Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1997-02-27
1999-03-09
Weddington, Kevin E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 31, 514824, 514825, 514838, 514851, 514859, 514861, 514863, 514866, 514877, 514894, 514899, 514903, 514930, 514931, A61K 3170
Patent
active
058801014
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP95/02518 filed Jun. 28, 1995.
The present invention relates to the use of at least one polyene macrolide for preparing a pharmaceutical composition for the treatment of diseases associated with an impaired energy turnover. The invention particularly allows a targeted stimulation of energy conversion in human cells, i.e., a stimulation of the cell metabolism and thus the treatment or prevention of a variety of diseases.
BACKGROUND OF THE INVENTION
At present more than 200 different polyene macrolide antibiotics have been described, most of them being produced by soil actinomycetes, mainly by the genus Streptomyces.
Polyene macrolides (referred to in the following also as polyenes or macrolides) are characterized by 20- to 40-membered lactone rings containing three to eight conjugated carbon-carbon double bonds. Often, the lactone ring carries a sugar moiety. Some macrolides contain an aliphatic side chain, optionally carrying an aromatic substituent. Usually, the macrolide ring carries at least one hydroxyl group.
Nystatin was the first substance from the class of the polyene macrolides to be described. In 1961 it was isolated as the metabolite of the fungus species Streptomyces noursei. Nystatin, referred to in the following as Nys, has the following structural formula: ##STR1##
Due to its .pi.-electron structure comprising 4 conjugated double bonds, Nys is referred to as tetraene macrolide.
Another example of a polyene macrolide is Amphotericin B (referred to in the following as Amp). In contrast to Nys, this compound has an additional double bond. Since Amp exhibits a total of seven conjugated double bonds, it is classified among the group of the heptaene macrolides. Amp has the following structural formula: ##STR2##
Although particularly Nys and Amp have been known for several decades and have been administered orally to millions of patients, their therapeutical use has been limited exclusively to the treatment of candidiases (mycoses). In vitro studies have shown that Nys and Amp administered in decreasing dosages may have fungicidal, fungistatic or mycotic growth enhancing effect. Most scientific publications are quite silent about the latter effect. In turn, there are many in vivo studies which found cell-stimulating effects of Nys and Amp in eucaryotic cells (J. Bolard, How do polyene macrolide antibiotics affect the cellular membrane properties, Biochim. Biophys. Acta (1986), 864, 257-304).
It is assumed in the art that the antimycotic effect of Nys and Amp is based on a specific interaction with the membrane-bound ergosterol of the fungi. This interaction is believed to effect disruption of the fungal membranes, the entry of ions and other soluble substances in the fungi, thereby inhibiting the fungal metabolism and bringing about lysis of the fungal cells. It will be shown in the present invention that this conventional concept is not capable of explaining the manifold pharmacological effects of the polyene macrolides. The wrong pharmacodynamic concept, on which the practical use of this class of substances has so far been based, only can give an explanation for the fact that the universal therapeutical potential of polyene macrolides so far has not be recognized.
In the art, Nys and Amp are only used in the therapy of superficial and gastrointestinal mycotic infections. For example, for the treatment of intestinal candidiases and monoliases the administration of Nys in a dose of 3-4.times.10.sup.6 I.U./day over a period of 8 days, followed by a dose of 1.5 to 2.times.10.sup.6 I.U./day in the following 8 days is recommended. For the treatment of mycotic infections of the skin, e.g., application of a Nystatin cream (1.times.10.sup.5 I.U./g ointment) 2 to 3 times a day until remission of the infection (about 6 days) is recommended. 1 g Nys corresponds to about 5.times.10.sup.6 I.U. The oral and topical dosages, however, which are recommended in the art and are usually administered, are far lower and/or the duration of the treatment is considerably shorter than
REFERENCES:
patent: 4289757 (1981-09-01), Glenn
Dr. Zerle GmbH
Weddington Kevin E.
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