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Ambisome

Amphotericin B (Fungilin®, Fungizone®, Abelcet®, AmBisome®, Fungisome®, Amphocil®, Amphotec®) is a polyene antimycotic drug, used intravenously in systemic fungal infections. It was originally extracted from Streptomyces nodosus fungi. Currently the drug is available as plain Amphotericin B, as cholesteryl sulfate complex, as lipid complex, and as liposomal formulation. The latter formulations have been developed to improve tolerability for the patient but may show considerable pharmacokinetic characteristics compared to plain Amphotericin B. more...

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Uses

Oral preparations of amphotericin B are used to treat oral thrush; these are virtually nontoxic. The main i.v. use is in systemic fungal infections (e.g. in immunocompromised patients), and in visceral leishmaniasis. Aspergillosis, cryptococcus infections (e.g. meningitis) and candidiasis are treated with amphotericin B. It is also used empirically in febrile immunocompromised patients who do not respond to broad-spectrum antibiotics.

Method of action

As with other polyene antifungals, amphotericin B associates with ergosterol, a membrane chemical of fungi, forming a pore that leads to K⁺ leakage and fungal cell death. Recently, however, researchers found evidence that pore formation is not necessarily linked to cell death (i.e. Angewandte Chemie Int. Ed. Engl. 2004). The actual mechanism of action may be more complex and multi-faceted.

Side effects

Very often a most serious acute reaction after the infusion (1 to 3 hours later) is noted consisting of fever, shaking chills, hypotension, anorexia, nausea, vomiting, headache, dyspnea, and tachypnea. This reaction sometimes subsides with later applications of the drug and may in part be due to histamine liberation. An increase in prostaglandin-synthesis may also play a role. Often the most difficult decision has to be made, whether the fever is disease- or drug-related. In order to decrease the likelihood and severity of the symptoms, initial doses should be low and increased slowly. The liposomal preperation obviously has a lower incidence of the syndrome. Acetaminophen, pethidine, diphenhydramine and/or hydrocortisone have all be used to treat or prevent the syndrome, but the prophylactic use of these drugs should be limited.

Nephrotoxicity (kidney damage) is a major issue and can be severe and/or irreversible. It is much milder when amphotericin B is delivered in liposomes (AmBisome). Electrolyte imbalances (e.g. hypokalema and hypocalcemia) may also occur.

Increased liver enzymes and hepatotoxicity up to acute liver failure, several forms of anemia and other blood dyscrasias (leukopenia, thrombopenia), serious cardiac arrhythmias (including ventricular fibrillation), and cardiac failure have also been reported frequently. Skin reactions, including serious forms, are also possible.

Interactions

Flucytosine : Toxicity of Flucytosine increased and vice versa
Diuretics or Cisplatin : Increased renal toxicity and incrised risk of hypokalema
Corticosterioids : Increased risk of hypokalema
Cytostatic drugs : Increased risk of kidney damage, hypotension and bronchospasms.
Other nephrotoxic drugs : Increased risk of serious renal damage. Monitor patients closely.
Foscarnet, Ganciclovir, Tenofovir, Adefovir : Risk of hematological and renal side-effects of Amphotericin B increased.
Transfusion of Leukocytes : Risk of pulmonal (lung) damage. Space intervalls between the application of Amphotericin B and the transfusion and monitor pulmonal function.

Read more at Wikipedia.org

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Mycograb ®: Human recombinant antibody to HSP90
From Indian Journal of Pharmacology, 1/1/05 by A. Garg

Byline: A. Garg, P. Rataboli

Systemic infection by Candida species in the United States still tags with it a significant 35-40% mortality rate and data does not look better in any other part of the world either.[1],[2] This high rate despite the advances in antifungal treatment can be attributed to non-Candida albicans Candida species and their growing resistance to commonly used antifungal drugs.[3],[4]

This has resulted in a thrust to produce newer and more powerful drugs and drug delivery systems giving birth to variconazole, pneumocandins like caspofungin acetate, ABCL (Amphotericin-B Lipid Complex), ABCD (Amphotericin-B Colloid Dispersion), AmBisome (Unilamellar vesicle formulation of amphotericin-B), and lyophilized powders.

