Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-14
2001-10-30
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S468000, C514S451000, C514S452000, C549S343000, C549S344000
Reexamination Certificate
active
06310091
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a novel fungicidal saponin and its isolation from cayenne pepper or other capsicum species fruit. This compound shows potential for improving crop resistance to a variety of aflatoxin-producing fungi and also as a pharmaceutical against human and animal fungal-induced diseases.
2. Description of the Prior Art
The identification of novel antifungal agents has been a continuing challenge. Due to the occurrence of new disease epidemics in agricultural crops and as a result of the growing resistance to antimicrobial drugs, there is an ongoing search for new antifungal compounds having unique structures.
The need for novel antifungal agents is significant, and is especially critical in the medical field. Immunocompromised patients provide perhaps the greatest challenge to modern health care delivery. During the last three decades there has been a dramatic increase in the frequency of fungal infections in these patients (Herbrecht, R.,
Eur. J. Haematol
., 1996, 56:12-17; Cox, G. et al.,
Curr. Opin. Infect. Dis
., 1993, 6:422-426; Fox, J. L.,
ASM News
, 1993, 59:515-518). Deep-seated mycoses are increasingly observed in patients undergoing organ transplants and in patients receiving aggressive cancer chemotherapy (Alexander, B. D. et al.,
Drugs
, 1997, 54:657-678). The most common pathogens associated with invasive fungal infections are the opportunistic yeast,
Candida albicans
, and the filamentous fungus,
Aspergillus fumigatus
(Bow, E. J.,
Br. J. Haematol
., 1998, 101:1-4; Wamock, D. W.,
J. Antimicrob. Chemother
., 1998, 41:95-105). There are an estimated 200,000 patients per year who acquire nosocomial fungal infections (Beck-Sague, C. M. et al.,
J. Infect. Dis
., 1993, 167:1247-1251); bloodstream fungal infections have a mean mortality rate of 55 w. Also adding to the increase in the numbers of fungal infections is the emergence of Acquired Immunodeficiency Syndrom (AIDS) where virtually all patients become affected with some form of mycoses (Alexander, B. D. et al.,
Drugs
, 1997, 54:657-678
; HIV/AIDS Surveillance Report
, 1996, 7(2), Year-End Edition; Hood, S. et al.,
J. Antimicrob. Chemother
., 1996, 37:71-85). The most common organisms encountered in these patients are
Cryptococcus neoformans, Pneumocystis carinii
, and
C. albicans
(
HIV/AIDS Surveillance Report
, 1996, 7(2), Year-End Edition; Polis, M. A. et al.,
AIDS: Biology, Diagnosis, Treatment and Prevention
, fourth edition, 1997). New opportunistic fungal pathogens such as
Penicillium marneffei, C. krusei, C. glabrata, Histoplasma capsulatum
, and
Coccidioides immitis
(
HIV/AIDS Surveillance Report
, 1996, 7(2), Year-End Edition; Ampel, N. M.,
Emerging Infectious Diseases
, 1996, 2:109-116) are also being reported with regularity in immunocompromised patients throughout the world.
Currently available drugs for the treatment of fungal infections include amphotericin B (a macrolide polyene), which interacts with fungal membrane sterols, flucytosine (a fluoropyrimidine), which interferes with fungal protein and DNA biosynthesis, and a variety of azoles (e.g. ketoconazole, itraconazole, and fluconazole) that inhibit fungal membrane-sterol biosynthesis (Alexander, B. D. et al.,
Drugs
, 1997, 54:657-678). Even though amphotericin B has a broad range of activity and is viewed as the “gold standard” of antifungal therapy, its use is limited due to infusion-related reactions and nephrotoxicity (Alexander, B. D. et al.,
Drugs
, 1997, 54:657-678; Wamock, D. W.,
J. Antimicrob. Chemother
., 1998, 41:95-105). Flucytosine usage is also limited due to the development of resistance and its narrow spectrum of activity. The widespread use of azoles is causing the emergence of clinically-resistant strains of Candida spp. (Alexander, B. D. et al.,
Drugs
, 1997, 54:657-678; Boschman, C. R. et al.,
Antimicrob. Agents Chemother
., 1998, 42:734-738). Although advances in the formulation of amphotericin B have decreased its nephrotoxicity (Graybill, J. R.,
Clin. Infect. Dis
., 1996, 22(Suppl. 2):S166-S178) and new classes of agents are in various stages of clinical development, the impact of fungal infections in the clinical management of patients underscores the clear need for new antifungals.
