Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-10-01
2002-12-17
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S030000, C514S063000, C514S409000, C514S278000, C514S432000, C514S444000
Reexamination Certificate
active
06495591
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the field of antimicrobial agents and more specifically it relates to the use of milbemycins and analogous compounds as efflux pump inhibitors to be co-administered with antimicrobial agents to inhibit the growth of microbial cells.
BACKGROUND OF THE INVENTION
Fungal infections are relatively rare in immunocompetent humans or other mammals. A number of Candida species are often present as benign commensal organisms in the digestive system of healthy individuals (Shepherd, M et al,
Ann. Rev. Microbiol.,
39:579-614, 1985). Fungal infections, however, can be life threatening for immunocompromised individuals. Three major groups of severely immunocompromised individuals have emerged in recent years, These are: 1) cancer patients undergoing chemotherapy, 2) organ transplant patients treated with immunosuppressive agents, and 3)AIDS patients. The frequency of fungal infections has risen world-wide in recent years. Data from the National Nosocomial Infections Surveillance System conducted in the United States showed 487 percent increase in Candida bloodstream infections between 1980 and 1989 (Reviewed in Rex, M. Rinldi, and M. Pfaller. 1995. Resistance of Candida species to fluconazole.
Antimicrob. Agents and Chemother.
39:1-8). Oropharyngeal candidiasis was shown to be the most common fungal infection in AIDS patients. Prevalence studies have suggested that up to 90% of patients with AIDS have had at least one episode of oropharyngeal candidiasis (Powderly. 1994. Resistant Candidiasis. 1994. AIDS research and Human
Retrovirusses.
10:925-929).
There are only a small number of therapeutic agents available for the treatment of serious fungal infections. Amphotericin B, flucytosine, fluconazole, itraconazole and ketoconazole are some of the few currently available drugs against systemic fungal infections (Odds. 1993. Resistance of yeasts to azole-derivative antifungals.
J. Antimicrob. Chemother.
31: 463-471).
The mechanism of action of amphotericin B, a polyene macrolide antibiotic, is based on its interaction with the plasma membrane of sensitive organisms, which impairs the barrier function of the membrane. Its selectivity may be related to its greater affinity for the ergosterol of fungal membranes than for the cholesterol of mammalian membranes. Amphotericin B is a fungicidal agent. Resistance to amphotericin B is rare and is based on a marked (74-85%) decrease in the ergosterol content in resistant variants. However, amphotericin B is associated with many toxic side effects and is poorly absorbed from the gastrointestinal tract, which necessitates intravenous administration.
The mechanism of action of flucytosine (5FC) is the inhibition of DNA and RNA synthesis. 5FC is taken up by a cytosine permease. It is converted to 5-fluorouracil (5FU) by cytosine deaminase inside the fungal cell. The low activity of cytosine deaminase in mammalian cells is the basis for the low toxicity of 5FC in human. 5FU is converted into 5-fluorouridilic acid, which is further phosphorylated and incorporated into RNA. As a result of formation of such aberrant RNA the fungal growth is inhibited. 5FU is also converted to a potent inhibitor of thymidilate synthase and, as a result, inhibits DNA synthesis. Thus, 5FC is a potent fungicidal agent. However, it rapidly becomes ineffective since mutations to resistance arise with high frequency. This resistance results from loss or mutation of any of the enzymes which are involved in its conversion into toxic intermediates for RNA and DNA synthesis (Reviewed in Vanden Bossche, P. Marickal, and F. Odds. 1994. Molecular mechanisms of drug resistance in fungi.
Trends Microbiol.
2:393-400).
Azoles (e.g., fluconazole, itraconazole and ketoconazole) are currently the most important agents for the treatment of fungal diseases. The primary mechanism of action of azole antifungals is inhibition of ergosterol biosynthesis. In azole-treated cells there is accumulation of 14&agr;-methyl-sterols, the precursor intermediates of ergosterol. Conversion of 14&agr;-methyl-sterols to ergosterol was shown to be dependent on cytochrome P-450. Azoles bind to P-450 and inhibit the function of this enzyme. (Reviewed in Saag and W. Dismukes. 1988. Azole antifungal agents: emphesis on new triazoles.
