Use of bronopol for the treatment of diseases in fish

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai

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A61K 31045

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active

061600237

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BRIEF SUMMARY
This invention relates Go the treatment of fungal infections (especially Saprolegnia parasitica) of fish, particularly, but not exclusively, trout, salmon, salmonids in general, and their eggs. The invention also provides treatments of other fish diseases such as bacterial infections (for example bacterial gill disease--Flavobacterium branchiophilum and Cytophaga psychrophila), protozoan infections such as ciliates (for example Ichthyophthirius multifiliis) and flagellates (for example Ichthyobodo necatrix).
Saprolegnia parasitica is a rapidly spreading and fatal fungal parasite affecting both fish and fish eggs. It is conventionally treated with malachite green (diamino-triphenylmethane), but though this treatment is highly effective, the use of malachite green carries with it a number of potential problems: the compound has been suggested as a possible carcinogen and teratogen, though these effects are as yet unproven; being a strong dye, it tends to discolour water, and can under certain conditions cause staining of fish which have been treated; it has a relatively long withholding period, so that significant residues can be present in treated fish when they are harvested and sold for consumption; and the compound is not licensed as a veterinary medicament, and is actually banned from use in U.S. Federal hatcheries. The article by D. J. Alderman in Journal of Fish Diseases 8 (1985) 289-298 gives a review of the use of malachite green in treating fish diseases, and discusses some of the problems associated therewith.
One currently available alternative to malachite green is formalin, which is the substance which is now used in US Federal hatcheries. However, due to the irritancy of this substance, it can only be used under strictly controlled conditions. There is therefore a need for an improved treatment for fungal and other diseases of fish, particularly one which combines high efficacy with low toxicity. Many attempts to identify new treatments have been made in the past and the results of the screening of 40 potential alternative substances are set out in the article by D. J. Alderman appearing at Journal of Fish Diseases 5 (1982) 113-123, which also sets down standard protocols for the testing of candidate treatments. However, despite this and other work (such as that described in the article by T. A. Bailey appearing at Aquaculture 38 (1984) 97-104), the applicants are not aware of any suitable alternative treatments to malachite green and formalin having reached the marketplace.
It has now been found that bronopol (2-bromo-2-nitropropane-1,3-diol) has good activity at relatively low concentrations against Saprolegnia parasitica, and is safe to use. Bronopol is a known compound, and is used in concentrations of between 0.01 and 0.2% as an antimicrobial preservative and antiseptic in topical pharmaceutical formulations, cosmetics, and toiletries. It is stated however in "Handbook of Pharmaceutical Excipients" published by The Pharmaceutical Press (1994) that one of bronopol's major disadvantages is its relatively poor activity against yeasts and moulds. It is therefore surprising that bronopol is effective at relatively low concentrations against Saprolegnia.
As will be described in more detail below, bronopol has been shown to be effective against Saprolegnia parasiticainfection in salmon, trout and trout eggs. It is envisaged however that the treatment will be effective against the same infection in other salmonid species, and indeed in other fish (for example ornamental or pet fish), fish eggs and other aquatic creatures (such as shrimps or prawns) in general. It is expected that there will also be efficacy against other fungal infections. Furthermore, as bronopol has been shown in the trials described below to prevent or slow the spread of infection, it may also be used as a prophylactic.
Bronopol is a commercial product available from a number of sources. It may be manufactured by reacting nitromethane with paraformaldehyde in an alkaline environment, followed by bromination. It is also known t

REFERENCES:
patent: 3880827 (1975-04-01), Eble et al.
patent: 5457025 (1995-10-01), Collins et al.
patent: 5834290 (1998-11-01), Egelrud et al.
patent: 5942528 (1999-08-01), Heil et al.

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