Tuesday, 26 October 2010

Nanoparticles deliver improved antifungal activity

The hydrophobic nature of many antifungal drugs is problematical for effective drug delivery and absorption in patients.
Considerable research on a drug delivery system based on bio-degradable polymers has been productive in identifying suitable carriers such as the thermoplastic polyesters eg poly(lactide-co-glycolide), which exhibit good biocompatibility and biodegradability alongside mechanical strength. These bio-degradable polymers have been developed into a new type of drug delivery system called nanoparticles - which can be used to deliver a wide range of drug classes including anti cancer drugs, antihypertensive agents and various peptides, proteins, and vaccines.
Last month a publication by Patel et al describes the development of nanoparticles loaded with the hydrophobic antifungal drug - itraconazole.
The particles were characterised for morphology and also for their ability to inhibit growth of Aspergillus flavus. The itraconazole loaded nanoparticles achieved an inhibition of A. flavus growth for an 11 day period at a concentration of 0.03mg/ml or rather 1/100th of the concentration of itraconazole alone (in emulsified form). It is envisioned that the use of nanoparticles loaded with itraconazole increases its bioavailability by improving its dispersion in water and greatly enhances its antifungal activity.
These results are promising for a significant improvement in the delivery of antifungal drugs and hence their efficiency, but more in vivo studies will help to advance this technology.

Another advantage of the nanoparticle technology which will hopefully prove fruitful, is targeting specific organ delivery.
For example the blood brain barrier precludes the transport of many drugs to the brain. However Chen et al published data in June this year that an itraconazole loaded nanoparticle with a special tag on it derived from the rabies virus, allowed transport of the itraconazole into the brain when compared to nanoparticles without the rabies derived tag. The potential for targeting intracranial fungal infections in this way is exciting.

From the perspective of delivering targeted treatment to lung infections -a special type of nanoparticle that penetrates mucus - was reviewed by Lai et al last year. If a nanoparticle/antifungal drug can be developed which avoids the normal rapid mucus clearance mechanisms, the prospect of delivering antifungal drugs right to the site of infection should greatly improve the chances of effective treatment. This approach would be particularly useful for cystic fibrosis patients too.

Tuesday, 19 October 2010

Oral Amphotericin Receives Orphan Drug Status

Amphotericin has long been a highly effective antifungal drug and is still widely used to treat aspergillosis. One of its strengths is that it attacks the cell wall of the fungus in a way that is highly specific to fungi (& insects) so the drug itself is potentially low in toxicity to humans. Most other available antifungal drugs (azoles)  attack the cell membrane but as human cells also have cell membranes there is potential for toxicity to human cells as well as fungal cells. This requires clinicians to carry out careful dose management.

Unfortunately amphotericin has poor solubility in water so cannot be given to patients without dissolving in substances that are fairly toxic to some patients, particularly affecting kidney and liver. This makes this drug tricky to give, requires accurate dose management and cannot be given as a pill or capsule as it will not dissolve in the stomach.

Fortunately there has now been a breakthrough in reformulation of amphotericin which we reported last year. The new drug is referred to as iCo-009. iCo-009 has already been shown to be able to achieve similar drug levels in the blood compared with giving its predecessor by intravenous injection, and there have been only low levels kidney toxicity, albeit in animal tests so far.

We can now report that the development of that drug has received another boost. iCo-009 (iCo Therapeutics) has been awarded orphan drug status by the American drug regulatory body the US Food and Drug Administration (FDA). This status is awarded to drugs that are intended to treat rare diseases and entitles them to extra funding to aid development, so it is great news for this next generation of amphotericin drugs and great news for everyone looking for antifungal drugs with fewer side effects.

Wednesday, 13 October 2010

The Natural Antifungal Properties of Garlic

A recent news story mentions that garlic has many beneficial properties including antifungal, antibacterial, antiparasitic all without damaging our normal microbial flora, stimulates the immune system, clears out the blood vessels, lowers blood cholesterol, cures cancer and more - quite an impressive list. How much of this is true?

