Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/17—Amino acids, peptides or proteins
  • A23L33/19—Dairy proteins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to a pharmaceutical composition comprising lactoferrin and/or lactoferricin for treatment and/or prevention of infections, inflamma- tions and/or tumours, to the use of lactoferrin and lactoferricin in the production of a pharmaceutical composition for treatment and/or prevention of infections, inflammations and tumours, and to a method for treatment and/or prevention of infections, inflammations and/or tu- mours comprising administration of lactoferrin and/or lactoferricin.
• human milk in several ways is anti- inflammatory.
• Goldman et al. pointed out that human milk is poor in initiators and mediators of inflammation but rich in anti-inflammatory agents (see Goldman A. S., et al., Anti-inflammatory properties of human milk, Acta Paediatr. Scand. 75 : 689-695, ' 1986) .
• Human milk contains several soluble anti-infective components, such as specific secretory IgA (SIgA) antibodies and non-specific components, including lactoferrin (LF) (see e.g. Hanson L. A., et al., Protective factors in milk and the development of the immune system, Pediatrics 75:172-176, 1983) .
• SIgA specific secretory IgA
• LF lactoferrin
• Lactoferrin is a single chain metalbinding glycopro- tein with a molecular weight of 77 kd. It occurs in three isoforms: LF- ⁇ , LF- ⁇ , and LF- ⁇ . These three variants have the same physical, chemical and antigenic characteris- tics, but differ in their functional properties.
• the iron-binding lactoferrin is also present in specific granules of polymorphonuclear leucocytes and in other exocrine secretions than milk such as saliva, tears and bronchial mucus, as well as cervical secretion, amni- otic fluid, decidua, and trophoblasts (see e.g. Montreuil J., et al., Isolement d'une lactosiderophiline du lait de appropriate, CR Acad. Sci. Paris 250 D: 1736-37, 1960; Montreuil J., et al., Preparation et proprietes de la lactosiderophiline (lactotransferrine) du fait de an, Biochim. Biophys.
• Lactoferrin an ironbinding protein neutrophilic leucocytes, J. Exp. Med. 130:643-656, 1969). Lactoferrin is associated with host defense at mucosal surfaces through its antibacterial and iron-binding properties. Human lactoferrin is found in colostrum and mature milk at levels of 2-5 g/1.
• Bovine lactoferrin shares 68% and 64% amino acid identity with human lactoferrin and murine lactoferrin, respectively.
• Lactoferricin is a pepsin-cleaved fragment of human and bovine lactoferrin. It has recently been found to contain the structural domain responsible for the bactericidal properties of lactoferrin (see e.g. Bellamy W., et al., Identification of the bactericidal domain of lac- toferrin, Biochim. Biophys.
• Lactoferrin receptors are found on many types of cells including monocytes and macrophages (Broxmeyer H.
• lactoferrin In addition to the role of lactoferrin as an essen- tial growth factor for both human B- and T-lymphocytic cell lines (see e.g. Hashizume S., et al., Identification of lactoferrin as an essential growth factor for human lymphocytic cell lines in serum-free medium, Biochem. Biophys. Acta 763:377-382, 1983) and as an inducer of growth of HT-29 cells (see e.g. Anuric M., et al., Effect of lactoferrin on the growth of a human colon adenocarci- noma cell line - comparison with transferrin.
• lactoferrin is a negative regulator of myelopoiesis (see e.g. Broxmeyer H. E., et al . , Specific- ity and modulation of the action of lactoferrin, a negative feedback regulator of myelopoiesis, Blood 55:324- 333, 1980, and Gentile P., et al., Suppression of mouse myelopoesis by administration of human lactoferrin in vivo and the comparative action of human transferrin, Blood 61:982-993, 1983). This latter function is mediated through suppression of IL-1 and GM-CSF release from ono- cytes and macrophages (see e.g.
• Lactoferrin acts on I-A and I-E/C antigen subpopulations of mouse peritoneal macrophages in the absence of T lymphocytes and other cell types to inhibit production of granulocyte-macrophage colony stimulatory factors "in vi- tro", J. Immunol. 133:306-314, 1984, and Zucali J. R. , et al., Lactoferrin decreases monocyte-induced fibroblast production of myeloid colony-stimulating activity by suppressing monocyte release of interleukin-1, Blood 74:1531-1536, 1989).
• TNF- ⁇ tumor necrosis factor- ⁇
• IL-1 interleukin-1
• IL-6 interleukin-6
• CSF colony- stimulating factor
• Such cells also have receptors for lactoferrin.
