Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1991-02-28
2003-03-04
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S280000, C514S281000, C514S895000
Reexamination Certificate
active
06528519
ABSTRACT:
This application is based on the inhibitory activity of tetrandrine and all of its derivatives, specifically against malaria, as well as the ability of such derivatives, some in particular, to potentiate the effectiveness of antimalarial drugs against multidrug resistant malarial cells in particular. A related application filed concurrently herewith discloses and claims the generic ability of methoxadiantifoline, tetrandrine and certain of its derivatives to potentiate the inhibitory action of primary drugs against multidrug resistant cells generically, and to apparently reverse the normal pump out action of P-glycoprotein in such cells.
BACKGROUND OF THE INVENTION
A number of diverse drugs have been found effective against malaria. However in many cases, the initial success of physicians in treating this disease is followed by total failure. Drugs which worked initially become totally ineffective after a period of time. An initial period of remission is often followed by a period of frustration during which nothing seems to be effective against the disease. Death becomes inevitable.
Such a phenomenon is often referred to as multidrug resistance. A malarial cell which initially responds to treatment by one or more drugs becomes resistant to treatment by not only the drugs previously used, but but any malarial treatment drug. Martin, Odula and Milhous disclosed the treatment of such multidrug resistance in malaria by using verapamil. “Reversal of Chloroquine Resistance in
Plasmodium falciparaum
by Verapamil,” Martin et al, Science, Feb. 28, 1987. Martin et al, reports that Verapamil did reverse chloroquine resistance in malaria cells, but that the verapamil alone had no effect on the malaria. The structural formula of verepamil is shown below:
The problem with this approach is that verapamil is a calcium channel blocker. While calcium channel blockers are therapeutic in the treatment of hypertension at moderate levels, they are toxic at levels high enough to effect MDR reversal.
Consequently, researchers throughout the world continue to press for techniques for reversing multidrug resistance. A successful clinical technique for reversing multidrug resistance in malaria will be one of the most important breakthroughs in the fight against malaria.
SUMMARY OF THE INVENTION
In the present invention, it has been surprisingly found that tetrandrine and its derivatives act to reverse multidrug resistance in malaria and do not show an affinity for calcium channel blocking. Thus the toxicity problems associated with verapamil and its derivatives are avoided.
Perhaps even more surprisingly, it has been found that tetrandrine and its derivatives are also specifically effective against malaria, including multidrug resistant strains, even in the absence of primary treatment drugs. Indeed, the most surprising of all is that the most preferred tetrandrine type structure is actually more effective against multidrug resistant malarial strains than it is against drug sensitive strains.
These surprising and unexpected results, as well as other objects, advantages and features of the present invention will be more fully understood and appreciated by reference to the Description of the Preferred Embodiment and appended drawings.
REFERENCES:
Fournet Et Al, 1988, Antiparisitic Activity of Bisbenzylisoquine Alkaloids I., Journal of Ethnopharmacology, vol. 24, pp. 327-335 (English Translation).*
Fournet Et Al, 1988, Antiparisitic Activity of Bisbenzylisoquinoe Alkaloids II Journal of Ethnopharmacology, vol. 24, pp. 337-343 (English Translation).*
Riou Et Al, 1986, Purification and Characterization ofPlasmodium bergheiDNA Topoisomerases I and II: Biochemistry, vol. 25, No. 7, pp. 1471-1479.*
Fournet Et Al 110 CA: 132057y 1980.*
Fournet Et Al 110 CA: 1322058z 1988.*
Neal Et Al, Transactions of Royal Society of Tropical Medicine & Hygiene (1989) vol. 83 pp. 197-198.*
The Merck Index, Eleventh Edition, notes 1168-1169.
Bacteriology Principles And Practice, Barnes & Noble, pp. 318-319.
Biochemical And Biophysical Research Communications, vol. 155, No. 1, 1988, pp. 476-481.
“A New Calcium Antagonist of Chinese Medicinal Origin: Tetrandrine,” Fang et al.
“Chemical Studies On Qinghaosu (Artemisinine),”Journal of Traditional Chinese Medicine, 2(1):3-8, 1982.
“The Chemistry And Synthesis Of Quinghaosu Derivatives,”Journal of Traditional Chinese Medicine, 2(1):9-16, 1982.
“Qinghaosu (Artemisinin): An Antimalarial Drug from China,”Science, vol. 228, pp. 1049-1055.
“Antimalarial Efficacy And Mode Of Action Of Qinghaosu And Its Derivatives In Experimental Models,”Journal of Traditional Chinese Medicine, 2(1):17-24, 1982.
“Clinical Studies On The Treatment Of Malaria With Qinghaosu And Its Derivatives,”Journal of Traditional Chinese Medicine, 2(1):45-50, 1982.
TheMayo Clinic Family Healthbook, pp. 868-869, ©1990.
Modern Pharmacology, Third Edition, ©1990, Chapter 56.
Price Heneveld Cooper DeWitt & Litton
Travers Russell
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