Much of it is based on laboratory experiments in test tubes with little or no evidence on its properties when used in humans (wikipedia). In those cases where it has been tested in humans the results are variable e.g. it has been found to be completely non-active in reducing blood cholesterol levels, but has been found to be a useful antiseptic and to alleviate some complications of diabetes - the latter to such an extent that it needs careful monitoring if used alongside some conventional drugs used to treat diabetes.

Is it useful to treat fungal infections, in particular infections by Aspergillus? This research paper from 2007 clearly demonstrates that garlic does have good antifungal activity in the laboratory but again no work is done on humans. Perhaps applying garlic directly to a superficial fungal infection might help but if eaten it seems highly unlikely that the levels used in the laboratory would be reached unless huge amounts of garlic were consumed. There is more bad news - the garlis must be eaten fresh and raw! Not a palatable option for most of us or our nearest & dearest.

This is a case of wait and see. We can look at the substances in garlic that are antifungal and they might provide a clue to a new way to attack fungi. This could lead to the development of new antifungal drugs that could be produced in concentrated (and odour-free) pill form.

Will eating a clove or two a day help prevent fungal infections? Probably not - even if eaten raw there is too little active ingredient when absorbed into our bodies. A clove might weight a few grams and that would be effectively diluted into our bodies that weigh many tens of kilos - a dilution rate of many thousands.

But never mind - it still tastes good!

Wednesday, 6 October 2010

Aspergillus is found to be the predominant organism in a group of paediatric Cystic fibrosis patients

Patients with cystic fibrosis are often susceptible to lung infections. Fibreoptic bronchoscopy (FB) and bronchoalveolar lavage (BAL) are often performed to aid the management of children with cystic fibrosis (CF). A study of a group of CF children ages 0-18 who had FB between 2005-8 in the NE of England, has revealed that 16 out of 45 patients tested positive for Aspergillus fumigatus - either in isolation or in combination with other organisms.
Other organisms such as pseudomonas aeruginosa and haemophilus influenza were isolated from some samples but Aspergillus was the most prevalent organism identified in BAL from these children. Of interest half of those with Aspergillus were also diagnosed with ABPA. (Report from the recent 20th ERS meeting, Davidson et al).
Cystic fibrosis patients generally have a poor response to the antifungal drug itraconazole (and posaconazole) - in part because they lack pancreatic enzymes necessary to absorb fats which are also required for itraconazole absorption; also because CF patients may need to take antacid medicines - acid helps to allow absorption of itraconazole.

A second report from the 20th ERS meeting has studied the pharmacokinetics of oral voriconazole in adult CF patients (Clifton et al ). They showed by monitoring blood levels of voriconazole that the drug was absorbed by the CF patients and blood levels achieved were sufficient for treatment of aspergillus. Two patients had to withdraw due to drug side effects - but they were shown to have high levels of the drug in their blood- underpinning the need to monitor antifungal drug levels for optimal effectiveness.
The study shows that voriconazole can be absorbed by CF patients and may be useful in the treatment of fungal infections in cystic fibrosis.

Friday, 1 October 2010

Promising new approach for rapid diagnosis of Invasive Aspergillosis


Scientists in San Antonio, Texas, presenting at the recent 5oth ICAAC conference in Boston, have been investigating a new approach looking at secreted proteases from Aspergillus fumigatus, hoping to find a more rapid diagnosis of invasive aspergillosis (IA). The A. fumigatus genome secretes nearly 100 proteases many of which are secreted in vivo during infection.

By designing fluorogenically labelled substrates for these enzymes - the protease activity in either the serum or broncheolar lavage fluid can be tested in infected patients, using the unique thermotolerance of Aspergillus proteases to distinguish them from host proteases.


The technique requires the identification of fungus specific substrates which were identified using a library of fluorescent probe/substrates in comparison with human serum. The tests were carried out in a guinea pig model of invasive aspergillus where a number of substrate probes proved specific for the A. fumigatus proteases at temperatures up to 50C.
The next stage of the work will be to identify which labelled substrates may be specifically broken down by fungal proteases during infection - these would be promising diagnostic candidates.

Fluorogenic probes have already been used successfully to image protease activity in oncology and in inflammation, if successful this paves the way for alternative methods for rapid diagnosis of IA and potentially for following the progress of treatment as well.

(Report from Abstract M1819 from 50th ICAAC by D Watson et al. 2010)

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