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(Title) Proteases (medical and related uses)

See also article: Protease, for structure and properties of proteolytic enzymes

Proteases (also sometimes referred to as proteolytic enzymes or peptidases) are in use, or have been proposed or tried, for a number of purposes related to medicine or surgery. Some preparations involving protease have undergone successful clinical trials and have regulatory authorization; and some further ones have shown apparently useful effects in experimental medical studies. Proteases have also been used by proponents of alternative therapies, or identified in materials of traditional or folk medicine.

Some of these uses rely directly on the proteolytic activity: others rely on observations of anti-inflammatory activity. For at least one significant use, the mechanism of action is unclear.

Medical and surgical applications based on proteolytic effect

Treatment of blood clots in ischemic stroke

Tissue plasminogen activator (TPA) is a serine protease occurring in animals including humans. Human-identical TPA (produced industrially by genetically recombinant microorganisms) has an established medical use in the treatment of ischemic stroke: by its proteolytic activity it enables the action of another enzyme (plasmin), which breaks down the protein (fibrin) of blood clots.

Wound debridement

Debridement involves the removal of dead or damaged tissue from wounds in order to assist healing. Much of the debris to be removed is proteinaceous, and proteolytic enzymes have been applied to this purpose.

Papain is a protease obtained from the latex of the fruit of the papaya tree. It has been used (without regulation) for wound debridement for many years, but in the USA in 2008 it was brought under regulation by the FDA and removed from sale for this purpose, following reports of adverse effects. On the other hand, recent research has been exploring new ways of administering papain for wound debridement.

Papain as well as other proteases, including bromelain, collagenase, trypsin and thermolysin, have also been tried or used according to other reports on the use of proteases for debridement of wounds and burns without damaging healthy tissue.

Maggot therapy for wound debridement is a traditional therapy which was in recent years approved by the FDA. It has been identified that the maggots produce proteolytic enzymes which take part in the debridement process.

Applications of proteases auxiliary to antibiotic therapy

Some pathogenic bacteria produce biofilms or exudates containing protein, which in some degree help the bacteria adhere to host tissue, or in some degree physically shield the bacteria or hinder the penetration of substances such as antibiotics administered with the intent that they contact the bacteria. Accordingly, proteolytic enzymes have been tried in conjunction with antibiotics. Thus, it has been reported that Serratia E-15 protease (also known as serratiopeptidase) was effective for eradicating infection caused by biofilm-forming bacteria in an experimental animal model (which involved carrying out experimental limb surgery on rats, at the same time experimentally introducing Staphylococcus infection). The authors considered that "The antibiofilm property of the enzyme may enhance antibiotic efficacy in the treatment of staphylococcal infections."

The same enzyme, when used concomitantly with an antibiotic, was also reported to increase antibiotic concentration at a target site.

Applications of protease based on anti-inflammatory activity

Bromelain is a protease usually obtained from pineapple stem tissue, which has been medically used for its anti-inflammatory effects (see Bromelain - medical uses and references cited in that article).

Serratia E-15 protease (also known as serratiopeptidase or 'serrapeptidase') is another protease that has been proposed as an anti-inflammatory agent. Anti-inflammatory effects of this protease have been reported again more recently, and the material has come into some use in alternative or complementary medicine. On the other hand, it does not appear that there are positive clinical trial results for this material of a kind that would be needed to gain regulatory approval for controlled pharmaceutical uses.

Medical applications of protease where the mechanism is unclear

Drotrecogin alfa (also known as Xigris (TM)) is a serine protease of human origin, designated protein C, produced in recombinant form and licensed for intensive-care treatment of severe sepsis. It appears unclear whether its effects arise by its proteolytic activity, or from anti-inflammatory effects, or other mechanism.

References

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This article discusses primarily the structure and properties of proteolytic enzymes. For medical, surgical and related applications of several proteases, see article: Proteases (medical and related uses)

This page is about uses of proteolytic enzymes for medical and related purposes. For the structure and enzymology of proteolytic enzymes, see Protease.

