Term
| Strategies for Finding Antifungal Agents |
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Definition
One exploitable area for finding antifungal agents is through differences in fungal cell membrane/wall morphology
Where mammals use cholesterol as the primary
component and transport agent of their cell membranes,fungi use ergosterol |
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Term
| Most common fungal pathogen |
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Definition
| Candida albicans results in thrush or “yeast infections” if not controlled, while Cryptococcus neoformans infects the lungs and can lead to meningitis |
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Term
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Definition
first broad spectrum antifungal agent, introduced the polyene class of antifungal agents. The polyenes work by binding to the ergosterol in the fungal membrane such that it leaks critical minerals and cellular components
available as a topical cream, an oral suspension or in pill form. It is used in the treatment of all forms of Candida infections and is given to immunodeficient patients in order to prevent adventitious fungal infection
toxic and teratogenic if given iv in animals, and is not available in injectible form for humans. It is not absorbed systemically from the skin, mucosal membranes or the gut, which is why it is still on the market |
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Term
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Definition
isolated from the bacterium Streptomyces natalensis from a sample obtained in South Africa
not absorbed systemically, and is used for the treatment of fungal keratitis. It is also widely used as a “natural” antifungal food additive |
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Term
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Definition
discovered the same year as Natamycin from Streptomyces nodosus by a team from Squibb (now part of BMS). Unlike the other polyene antifungals, Amphotericin B is suitable for injection as well as in pill form
practically insoluble in water and must be formulated as a suspension that is not absorbed in the gastrointestinal tract. Systemic use is achieved via intravenous administration. It is highly protein bound (> 90%) which creates a depot effect and a half-life of > 18 hours. It does NOT readily cross the blood brain barrier, so it must be administered intrathecally for fungal meningitis.
use is limited due to toxicity in the liver and kidneys. It should never be given with other nephrotoxic drugs. Formulation with liposomes has been approved to limit this liability |
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Term
| Polyene Antifungal Agents |
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Definition
Although complex natural products, the polyenes can be mass produced via fermentation on large scale
Although complex natural products, the polyenes can be mass produced via fermentation on large scale
The polyenes are one of the only fungicidal (as opposed to fungistatic) classes of antifungal agents
The toxicity is likely due to the fact that the polyenes bind to cholesterol, although they have a 500x affinity for ergosterol over cholesterol
Even in the face of this toxicity, they are still widely used as part of the > $10 billion/year antifungal market |
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Term
| 14a-Sterol demethylase (aka CYP51) |
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Definition
| first step in the ergosterol biosynthetic pathway that branches away from the biosynthesis of cholesterol, making it an ideal target for the development of antifungal agents. This breakthrough, though, came from the agricultural industry |
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Term
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Definition
(Lotrimin)
research team believed that the
imidazole group was cleaved from the molecule, creating a stable carbocation that was likely acting as the active agent. It is widely used for athlete’s foot and yeast infections
not well absorbed, which prevents drug interactions that would arise from inhibition of other CYPs. In addition to cream and aerosolized spray, it is available as a solution for fungal ear infections
Subsequent attempts to study analogs of
Clotrimazole led to the realization that the
imidazole wasn’t cleaved from the molecule – it is
a critical component that makes this the parent of the “azole” class of antifungal agents |
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Term
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Definition
(Desenex/Monistat)
2nd member of the azole class of antifungals, and helped demonstrate the importance of the heterocycle in its activity. Note that both clotrimazole and miconazole contain an imidazole ring, which is one of two primary classes of azoles, both of which exert their activity against 14a-sterol demethylase
arguably the most widely used antifungal agent sold over the counter, primarily for superficial fungal infections
used for internal fungal
infections, and is used for neonatal thrush.
However, unlike the polyenes, iconazole is absorbed when taken internally, and can lead to drug-drug interactions, including those that arise from CYP inhibition. Note also that Miconazole is a racemic compound – all of the activity is contained only in the (R)-enantiomer. |
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Term
| Why not just use the active enantiomer of Miconazole? |
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Definition
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Term
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Definition
(Travogen
A number of other azole antifungals are readily
available and widely used/prescribed. They all
have similar activity, but having different ones
helps to limit fungal resistance. They are all
generally used for exterior (non-systemic)
indications. Isoconazole, produced by Bayer and others, differs from Miconazole only by chlorine substitution pattern. |
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Term
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Definition
Spectazole)
another example of a chlorine
substitution analog that is widely available in the United States and around the world. It also exists as a cream that is formulated with a corticosteroid to alleviate itching. |
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Term
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Definition
(Exelderm)
first example of an azole drug
with a sulfur linkage instead of an oxygen linkage.
The sulfur provides a site for metabolism that helps clear the drug faster, but Sulconazole is still only used for non-systemic fungal applications. |
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Term
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Definition
(Lomexin)
contains a sulfur atom that serves as a metabolic handle and allows for more rapid clearance than the chlorinated analogs. It is available as a slow-release pessary to allow a single application. |
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Term
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Definition
Trosyd)
first example of a more subtle
use of sulfur (in the ring instead of as a linker), but it serves the same purpose. It is marketed by Pfizer for non-systemic fungal applications, and is also available in slow-release formulations. |
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Term
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Definition
(Ertaczo/Dermofix)
(marketed worldwide by Ortho) contains a cyclic sulfur atom to build in metabolic clearance and limit extended exposure.
