Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1995-04-12
1997-06-10
Krass, Frederick
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514788, 514789, 514905, 536 64, A61K 3171
Patent
active
056375727
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a new use of an already known anthracycline with antitumoral activity.
More particularly, the invention relates to a new use of 4'-iodo-4'-deoxydoxorubicin and its pharmaceutically acceptable salts in the treatment of amyloidosis.
4'-iodo-4'-deoxydoxorubicin (IDX), of formula ##STR1## is described and claimed, together with its method of preparation, in U.S. Pat. No. 4,438,105 in the name of A. Suarato et al.
Said anthracycline, which differs from doxorubicin in that the hydroxyl in position 4' of the sugar is replaced by one atom of iodine, possesses good antitumoral activity.
The term "amyloidosis" indicates various morbid states having as their common pathological characteristic the tendency of particular proteins to polymerize and precipitate in the extracellular space in the form of insoluble fibrils, causing structural and functional damage to organs and tissues.
Although they contain a wide variety of different protein sub-units, the various types of amyloids have the same ultrastructural organization in the form of interlaced .beta.-antiparallel sheets.
The fibrils are formed from particular light chains of monoclonal immunoglobulins and numerous other amyloidogenic proteins such as protein AA, transthyrethyne .beta.-2-microglobulin, beta protein, which constitutes the amyloidosis of Alzheimer's disease and Down's syndrome, etc.
It has now been surprisingly found that IDX, and in particular its hydrochloride, is active in inducing degradation of amyloid fibrils.
The drug/fibril interaction is at the basis of the beneficial clinical effects observed in patients with amyloidosis. As the structure is known to be in the form of beta-parallel sheets, common to all forms of amyloidosis, 4'-iodo-4'-deoxydoxorubicin represents a reasonable hope of cure for all forms of amyloidosis and in particular for Alzheimer's disease. of Various Biochemical Compositions
A predetermined quantity of amyloid fibrils (1 mg/ml) was incubated with different concentrations of IDX hydrochloride.
The incubation was conducted for 2 hours in physiological solution, the system being under constant delicate agitation.
The fibrils were then centrifuged at 5000 rpm, the optical density of the supernatant being determined at 478 nm.
The wash procedure was repeated three times.
After the final centrifuge step, the quantitative and qualitative analysis of the linkage with the fibrils was effected using a pellet.
The pellet was suspended in a phosphate buffer solution (PBS) and then incubated overnight with the enzyme protease. This pronase causes complete hydrolysis of the proteins.
The quantity of IDX bound to the fibrils can be measured in the supernatant by spectrophotometry at 478 nm.
The tests showed a linkage of 4.+-.2 g of IDX per mg of fibrils.
The given data were obtained by testing the amyloid fibrils of two patients (ND and CAT) suffering from amyloidosis.
Qualitative analysis, conducted by immunofluorescence microscope, was effected by utilizing the spectrofluorometric properties of IDX. The following fibrils composed of:
The fibrils were incubated with 10.sup.-7 M IDX and with DOX in 0.15M NaCl for 1 hour and washed extensively with 0.15M NaCl. The characteristic anthracycline fluorescence was evaluated by exciting at 484 nm and reading at 610 nm.
All the fibrils incubated with IDX showed intense fluorescence, whereas incubation with DOX produced no appreciable fluorescence.
10 mg of commercial bovine insulin suspended in 1 ml (1.74.times.10.sup.-3 M) of 5% acetic acid were incubated at 85.degree. C. for two hours until a clear gel formed. After freezing at -80.degree. C., thawing at 37.degree. C. and repeating this 5 times, the fibrils were centrifuged in a microcentrifuge.
IDX and DX were added in various molar ratios with respect to the fibril protein precursor (insulin). (IDX-DX:insulin; 1:2, 1:4, 1:8).
IDX but not DX completely inhibited amyloid fibril formation at molar rations of 1:1 and 1:2 and partly at a molar ratio of 1:4.
The test shows that IDX inhibits fibrilogenesis "in vitro". of t
REFERENCES:
patent: 4438105 (1984-03-01), Suarato et al.
"Tumori", vol. 75, No. 4, pp. 358-361, Protein Kinase C Activation and Lipid Peroxidation By Doxorubicin Analogues, Gambetta et al. 1989.
"Journal of Neurochemistry", vol. 61, No. 6, Inhibition of Beta-Amyloid Production by Activation of Protein Kinase C, Gabuzda et al. 1993.
Gianni Luca
Merlini Giampaolo
Istituto Nazionale Per Lo Studio E La Cura Dei Tumori
Krass Frederick
Policlinico San Matteo, Istituto Di Ricovero E Cura A Carattere
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