medicină veterinară - Ion Ionescu de la Brad

Universitatea de Știinţe Agricole și Medicină Veterinară
ANTIFUNGAL THERAPY BASED ON VECTOR TARGETED
SYSTEMS
MIRON L., NĂSTASĂ V., MAREŞ M.
University of Agricultural Sciences and Veterinary Medicine Iași
In this paper, is explained how is was made the synthesize, characterize and compare the
activity of 5-Flucytosine (FLUCYTOSINE) and 1- (2-[p-Chlorobenzylthiol]-2-[2,4-
dichlorophenylethyl]-H-imidazole (SULCONAZOLE), anti-mycotic drugs and cyclodextrins (α-, β-
cyclodextrin ) and their derivatives (hydroxypropyl-cyclodextrin, cyclodextrin-sulphate) first
molecular complexes in vitro conditions. Also, it was studied the biological activities of inclusion
complexes and acute tests of toxicity.
The complexation of 5 FC into CD cavity increases the 5 FC solubility and dissolution in water
for 41 times. Due to this aspect, cyclodextrin based supramolecular systems represent an
interesting formulation platform for delivery of drugs with poor physicochemical and
biopharmaceutical properties.
In vitro antifungal activity of the complexed drugs (inclusion complexes of 5 FC and β-CD) is
higher (MIC50 is ten times and MIC90 is four times smaller), than of the pure active compound.
β-ciclodextrin acute toxicity tests are indicate an reduced toxic effect like in literature absent
in oral administration. The acute toxicity studies data show, that the acute toxicity of the 5 FC-β-
CD inclusion complex is smaller, comparing with the free 5 FC.
Technical literature attests the considerable scope for the use of cyclodextrins [CD] and their
derivatives in antimycotic therapeutic products4,6,7,8,11. Recent studies have given encouraging
results with antimycotics and the cyclodextrins widely used in pharmaceutical industry3
Flucytosine (FLU) has been renewed as a result of two recent developments11: 1) it is now
used increasingly in combination with azole agents (ketoconazole, fluconazole and itroconazokle); 2)
it plays an important role in a new therapeutic approach in the treatment of certain tumors,
especially colorectal carcinoma.
Sulconazole (SUL) possesses a broad spectrum of activity in vitro against dermatophytes,
yeasts and Gram-positive bacteria. To best our knowledge, these drugs neither have been complexed
with cyclodextrins nor used in combination in antifungal therapy. This is why we chose to prepare the
following series of cyclodextrin/drug inclusion complexes and to test them in antimycotic therapy:
(β, γ)-Cyclodextrin / FLU; methyl β-cyclodextrin / FLU; hydroxypropyl-β-cyclodextrin / FLU;
(β,γ )-Cyclodextrin-sulphate / FLU.
(α, β,)-Cyclodextrin / SUL; methyl β-cyclodextrin / SUL; hydroxypropyl-β-cyclodextrin / SUL;
β-Cylodextrin-sulphate/SUL
Material and methods
The cyclodextrin – drug complexations will be performed under three reaction conditions : 1)
liofilization, 2) sonication and 3) co-precipitation.
Step1: Synthesis of precursors with controlled structure: synthesis, physico-chemical
characteristics. Preparation of inclusion complexes with - or -CD/Sulconazole; methyl -CD; hydroxyl
propyl CD/Sulconazole; sulfate -CD using liofolization,and co-precipitation methods. Prepartion of
inclusion complexes CDs or modified CDs/drug (Flucitosine or Sulconazole) using sonication method.
Characterization of inclusion complexes using X-Ray, DSC (differential scanning calorimetry), NMR, IR,
SEM, MALDI-TOF, ATG methods. Determination of the complex stability constant using NMR
spectroscopy.
Step2: Determination of biological activities of inclusion complexes in vitro conditions;
Antifungal effect evaluation of FLU and SUL.
Step3 Acute toxicity studies - on laboratory mice, nulliparous healthy young females, 8-12
weeks old, and weight around 20±0,2 g. The animals were housed individually, in respect of
microclimate conditions12*. LD50 was established using the Dixon and Mood method.
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