In the United States it is sold under the trade name Ertaczo and outside of the U.S. as Dermofix (which is the name of a domestic herbal product). |
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Term
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Definition
(Fongamil)
first example of an azole antifungal that has designed simple pH sensitivity into the limited half-life of the active ingredient. It
is marketed by Sanofi-Aventis and is intended only for external use, but any accidental ingestion would not survive exposure to stomach acid,making it a “safer” alternative. |
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Term
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Definition
(Oxistat)
acid-sensitive functional group that helps render the compound safer for accidental ingestion. It is primarily used in cream or lotion form for the treatment of severe ringworm, athlete’s foot or jock itch in children. |
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Term
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Definition
(Gynazole)
another example of a sulfurcontaining
azole antifungal, but this compound is
structurally unique compared to all of the previous examples because the “linker” atom is on the “other” ring, setting the stage for more drastic structural changes to the scaffold. |
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Term
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Definition
(Canesten)
structurally-unique azole antifungal created by Bayer which is the first example of an azole that targets two different processes in the sterol biosynthetic pathway. Bifonazole is also active against HMG CoA reductase.
poster child for why
AZOLE USE SHOULD BE LIMITED BY PEOPLE WHO ARE TAKING STATINS TO CONTROL THEIR
CHOLESTEROL. They both regulate portions of the same pathway and could have severe drug-drug interactions. |
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Term
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Definition
(Nizoral)
first example of a ketal-containing azole antifungal agent. It is also the first one that has suitable pharmacokinetics for systemic use against fungal infections. Systemic fungal infections, which are not typically a concern for most people, represent a significant health risk for immunocompromised patients.
used to treat systemic Candida infections. It has
poor PK (moderate absorption, high protein
binding, relatively short half-life), but is still used
on occasion, although it has been supplanted by other azoles with better profiles. |
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Term
| Systemic Fungal Infections |
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Definition
For people with diminished immune capacity (HIV+ patients or transplant patients), fungal infections can become lethal. Statistics show:
90% develop oral Candidiasis
40% develop esophogial Candidiasis,
35-40% of women develop vulvo-vaginal Candidiasis
5% develop Cryptococcal meningitis
Aspergillosis is frequently developed in late stage HIV infections and is a leading cause of death |
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Term
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Definition
(Onmel/Sporal)
Itraconazole has a dramatically improved pharmacokinetic profile compared to
Ketoconazole. In addition to having activity against systemic Candida infections, Itraconazole is the first azole with activity against Cryptococcal meningitis and Aspergillus pulmonary infections.
much better pharmacokinetics
than Ketoconazole. It has an oral bioavailability of 55% and a half-life of 24 hours. While it is readily metabolized by CYP 3A4, it is 99.8% protein bound,which protects it from rapid metabolism and clearance. |
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Term
| Ketoconazole vs Itraconazole |
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Definition
The imidazole antifungal agents are typically used for
external fungal infections. The triazole antifungal agents
are more commonly used for systemic infections. |
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Term
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Definition
(Terazol)
Once the triazoles were recognized as viable (and even improved) azole antifungals, a number of new analogs were tested and reached the market.
Terconazole, for example, is a simplified (and cheaper) triazole antifungal that is available, but is not widely used in the United States. |
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Term
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Definition
(Noxafil)
one of the most active triazole
antifungal agents for systemic fungal infections. It is marketed by Schering-Plough (now Merck) for candidiasis, aspergilliosis, Cryptococcal meningitis and fusariosis infections. It is also under investigation for Chagas’ disease suggesting possible antibacterial activity as well
excellent pharmacokinetic
profile that is comparable to Itraconazole (50% oral bioavailability, 24 hour half-life, high metabolism protected by high protein binding), but with an excellent toxicity profile (no significant adverse events up to 1600 mg/day). |
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Term
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Definition
(Diflucan/Forcan)
structurally unique triazole antifungal. Note that it contains two triazole units and does not contain a chiral center, making it less expensive and less likely to have an undesired side effect by a “spectator” isomer.
broad spectrum antifungal agent
that is active against all of the fungi previously discussed. It has excellent pharmacokinetics (90% oral bioavailability, 10% protein binding, 24 hour half-life) and is not highly metabolized.
does inhibit CYP 2C9 and 3A4, so
there is the potential for drug-drug interactions (above and beyond not mixing cholesterol drugs).
There are also reports of increased cardiac arrhythmia associated with Fluconazole (although no report of hERG inhibition). |
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Term
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Definition
next generation analog of
Fluconazole. It is reported to be equally active while mitigating the side effects such as cardiotoxicity. It has a similar PK (96% bioavailability), but it is considerably more expensive. |
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Term
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Definition
(Abasol)
although not an azole compound, acts
through the inhibition of 14a-sterol demethylase,the same target as the azoles. It also shows limited antibacterial activity, suggesting more than one mechanism of action. It was introduced by Yorke Pharma, a dermatology company, and may not extend beyond topical indications. |
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