• An interaction between LPS and lactoferrin has been observed, the complex being bound to the cells also via LPS receptors (see Miyazawa K. , et al., Effect on lactoferrin binding to monocyte/macro- phage-differentiated HL-60 cells. J Immunol. 146:723-729, 1991) .
• lactoferrin exerted an inhibitory effect on the production of IL-1 and TNF- ⁇ in LPS stimulated monocytes (see Crouch P. M. , et al., Regulation of cytokine release from mononuclear cells by the iron-binding protein lactoferrin, Blood 80:235-240, 1992) .
• IL-6 response when added to fresh monocytes or cultured monocytic cells.
• lactoferrin and lactoferricin have an in vivo effect on all kinds of inflammation, i.e. not only when IL-6 is involved, as well as on infections, such as urinary tract infection, and tumours.
• an object of the present invention is to provide a pharmaceutical composition for treatment and/or prevention of infections, inflammations and/or tumours comprising an effective amount of lactoferrin and/or lactoferricin.
• Another object of the present invention is use of lactoferrin and/or lactoferricin in the production of a pharmaceutical composition for treatment and/or prevention of infections, inflammations and/or tumours.
• a third object of the present invention is to pro- vide a method for treatment and/or prevention of infections, inflammations and/or tumours by administration of an effective amount of lactoferrin and/or lactoferricin.
• the pharmaceutical composition comprising an effective amount of lactoferrin and/or lactoferricin, is preferably administered systemically, and most preferably orally.
• the infections treatable with the pharmaceutical composition according to the present inventions include infections caused by all kinds of pathogens, such as bacteria, viruses, fungi, etc.
• Inflammation is a phenomenon marked by abnormal "redness” and swelling of tissues and organs, pain and heat in affected areas, capillary dilation, leucocyte infiltration, etc. Inflammation is primarily caused by exposure to bacterial and other noxious agents and physical injury. Inflammation is mediated by a variety of cytoki- nes and other chemical signals. These mediators of inflammation include tumor necrosis factor- ⁇ (TNF- ⁇ ) , in- terleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and various colony-stimulating factors (CSFs) .
• TNF- ⁇ tumor necrosis factor- ⁇
• IL-1 in- terleukin-1
• IL-6 interleukin-6
• IL-8 interleukin-8
• CSFs colony-stimulating factors
• Prevention refers to minimizing, reducing or sup- pressing the risk of developing a disease state or progression or other abnormal or deleterious conditions.
• a “patient” is a subject at risk for or suffering from a disease state, disease progression or other abnormal or deleterious condition.
• An “effective amount” is an amount sufficient to treat or prevent a disease state, disease progression or other abnormal or deleterious condition.
• Systemic administration can be undertaken by oral, nasal, intravenous, intraartery, intracavitary, intramus- cular, subcutaneous, transdermal, suppositories
• the pharmaceutical composi- tion according to the present invention is formulated for oral administration.
• lactoferrin and lactoferricin used according to the present invention can e.g. be obtained through isola- tion and purification from natural sources, such as human milk, through use of genetic engineering techniques, such as recombinant expression or direct production in genetically altered animals, or through chemical synthesis.
• the lactoferricin can also be obtained by enzymatic degrada- tion of lactoferrin (hydrolysate) .
• the lactoferrin used according to the present invention is preferably human lactoferrin or bovine lactoferrin, and it is preferably administered as a hydrolysate.
• the lactoferricin used according to the present in- vention is preferably human lactoferricin or bovine lactoferricin.
• the pharmaceutical composition comprising lactoferrin and/or lactoferricin according to the present invention is particularly well suited for treatment and/or prevention of urinary tract infection and colitis, but several other inflammatory and infectious diseases are also treatable according to the present invention, such as inflammatory bowel diseases, rheumatoid arthritis, conditions caused by the virus HIV-1, conditions caused by the virus CMV, and conditions caused by the fungus Candida albicans.
• the pharmaceutical composition according to the present invention is also well suited for preventive medical care by reducing the risk of developing urinary tract in- fection or other inflammatory or infectious diseases in patients with an increased risk of attracting such complications .
• the pharmaceutical composition according to the present invention may also comprise other components, such as pharmaceutically acceptable carriers, vehicles, preservatives, lubricators etc., which is well known to persons skilled in the art.
• pharmaceutically acceptable carriers such as pharmaceutically acceptable carriers, vehicles, preservatives, lubricators etc.
• lactoferrin and/or lactoferricin in an effective amount, in any kind of food or beverage intended to reduce infections and/or inflammations in pa- tients running an increased risk of such conditions due to an underlying disease or a medical treatment.
• lactoferrin and/or lactoferricin in an effective amount, in an infant formula food intended to inhibit harmful effects of bacteria, such as weight loss caused by inflammation induced by bacteria, viruses or fungi in infants.
