Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-05-30
2001-12-11
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S400000, C424S438000, C424S234100, C424S114000
Reexamination Certificate
active
06328989
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new use of bicozamycins. More particularly, it relates to use of bicozamycins for the prophylaxis and treatment of infections with a verotoxin-producing
Escherichia coli
, as well as for eradicating verotoxin-producing
Eschetichia coli
in livestock.
BACKGROUND OF THE INVENTION
There are increasing numbers of reported cases of infections with enterohemorrhagic
Escherichia coli
(EHEC), such as
E. coli
O-157, in recent years. Given that EHEC infection often causes life-threatening diseases such as hemorrhagic colitis, hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpra (TTP), an urgent need exists for establishing a method for the prevention and treatment of EHEC infection. EHEC produces verotoxins which are similar to Shiga toxin produced by
Shigella dysenteriae
, and said verotoxins are considered to be the main pathogen of the above-mentioned serious diseases.
While many antimicrobial agents having a potent antimicrobial effect against a verotoxin-producing
Escherichia coli
(VTEC) are known, almost all of them enhance production of verotoxins or release of them from VTEC. Those antimicrobial agents are not only useless but also harmful, because increased verotoxins often cause severe and fatal symptoms in the patients. A most preferable method for treating VTEC infections has not been established.
Meanwhile, VTEC colonizes in the intestine of livestock such as cow, pig and the like, which most likely carry and transfer VTEC to humans. Therefore, eradication of said VTEC in livestock is extremely important for the prevention of VTEC infection in humans.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide an antimicrobial compound having not only an antimicrobial activity against VTEC, but also a suppressive activity on the production and release of verotoxins, and provide a method for the prophylaxis and treatment of VTEC infections and for eradicating VTEC in livestock, by using said compound. inventors have found the unexpected and surpprising fact that bicozamycin or a derivative thereof (hereinafter also collectively referred to as bicozamycins) have a high suppressive action on the production and release of verotoxins in vitro and in vivo even at the antimicrobially effective concentration against VTEC.
Accordingly, the present invention provides a composition for suppressing the production and/or release of verotoxins, particularly, an agent for the prophylaxis and treatment of VTEC infections, comprising a bicozamicin as an active ingredient. The present invention yet provides an agent for eradicating VTEC in animals.
The present invention also provides a method for suppressing the production and/or release of verotoxins, comprising treating said
E. coli
with an effective amount of a bicozamycin for suppressing production and release of verotoxins. More particularly, the present invention provides a method for the prophylaxis and treatment of VTEC infections, comprising administering a prophylactically and therapeutically effective amount of a bicozamycin. The present invention further provides a method for eradicating VTEC in animals, comprising administering an effective amount of a bicozamycin for eradicating VTEC.
The present invention yet provides use of a bicozamycin for the preparation of a medicament for the suppression of the production and/or release of verotoxins. More particularly, the present invention provides use of a bicozamycin for the preparation of a medicament for the prophylaxis and treatment of VTEC infections. The present invention further provides use of a bicozamycin for the preparation of a medicament for eradicating VTEC in animals.
Furthermore, the present invention provides a commercial package comprising the above-mentioned composition and a written matter associated therewith, the written matter stating that said composition can or should be used for suppressing the production and/or release of verotoxins from VTEC, preventing and treating VTEC infections or eradicating VTEC in animals.
DETAILED DESCRIPTION OF THE INVENTION
Bicozamycin is a known antibiotic produced by
Streptomyces sapporoensis
(ATCC No. 21532) isolated from a soil sample and has been conventionally used for a feed additive and the treatment of bacterial diarrhea in an animal. Bicozamycin can be obtained by, for example, culturing the above-mentioned microorganism, followed by isolation and purification from the culture filtrate using a conventional method known in the art (THE MERCK INDEX, TWELFTH EDITION, 1249 (1996)). In the present invention, bicozamycins may include bicozamycin and a derivative thereof. The derivative is subject to no particular limitation as long as it shows suppression of the production and release of verotoxins, as well as antimicrobial activity against VTEC. Examples thereof include esters (e.g., benzoate, palmitate, etc.) and the like, inclusive of prodrug compounds which show the above-mentioned activities after being metabolized in the body of animals.
Inasmuch as bicozamycins have a suppressive activity on the production and/or release of verotoxins, besides an antimicrobial activity against VTEC, they are useful for the prophylaxis and treatment of diarrhea caused by VTEC infection in a human, and thus, useful for the prophylaxis of complications caused by verotoxins, including hemorrhagic colitis, HUS and TTP. Bicozamycins are also useful for eradicating said VTEC in livestock (e.g., cow, pig, horse, sheep, goat, chicken, etc.), which livestock being the main VTEC infection source for humans.
According to the present invention, a bicozamycin is used in the form of a pharmaceutical preparation comprising said bicozamycin as an active ingredient, in admixture with a pharmaceutically acceptable carrier or excipient suitable for oral or parenteral (inclusive of intravenous, intraperitoneal, subcutaneous and intramuscular injections) administration.
Formulations suitable for oral administration include, for example, solutions containing an effective amount of the active ingredient dissolved in diluents, such as water, saline or orange juice; capsules, sachets and tablets, each containing a predetermined amount of the active ingredient in solids or granules; suspensions using appropriate liquid; and suitable emulsions. Tablets can contain one or more members from lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmaceutically compatible carriers. Lozenge can contain the active ingredient in a flavor, usually sucrose and acacia or tragacanth. Pastilles can contain the active ingredient in an inert base, such as gelatin, glycerol, sucrose and acacia. Emulsions, gels, and the like can contain, in addition to the active ingredient, such excipients as are known in the pertinent art.
Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers and solutes that render the formulation isotonic with the blood of an intended recipient, and aqueous and non-aqueous sterile suspensions that can contain suspending agents, solubilizers, thickeners, stabilizers and preservatives. The formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition which will require only the addition of a sterile liquid excipient, such as water, for injections, immediately prior to use.
While the dosage of bicozamycins may vary depending upon recipient species, age and/or body weight of the recipient, administration route, and the like, when the recipient is a human suffering from diarrhea, the preferable dosage of bicozamycins may be selected from the range of 1-100 mg/kg daily for an adult, which may be administ
Ikemoto Akiko
Matsumoto Yoshimi
Morinaga Chizu
Tawara Shuichi
Yokota Yoshiko
Di Nola-Baron Liliana
Fujisawa Pharmaceutical Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Page Thurman K.
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