Historically, the screening of soil microorganisms and extracts obtained from terrestrial plants and animals has yielded novel natural products which themselves, or through chemical modification and synthesis, have been a rich source of bioactive agents for the treatment of plant, animal and human diseases (Gullo, V. P.,
The discovery of natural products with therapeutic potential
, Butterworth-Heinemann, Boston, 1994; Shu, Y.-Z.,
J. Nat. Prod
., 1998, 61:1053-1071). A review of the 520 newly-approved drugs reported between 1983 and 1994 indicates that 157 (30%) are unmodified natural products or semi-synthetic analogs (Cragg, G. M. et al.,
J. Nat. Prod
., 1997, 60:52-60).
The screening of natural sources such as microbial fermentations and plant extracts has led to the discovery of many clinically useful drugs that play a major role not only in the treatment of microbial infections, but also in the treatment of many human and plant diseases. The increasing clinical importance of emerging pathogens as well as drug-resistant fungi has lent additional urgency to identify novel, active compounds. The most promising lead antifungal compounds are those derived from natural products. The lipopeptides are potent broad-spectrum antifungal agents that inhibit the synthesis of the fungal cell-wall polymer, (Gullo, V. P.,
The discovery of natural products with therapeutic potential
, Butterworth-Heinemann, Boston, 1994; Cragg, G. M. et al.,
J. Nat. Prod
., 1997, 60:52-60) &bgr;-D-glucan (Denning, D. W.,
J. Antimicrob. Chemother
., 1997, 40:611-614). The pradimicins are a group of benzonaphthacene quinones which posses a broad spectrum of activity and bind to the mannoproteins of the fungal cell membrane (Oki, T. et al.,
J. Antibiot
., 1998, 41:1701-1704). The sordarins are tetracyclic diterpene glycosides, which have a broad spectrum of antifungal activity and inhibit the elongation step of fungal protein synthesis (
Drugs Future
, 1997, 22:1221-1225).
Another class of antifungal agents are the saponins, which are glycosides consisting of one or more sugars linked to a steroid or triterpene core. They are noted for their detergent properties and some have been found to be microbicidal. Some are antiviral (Sindambiwe, J. B. et al.,
J. Nat. Prod
., 1998; 61:585-590; Simões, C. M. O. et al.,
Planta. Med
., 1990, 56:652-653; Simões, C. M. O. et al.,
Phytother. Res
., 1999, 13:323-328) and appear to inhibit viral DNA and capsid protein syntheses (Simões, C. M. O. et al.,
Phytother. Res
., 1999, 13:323-328), while others have antifungal properties. Extracts of
Eriocephalus africanus L., Felicia erigeroides
DC, and
Helichrysum crispum
(L.) D. Don, inhibited
Candida albicans
growth (Salie, F. et al.,
J. Ethanopharmacol
., 1996, 52:27-33). Saponins from the tubers of
Cyclamen coum
Miller inhibited the growth of several Candida species and
Cryptococcus neoformans
(Calis, I. et al.,
Planta. Med
., 1997, 63:166-170).
Triterpenoid saponins
have been shown to exhibit a wide spectrum of activity against yeast as well as the dermatophytes,
Trichophyton rubrum
and
T. mentagrophytes
(Favel, A. et al.,
Planta. Med
., 1994, 60:50-53). Recently, a jujubogenin saponin isolated from
Colubrina retusa
, a rhamnaceous plant growing in Venezuela (Li, X. C. et al.,
J. Nat. Prod
., 1999, 62:672-677), was shown to be moderately effective against
C. albicans, Cryptococcus neoformans
, and
A. fumigatus
(MICs, 50 &mgr;g/ml). Oats contain two families of saponins, the triterpenoid avenacins and the steroidal avenacosides (Osborn, A. E. et al.,
The Plant Cell
, 1996, 8:1821-1831).
Fenugreek produces a steroid saponin and the corresponding aglycone that becomes inhibitory against fungi such as
Candida albicans
after treatment with &bgr;-glucosidase (Sauvair
Bland John M.
De Lucca, II Anthony J.
Selitrennikoff Claude P.
Vigo Craig B.
Desai Rita
Fado John D.
Lipovsky Joseph A.
Rotman Alan L.
Silverstein M. Howard
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