• Fig. 1 a - d illustrate bacterial recovery from the kidney (a and b) and bladder (c and d) , respectively, of C3H/Tif and C3H/HeN mice infected with E. coli in the urinary tract and perorally given human lactoferrin (LF hum) , bovine lactoferrin (LF bov) , or PBS, 30 min after the injection of bacteria.
• LF hum human lactoferrin
• LF bov bovine lactoferrin
• FIG. 3 a and b illustrate the kinetics of the urinary IL- 6 response in E. coli infected C3H/Tif and C3H/HeN mice treated with human lactoferrin (LF hum) , bovine lactoferrin (LF bov) , or PBS, 30 min after the injection of bacteria.
• Fig. 3 a and b illustrate the kinetics of the urinary IL- 6 response in E. coli infected C3H/Tif and C3H/HeN mice treated with human lactoferrin (LF hum) , bovine lactoferrin (LF bov) , or PBS, 30 min after the injection of bacteria.
• Fig. 3 a and b illustrate the kinetics of the urinary IL- 6 response in E. coli infected C3H/Tif and C3H/HeN mice treated with human lactoferrin (LF hum) , bovine lactoferrin (LF bov) , or PBS, 30
• FIG. 4 illustrates the serum IL-6 response 24 h after experimentally induced urinary tract infection in C3H/Tif and C3H/HeN mice treated with human lactoferrin (LF hum) , bovine lactoferrin (LF bov) , or PBS, 30 min after the injection of bacteria.
• human lactoferrin LF hum
• bovine lactoferrin LF bov
• PBS PBS
• Fig. 5 illustrates the cytokine concentration in serum from mice with experimentally induced colitis after treatment with bovine lactoferrin (LF bov) compared to a control group not receiving lac- toferrin.
• LF bov bovine lactoferrin
• Example 1 Treatment of urinary tract infection in mice by oral administration of human lactoferrin
• lactoferrin The antibacterial and anti-inflammatory properties of lactoferrin were explored by studying the effects of lactoferrin given to mice (C3H/Tif and C3H/HeN) with experimentally induced urinary tract infection (UTI) .
• mice In order to induce urinary tract infection (UTI) in the mice, the animals were injected with 100 ⁇ l of a bac- terial solution containing 2xl0 9 E. coli-bacteria/ml diluted with phosphate-buffered saline (PBS) directly into the bladder via a catheter according to Svanborg-Eden et al (see C. Svanborg-Eden et al Infect. Immun. 55:1224- 1232, 1987). A solution containing 10 mg/ml of either human lactoferrin, bovine lactoferrin, or bovine lactoferricin was orally administered (50 ⁇ l) to the mice 30 min after the instillation of bacteria.
• PBS phosphate-buffered saline
• Urine samples from the mice were collected 0, 2, 5, and 24 hours after infection. 50 ⁇ l of each of the undiluted urine samples were cultured. The number of leucocytes in uncentrifuged urine was analyzed for each sample. The remaining urine from each animal at each sampling time was centrifuged and saved for IL-6 analysis. After 24 h the mice were bled and killed. The bladder and kidneys were taken out aseptically. The organs were homogenized, and serial dilutions thereof (bladder 1/1, 1/10, kidneys 1/1, 1/10, 1/100, 1/1000) were cultured on Drigalsky plates.
• a significant p value should be adjusted to p ⁇ 0.025 t illustrates a significant increase in the treatment group compared to the infected but untreated control group.
• I illustrates a significant decrease in the treatment group compared to the infected but untreated control group.
• lactoferrin both human and bovine significantly decreased the number of bacteria in the urinary tract of the infected mice, compared to the control group.
• Example 2 Treatment of experimental colitis by oral administration of human lactoferrin
• Acute colitis was induced in C57BI/6J mice by giving 5% dextransulphate in the drinking water for 6 days.
• Human lactoferrin was orally given to ten mice twice a day in a dose of 1 mg/mouse, starting from day 3 of the experiment.
• Two control groups (in total 17 mice) were given the same volume of drinking water or bovine serum albumin (BSA) (2 mg per mouse and day) .
• BSA bovine serum albumin

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• 1997
  • 1997-08-12 JP JP50964098A patent/JP2001504447A/ja active Pending
  • 1997-08-12 EP EP97935939A patent/EP0920331A1/de not_active Withdrawn
  • 1997-08-12 WO PCT/SE1997/001344 patent/WO1998006425A1/en not_active Application Discontinuation
  • 1997-08-12 AU AU38727/97A patent/AU3872797A/en not_active Abandoned
  • 1997-08-12 CA CA002263416A patent/CA2263416A1/en not_active Abandoned

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