In fungal infections, and especially deep-seated systemic infections, heat shock protein 90 (HSP90) plays a crucial role and is essential for the viability of the yeast.[5] Considering this, a new molecule is developed called Mycograb [R] (Neu Tec Pharma plc).[6] Mycograb [R] is a polyhistidine tagged purified human recombinant antibody to HSP90. It is the first human recombinant antibody fragment to be used in fungal infections.[7] In the pre-clinical studies it was found to be highly effective when used in combination with amphotericin-B and showed significant antifungal activity against all five species of Candida, namely C. albicans, C. krusei, C. tropicalis, C. parapsilosis, and C. glabrata. However, when combined with fluconazole, it did not increase the response rate in fluconazole-resistant species but increased the clearance of fluconazole-sensitive species of Candida.[8]

Phase I clinical trials began in December 2000 with five patients of systemic candidiasis. The drug was given intravenously and safety assessment, kinetic, and dynamic parameters were studied. Results of these data were first presented at the American Society of Microbiologists Annual Conference, 2001. After confirming the favorable side-effect profile in July 2001, the drug entered Phase II trials. It was a double-blind randomized controlled trial involving 60 patients with culture-confirmed systemic candidiasis. The results were so encouraging that the company was hopeful of getting Phase III waiver from the United States Food and Drug Administration (US FDA) and directly marketing the drug. In January 2003, the Multi Research Ethical Committee (MREC) approved the drug to be tested in the UK and in February of the same year, the company filed the Investigational New Drug (IND) application with FDA. Mycograb [R] has been granted the status of orphan drug in Europe and the US by the European Medicine Evaluation Agency (EMEA) and the US FDA respectively.

The time has come to look beyond the physical molecules for the treatment of various infections and to search for some ways to produce biological agent which can take care of biology itself. Mycograb [R] is a major leap ahead in this field and like all other drugs it brings with it two hopes: first, it will be useful for the prophylaxis and treatment of systemic candidiasis, and second, that it could be of immense help in overcoming the growing resistance against antifungal agents.

References

1. McNeil MM, Nash SL, Hajjeh RA, Phelan MA, Conn LA, Plikaytis BD, et al. Trends in mortality due to invasive mycotic diseasea in United States, 1980-1997. Clin Infect Dis 2001;33:641-7.

2. Narang A, Agarwal PB, Chakrabarti A, Kumar P. Epidemiology of systemic candidiasis in tertiary care neonatal unit. J Trop Pediatr 1998;44:104-8.

3. Krcmery V, Barnes AJ. Non-albicans Candida spp. causing fungaemia: Pathogenicity and antifungal resistance. J Hosp Infect 2002;50:243-60.

4. Hope W, Morton A, Eisen DP. Increase in prevalence of nosocomial non-Candida albicans candidaemia and the association of Candida krusei with fluconazole use. J Hosp Infect 2002;50:56-65.

5. Porsius JC, van Vliet HJA, van Zeijl HJ, Goessens WHF, Michel MF. Detection of an antibody response in immunocompetent patients with systemic candidiasis or Candida albicans colonisation. Eur J Clin Microbiol Infect Dis 1990;9:352-5.

6. Mycograb [R] available on http://81.201.142.226/companyInfo/history.asp. Accessed on 20th October 2004.

7. Burnie J, Matthews RC. Genetically recombinant antibodies: New therapeutics against candidiasis. Expert Opin Biol Ther 2004;4:233-41.

8. Matthews RC, Rigg G, Hodgetts S, Carter T, Chapman C, Gregory C, et al. Preclinical assessment of the efficacy of mycograb, a human recombinant antibody against fungal HSP90. Antimicrob Agents Chemothr 2003;47:2208-16.

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