Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-07-28
1999-07-06
Cook, Rebecca
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514185, 514815, A61K 3140
Patent
active
059197552
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the use of heme or a derivative thereof for the prevention of or for the decrease of risk of mutagenesis in mammalian cells. The invention relates further to the use of heme or a derivative thereof to decrease the proportion of blasts in bone marrow in mammals and consequently to prevent the transformation of preleukemic conditions into leukemias, to prevent the disease progression in leukemias and to cure leukemias in mammals. In addition, the invention relates to the use of heme or derivatives thereof to ameliorate clinical symptoms of hemoglobinopathic conditions (e.g. .mu.-thalassemias and sickle cell anemias) in mammals especially via inducing production of fetal hemoglobins.
BACKGROUND OF THE INVENTION
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
Heme is an important endogenous substance (haem, iron protoporphyrin IX). There is no International Nonproprietary Name (DCI) for heme. The chemical state and stability of heme are influenced by the solvent and other environmental conditions.
The term "heme" is used generically here. Other terms refer to specific chemical states of heme. The Fe of heme may be either in the ferrous (Fe.sup.2+) or ferric state (Fe.sup.3+) and is coordinated with the 4 pyrrole nitrogens. "Hematin" is a ferric form and refers to heme dissolved in alkaline solution (heme hydroxide) or neutral solution. "Hemin" is another ferric form in which a chloride ion is coordinated to iron at the fifth or sixth position, as occurs when heme is dissolved in an aqueous solution containing HCl. Hemin is highly stable in crystalline form but is poorly soluble. When heme chloride is dissolved in alkaline solution the chloride is replaced by hydroxyl to form hematin, which is poorly stable and readily forms poorly characterized degradation products.
Heme is also stable when bound to proteins or amino acids such as arginine or lysine. Heme arginate is a product of heme and L-arginine (1). Arginine increases the aqueous solubility and stability of heme. Once heme arginate is infused into the blood stream the heme arginate dissociates and the heme moiety is quickly bound to the plasma proteins in monomeric form (1). Therefore, the formulation of heme as heme arginate augments the stability of heme for intravenous infusion and does not change its physiological utilization. Thus the discoveries presented hereinafter for heme arginate are valid also for other heme preparations. The benefit of using heme arginate instead of other presently known heme preparations is its higher stability and consequently consistent efficacy and lack of serious adverse effects known to be caused by degradation products of heme.
Lyophilized hematin (Panhematin.RTM., Abbott) was approved by the U.S. Food and Drug Administration in 1983. Heme arginate (Normosang.RTM., Leiras) was developed in Finland and is now marketed in several countries in Europe for treatment of acute porphyric attacks. Previously, hematin was prepared in research laboratories or hospital pharmacies, usually from outdated human blood. A preparation of heme albumin was developed in Germany.
The use of hematin (either Panhematin.RTM. or hematin prepared in research laboratories) is often complicated by adverse effects, including phlebitis at the infusion site and disturbances in hemostasis (2, 3, 4). Heme arginate seldom produces these effects and therefore is better tolerated. The side effects of Panhematin.RTM. are greatly reduced if the drug is reconstituted with human albumin in equimolar amounts (5). However, this adds considerable expense and the potential risk of administration of a protein product originating from human blood.
Heme and its derivatives have also been reported in the patent literature. The Finnish patent publication Fl 68970 discloses a method for the preparation of heme arginate and heme lysinate and the use of sa
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Medline AN 95261065. Fibach et al, May 15, 1995.
Malik, Z. and Djaldetti, M. (1980). "Cytotoxic Effect of Hemin and Protoporphyrin on Chronic Lymphocytic Leukemia Lymphocytes." Exp. Hematol. 8:867-879.
Timonen, T.T.T. and Kauma, H. (1992). "Therapeutic effect of heme arginate in myelddysplastic syndromes." Eur. J. Haematol. 49:234-238.
Volin, L. et al. (1988). "Heme Arginate Treatment for Myelodysplastic Syndromes." Leukemia Res. 12:423-431.
Chemical Abstracts 109:229181b (1988). "Manufacture of iron-enriched cheese for treatment of cancer".
Chemical Abstracts 111:89902f (1989). "Cytotoxic effect of hemin on L615 mouse leukemia cells".
Kangasaho Mauno
Relander Klaus
Cook Rebecca
Leiras Oy
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