent exudates (pus) from a variety of topical lesions. Necrotic tissue is removed, leaving healthy tissue intact and clean surfaces for healing.