Antimicrob. Agents Chemother.
32:1-8). The first oral azole which was proven to be effective in mycoses was clotrimazole. However, brief treatment with clotrimazole rapidly induces liver microsomal enzymes which increases metabolism of the drug and diminishes its antifungal activity. Another azole, miconazole, is not rapidly metabolized, but it has multiple toxic effects. As a result, it has very limited use as a topical agent for cutaneous mycoses. Ketoconazole was developed in the late 1970s. It was the first azole that could be given orally for systemic use and for some time it was the most important azole antifungal agent. It is less toxic than miconazole, however, dose-related inhibition of testosterone synthesis may result in menstrual irregularities, sexual impotence or oligospermia (Saag and W. Dismukes. 1988. Azole antifungal agents: emphasis on new triazoles.
Antimicrob. Agents Chemother.
32:1-8). Relatively recently, two new azole, fluconazole and itraconazole, have been developed.
Fluconazole is currently the most extensively used agent for the treatment of patients with severe candidiasis. It has several advantages over the earlier azole antifungals, including ketoconazole. It has higher solubility in water, longer plasma-half-life, and relatively low toxicity. The bioavailability of fluconazole after oral administration is 90%. Between 1988 and 1993, fluconazole was used to treat over 15 million patients, including at least 250,000 AIDS patients (Hitchcock, C. A. 1993. Resistance of
Candida albicans
to azole antifungal agents.
Biochem Soc. Trans.
21:1039-1047), and fluconazole treatment of patients with oropharyngeal candidiasis has been adopted by many clinics. (Recently licensed itraconazole is not used as extensively because of its much lower bioavailability).
Due to wide use of fluconazole for both treatment (and in many cases, this treatment is continued over long periods of time) and prophylaxis, reports of failure of therapy due to appearance of Candida which are resistant to fluconazole began to appear (reviewed in Rex, M. Rinldi, and M. Pfaller. 1995. Resistance of Candida species to fluconazole.
Antimicrob. Agents and Chemother.
39:1-8, Vanden Bossche, P. Marickal, and F. Odds. 1994. Molecular mechanisms of drug resistance in fungi.
Trends Microbiol.
2:393-400). Three different routes of acquisition of resistant variants were described. In the first scenario, infecting
Candida albicans
(
C. albicans
) were initially susceptible, but mutated and become resistant. Mutants resistant to fluconazole only and mutants which are cross-resistant to other azoles (ketoconazole, itraconazole) have been isolated. In the second scenario, patients were initially colonized with fluconazole resistant
C. albicans
. In the third scenario, the recent widespread use of fluconazole led to a rise in the prevalence of colonization and infection by other Candida species, such as
Candida glabrata
and
Candida krusei
, which are intrinsically less susceptible to fluconazole (reviewed in Odds. 1993. Resistans of yeasts to azole-derivative antifungals.
J. Antimicrob. Chemother.
31: 463-471).
A limited number of studies on the mechanism of resistance to fluconazole in clinical isolates have appeared in the literature. It was shown that in one, probably exceptional case, amplification of the gene CYP51, encoding P-450 (fluconazole target) is implicated in drug resistance (Vanden Bossche, P. Marickal, F. Odds, L. Le Jeune, and M.-C. Coene. 1992. Characterization of an azole resistant
Candida albicans
isolate.
Antimicrob. Agents and Chemother.
36: 2602-2610). In another case resistance to fluconazole was correlated with the appearance of an altered P-450 which had decreased affinity to fluconazole (Hitchcock, C. A. 1993.
Chamberland Suzanne
Lee May
Lomovskaya Olga
Bingham McCutchen
Delacroix-Muirheid C.
Essential Therapeutics, Inc.
Fay Zohreh
Rose Bernard F.
LandOfFree
Fungal efflux pump inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Fungal efflux pump inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Fungal efflux pump inhibitors will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2981772