Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-03-13
2002-02-05
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S350000, C530S300000
Reexamination Certificate
active
06344440
ABSTRACT:
The present invention relates to new antisecretory factors having fluid transport and/or inflammatory reactions regulating properties as well as polynucleic regulating properties, and polynucleic acids coding therefor, and the use thereof.
All cells and tissues of the body are critically dependent on a constant and normal fluid environment in combination with an adequate blood supply. Derangement of one or both of these supporting systems may rapidly become fatal. Concerning fluid imbalance, two principally different systems exist:
A. edema, which is characterised by the abnormal accumulation of fluid in the intercellular tissue spaces or body cavities, or
B. dehydration, which, in a strict sense, means loss of water only, but is in fact commonly used to describe the combined loss of water and ions.
The most common forms of either edema or dehydration are:
diarrheas, inflammatory bowel diseases, brain edema, asthma, rhinitis, conjunctivitis, arthritis, glaucoma, various forms of pathological intracranial pressure (increase or decrease), pressure alteration in the middle ear such as Morbus Meniere, dermatitis, chemical or physical derangement of the skin and skin adjacent glands such as mastitis, various forms of endocrine disorders, such as diabetes insipidus. Conn's syndrome, Cushing's syndrome and Morbus Addison, kidney diseases such as pyelonephritis and glomerulonephritis, metabolic diseases such as myxedema and acute intermittent porphyria, side effects during treatment with various drugs such as anti-diabetics, tricyclic antidepressants, cytostatics, barbiturates, narcotics and narcotic analogues.
Diarrhea is caused by a change in the permeability in the gut for electrolytes and water. This disturbance is often caused by bacterial enterotoxins such as those produced by
Escerichia coli, Campylobacter jejuni, Vibrio cholerae, Shigella dysenteriae
and
Clostridium difficile.
The disturbance could also be caused by intestinal inflammation. Since the uptake of water is coupled to the uptake of electrolytes and nutrients, animals with frequent diarrhea suffers from malnutrition, resulting in retardation of the daily weight gain in the growing animal. The body counteracts these reactions by neuro-hormonal mechanisms such as the release of somatostatin and opiate peptides from interneurons in the intestinal mucosa. These polypeptides are capable of reversing fluid secretion and diarrhea.
The recently described antisecretory factor (AF) has been partially purified from pig pituitary gland and shown to reverse pathological secretion induced by various enterotoxins. High levels of AF in sow milk protect the suckling piglets against neonatal diarrhea.
Antimicrobial drugs have been widely used in the treatment of diarrhea in both human and veterinarian medicine. They are also used as feed additives for pigs, calves and chicken. However, due to the rapid development of resistant bacteria in the gut, the use of antibiotics against enteritis is generally not accepted in human medicine and their use is also diminishing in veterinarian medicine.
Other antidiarrheal drugs counteract the secretion in the intestinal mucosa. Since these drugs are directed against the host animal, it is unlikely that resistance against the drugs will develop. These types of drugs include nerve-active drugs like phenothiazines and thioxanthenes. Due to some serious side effects these types of drugs have not been accepted for treatment of diarrhea in most countries. Other drugs are derivatives of opiates like codeine and loperamide. Since these drugs mainly acts by inhibiting intestinal mobility, they also inhibit the clearance of pathogenic bacteria from the gut and should definitely not be recommended against dysenteric bacteria or parasites. Derivatives of somatostatin have been introduced recently, but have so far a limited use due to difficulties in the administration of the drugs and possible interactions with the endocrine regulation of growth.
The antisecretory factor (AF) has so far not been used directly for treatment of diarrhea or malnutrition due to the difficulties involved in obtaining a pure preparation of this protein. However, it has been possible to induce similar proteins in domestic animals which have been given a specific feed (SE Patent No. 9000028-2). Pigs given this feed obtained high levels of AF-like proteins and had a significant increase in the daily growth rate compared to matched controls. AF in rats challenged with toxin A from
C. difficile
protects not only against intestinal secretion but also against inflammation and bleeding in the gut.
A major object of the present invention is to provide a new recombinant protein and homologues and fragments (peptides) thereof for use in normalizing pathological fluid transport. These proteins and peptides are collectively called antisecretory factors (AF). The use of AF also partly inhibits, or totally eliminates the development of inflammatory reactions of various aetiologies. Reconstitution back to normal (fluid transport or inflammation) is obtained by the use of proteins or peptides. Further the AF proteins or peptides are effectively absorbed via various mucus membranes without losing in potency (when compared to intravenous administration). Consequently, a multitude of treatment regimens exist, and a correctly administrated protein or peptide make it possible to rapidly reconstitute a deranged fluid (water and ion) balance, an inflammatory reaction, or both.
In summary, the recombinant AF (rAF) and the homologues and fragments thereof could be used for immunodetection, as feed additive for growing animals and as antidiarrheal and drugs against diseases involving edema, dehydration and/or inflammation.
The objects of the present invention are the following:
A recombinant protein having essentially the amino acid sequence shown in SEQ ID No. 2, or homologues or fragments thereof.
A fragment of the recombinant protein shown in SEQ ID No. 2, which fragment is chosen from the group comprising
a) amino acids nos. 35-42
b) amino acids nos. 35-46
c) amino acids nos. 36-51
d) amino acids nos. 36-80
e) amino acids nos. 1-80
of the amino acid sequence shown in SEQ ID No. 2.
A peptide X
1
VCX
2
X
3
KX
4
R corresponding to the fragment comprising the amino acids no. 35-42 of the recombinant protein shown in SEQ ID No. 2, wherein X is I or none, X
2
is H, R or K, X
3
is S, L or another neutral amino acid and X
4
is T or A.
Antibodies against a recombinant protein having essentially the amino acid sequence shown in SEQ ID No. 2, or homologues or fragments thereof.
A protein binding to antibodies specific to a recombinant protein having essentially the amino acid sequence shown in SEQ ID No. 2, or homologues or fragments thereof.
A composition for normalising pathological fluid transport and/or inflammatory reactions comprising as an active principal an effective amount of the recombinant protein having essentially the amino acid sequence shown in SEQ ID No. 2, or homologues or fragments thereof.
Use of a recombinant protein having essentially the amino acid sequence shown in SEQ ID No. 2, or homologues or fragments thereof for manufacturing a composition for normalising pathological fluid transport and/or inflammatory reactions.
Feed for normalising pathological fluid transport and/or inflammatory reactions in vertebrates, comprising as an active agent a recombinant protein having essentially the amino acid sequence shown in SEQ ID No. 2, or homologues or fragments thereof, or an organism capable of producing such a protein or homologues or fragments thereof.
A process of normalising pathological fluid transport and/or inflammatory reactions in vertebrates, comprising administering to the vertebrate an effective amount of a recombinant protein having essentially the amino acid sequence shown in SEQ ID No. 2, or homologues or fragments thereof, or an organism producing said protein or homologues or fragments.
Use of specific antibodies against a recombinant protein having essentially the amino acid sequence shown in SEQ ID No. 2, o
Jennische Eva
Johansson Eva
Lange Stefan
Lönnroth Christina
Lönnroth Ivar
Burns Doane Swecker & Mathis L.L.P.
Carlson Karen Cochrane
Rural Patent Svenska AB
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