Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1992-01-13
1993-08-31
Wityshyn, Michael G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 6, 530350, 530380, 424 851, 424 858, A61K 3702, A61K 3714
Patent
active
052409090
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The invention relates to the use of lactoferrin as an agent for the propylactic and therapeutic treatment of the toxic effects of endotoxins.
Lactoferrin is a glycoprotein with an average molecular weight of 77,000 Dalton. It can bind two molecules of iron reversibly. It can also bind other bivalent or trivalent metal ions instead of iron such as copper, magnesium, zinc, manganese and cobalt.
Lactoferrin was first isolated from milk in 1960. The lactoferrin content of human milk is approx. 1 mg/dl. Lactoferrin has also been found in the blood, in the granula of the neutrophil granulocytes, in lacrimal fluid, in gastric fluid and in the secretions of the intestinal tract. The lactoferrin concentration found in the blood ranges from 40 to 200 .mu.g/dl.
Lactoferrin in the blood, which is released mainly by the granula of the neutrophil granulocytes, contributes to some aspects of iron transport to the cells of the reticulo-endothelial system, especially during infections or inflammatory processes. [Van Snick JL, Masson L, Heremans JF. The involvement of lactoferrin in the hyposideremia of acute inflamation. J Exp Med 1974; 140: 1068-1084]. In animal experiments, due to the rapid release of lactoferrin from the granulocytes, the administration of endotoxin or bacteria was seen to be nearly concurrent with the increase in plasma lactoferrin levels. For this reason, an increase in plasma lactoferrin concentration is considered to be an early indicator for endotoxemia or septicemia (Gutteberg TJ., Rokke O., Joergensen T.; Andersen O.,: Lactoferrin as an Indicator of septicemia and Endotoxemia in Pigs. Scand J Infect Dis (1988), 20: 659-666).
Another essential function of lactoferrin, particularly in the neonatal period, is the regulation of iron absorption in the intestinal tract [Brock JH, Lactoferrin in human milk: its role in iron absorption and protection against enteric infections in the newborn infant. Arch Dis Child (1980) 55: 417-422], since the lactoferrin in human milk is capable of releasing the bound iron to the cells of the gut mucosa.
The most important biological function of lactoferrin derives, however, from its bacteriostatic effect [Arnold RR, Brewer M, Gauthier JJ. Bactericidal activity of human Lactoferrin: Sensitivity of a variety of microorganisms. Infection and Immunity (1980) 28: 893-898; Arnold RR, Russel JE, Champion WJ, Gauthier JJ. Bactericidal activity of human Lactoferrin: influence of physical conditions and metabolic state of the target microorganisms. Infection and Immunity (1981) 32: 655-660; Gutteberg T.J., Rokke O., Andersen O., Joergensen T.; Early Fall of Circulating Iron and Rapid Rise of Lactoferrin in Septicemia and Endotoxemia: An Early Defence Mechanism. Scand J Infect Dis,(1989) 21: 709-715]. Due to its bacteriostatic effect, the lactoferrin in human milk plays an important role as a defense mechanism in that it protects the newborn against intestinal infections. This bacteriostatic effect results from the high iron-binding capacity of lactoferrin. Iron is an essential growth factor for bacteria. The complexing of iron and lactoferrin keeps the concentration of free iron around the bacteria below the level conducive to bacterial growth. This results in an inhibition of bacterial growth. The higher the iron content, the less bacteriostatic effect lactoferrin has. Since iron-free lactoferrin (apoform) is released as early as the initial phase of bacteriemia and endotoxemia, GUTTEBERG et al. assumed that iron-free lactoferrin, in view of its bacteriostatic effect, might be an early defense mechanism against bacterial invasion [Gutteberg T.J., Rokke O., Andersen O., Joergensen T.; Early Fall of Circulating Iron and Rapid Rise of Lactoferrin in Septicemia and Endotoxemia: An Early Defence Mechanism. Scand. J. Infect. Dis.,(1989), 21: 709-715]. The publication cited above does not contain any evidence that the iron-free apoform of lactoferrin released from granulocytes plays the role of a defense mechanism against the endotoxin in addition to its
REFERENCES:
patent: 4726948 (1988-02-01), Prieels
patent: 4780529 (1988-10-01), Hao
Berger et al, Bacterial Endotoxins: Pathophysiological Effects, Clinical Significance & Pharm. Control, pp. 115-124.
Arnold et al, Inf. & Immun. vol. 32, No. 2, pp. 655-660, May 1981.
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Koh Choon
Larson Herbert W.
Wityshyn Michael G.
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