See also article: Proteases (medical and related uses)

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Eckert also took a notable part in bringing the calculations of the Moon's position for the Nautical Almanac into the digital age. During Eckert's time at Yale, he had worked with E W Brown, whose Tables of the Motion of the Moon had previously been adopted by the national nautical almanac offices in US and UK for their calculations of the Moon's position as from 1923.

Brown's theory and tables were the last of the manually-produced classical lunar theories and tables, and it had taken over 30 years of work to bring them to completion.

But even to use them manually to produce the annual tabulations of lunar positions in the almanacs was a laborious undertaking. Steps had been taken during the inter-war years towards partly automating this part of the process using Hollerith punched-card machines: Eckert became responsible, in the late 1940s for implementing these calculations by programmable computing, using the IBM Selective Sequence Electronic Calculator (SSEC) from 1948 onwards.

What Eckert did was to use Brown's original trigonometrical expressions, given in the introduction to the 1919 tables (and from which the tables had been constructed), for direct computation, instead of using the tables themselves. This already gained some improvement in precision, because the tables had included some minor approximations in a trade-off between accuracy and the amount of labor need to use them in those days of manual calculation.

Also, by mid-century, the difference between Universal and Ephemeris Time had been recognised and evaluated. Up to that point, a doubtful empirical term had been included in the lunar calculations, as part of an attempt to account for effects on lunar motion which became firmly recognised during the first half of the 20th century as the result of past irregularities in the rotation of the Earth rather than in the motion of the Moon. This term was removed in Eckert's newly computed version of the lunar ephemeris, which was adjusted to match the history of the newly defined timescale, named Ephemeris Time. The result was the Improved Lunar Ephemeris. (It has sometimes been reported that the resulting tables of the early 1950s were used to guide the Apollo 11 spacecraft to the Moon in 1969, but records cited in the article IBM SSEC make it seem more likely that subsequent indirectly-related and corrected derivative data were used.)

It has been reported that the SSEC was set busy calculating lunar positions during its formal opening in January 1948.

Eckert later made further adjustments to Brown's theory in a later stage, arising from improved observational values of the fundamental astronomical constants used in the theory, and from re-working Brown's original analytical expansions to gain more precise versions of the coefficients used in the theory (Eckert et al., 1966, cited below).

(Eckert et al., 1954, already cited)

It was only as recently as in the almanacs for 1984 that Brown's work, as modified by Eckert, was superseded: it was replaced by results gained from more modern observational data (including data from lunar laser ranging) and by altogether new computational methods for calculating the Moon's ephemeris (see 'Explanatory Supplement' 1992, cited below).

Tabular data based on Brown's theory continued to be used, eventually with some modification, for most of the remainder of the 20th century (until 1983).

• Brown, E.W. An Introductory Treatise on the Lunar Theory. Cambridge University Press, 1896 (republished by Dover, 1960).
• Brown, E.W. Tables of the Motion of the Moon. Yale University Press, New Haven CT, 1919.
• Brown, E.W. and Shook, C.A. Planetary Theory. Cambridge University Press, 1933 (republished by Dover, 1964).

• Eckert, W J, et al., Improved Lunar Ephemeris, 1954, US Government Printing Office.
• Eckert, W J, et al., 1966, Transformations of the Lunar Coordinates and Orbital Parameters, Astron J 71, 314.

• Explanatory Supplement to the Astronomical Almanac p 317. University Science Books, Mill Valley, CA, 1992, ISBN 0-935702-68-7.

Mulholland and Devine (1968) mention that the JPL Ephemeris Tape System was "used for virtually all computations of spacecraft trajectories in the US space program", and had, as its current lunar ephemeris, an evaluation of the Improved Lunar Ephemeris incorporating a number of corrections, referenced as 'The Improved Lunar Ephemeris' (which was the documented result of the Eckert computations carried out by the SSEC, giving lunar position results from 1952-1971), with corrections as described in references Eckert et al (1966), and Supplement to the AE 1968 . Thus the JPL appears to have been using lunar data generated by a modified derivative of the computational procedure pioneered using the SSEC, rather than the directly resulting tabulations.