Volumen 65 (2015): Heft 2 (June 2015)

A virosome is an innovative hybrid drug delivery system with advantages of both viral and non-viral vectors. Studies have shown that a virosome can carry various biologically active molecules, such as nucleic acids, peptides, proteins and small organic molecules. Targeted drug delivery using virosome-based systems can be achieved through surface modifications of virosomes. A number of virosome- -based prophylactic and therapeutic products with high safety profiles are currently available in the market. Cancer treatment is a big battlefield for virosome-based drug delivery systems. This review provides an overview of the general concept, preparation procedures, working mechanisms, preclinical studies and clinical applications of virosomes in cancer treatment.

(1,4,5-Triphenylimidazol-2-yl-thio)butyric acid hydrazide (3) was obtained via alkylation of 1,4,5-triphenylimidazol-2- thiol (1) with ethylbromobutyrate, followed by addition of hydrazine hydrate. Treatment of acid hydrazide 3 with carbon disulfide in an ethanolic potassium hydroxide solution gave the intermediate potassium dithiocarbazinate salt, which was cyclized to 4-amino-5-[(1,4,5-triphenylimidazol- -2-yl)thiopropyl]-2H-1,2,4-triazole-3-thione (4) in the presence of hydrazine hydrate. Condensation of compound 3 with alkyl/arylisothiocyanate afforded the corresponding 1-[4-(1,4,5-triphenylimidazol-2-ylthio)butanoyl]-4-alkyl/arylthiosemicarbazides (5-7), which upon refluxing with sodium hydroxide, yielded the corresponding 1,2,4-triazole - -3-thiols 8-10. Under acidic conditions, compounds 4-6 were converted to aminothiadiazoles 11-13. Moreover, the series of Schiff bases 14-18 were synthesized from the condensation of compound 3 with different aromatic aldehydes. The newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR and mass spectral analyses. They were also preliminarily screened for their antimicrobial activity.

This study addressed the possibility of forming of co-amorphous systems between clozapine (CZ) and various carboxylic acid plasticizers (CAPs). The aim was to improve the solubility and oral bioavailability of clozapine. Co-amorphous dispersions were prepared using modified solvent evaporation methodology at drug/plasticizer stoichiometric ratios of 1:1, 1:1.5 and 1:2. Solid state characterization was performed using differential scanning calorimetry, X-ray diffraction and infra red spectroscopy. Highly soluble homogeneous co-amorphous dispersions were formed between clozapine and CAPs via hydrogen bonding. The co-amorphous dispersions formed with tartaric acid (1:2) showed the highest dissolution percentage (> 95 % in 20 minutes) compared to pure crystalline CZ (56 %). Highly stable solutions were obtained from co-amorphous CZ-citric and CZ-tartaric acid at 1:1.5 molar ratio. The prepared dispersions suggest the possibility of peroral or sublingual administration of highly soluble clozapine at a reduced dose with the great chance to bypass the first pass metabolism.

Fructose-1,6-diphosphate (FDP), a glycolytic metabolite, has been reported to protect susceptible organs during hypoxia or ischemia. However, there is paucity of human data on its pharmacokinetics after being exogenously administered. In the current study, the preliminary pharmacokinetics of FDP given orally to humans was investigated, and no typical peak was observed in the serum drug-time curve. Then, the pharmacokinetic studies were performed following multiple doses of FDP in rats, and the Caco-2 monolayer model was used to study the absorption of FDP in vitro. The results suggested that plasma FDP concentration was significantly increased after oral multiple doses of 180 mg kg^-1 but not 90 mg kg^-1 of FDP, and FDP was partly depleted during the absorption, which was supposed to be consumed by the intestinal epithelium cells. Thus, we conclude that a high dose of FDP should be orally administered in order to get an effective plasma level.

This report presents the application of ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry with positive electrospray ionization, to determine ramipril in human plasma. First, the proteins in human plasma were precipitated using acetonitrile, then the supernatant was extracted by ethyl acetate at pH 3 and finally, the extract was analyzed using a UPLC-QTOF- MS system. The method was validated and the coefficient of determination (R²) was > 0.999, the lower limit of quantification (LLOQ) was 0.5 ng mL^-1. Precision, recovery and stability were determined for three different concentrations of ramipril. RSD for this method ranged from 3.3 to 8.6 %. The intra-day mean recovery was from 65.3 to 97.3 %. In addition, the fragmentation of ramipril was studied. Due to high resolution of the spectrometer, it was possible to measure fragment masses accurately and determine their molecular and chemical formulas with high accuracy.

Inosine pranobex (inosine dimepranol acedoben, isoprinosine) (Inos) is an immunomodulatory and antiviral drug used in some viral infections, especially in patients with weakened immunity. In the present study, effects of Inos on the production of cytokines attributable to Th1 (IL-2, IFN-g, and TNF-a) or Th2 cells (IL-4, IL-5, and IL-10) were tested in human peripheral blood lymphocyte cultures stimulated with phytohemagglutinin (PHA). Inos enhanced TNF-a secretion significantly (in short-term - 24-hour, and prolonged term - 72-hour cultures) and IFN-g (in 72-hour cultures). Surprisingly, production of IL-10 by PHA-stimulated lymphocytes was suppressed by Inos in a dose-dependent manner in both 24-hour and 72-hour cultures. These results shed some light on immunomodulatory properties of Inos and suggest applicability of this agent in patients with a depressed function of the immune system.

The aim of this study was to investigate the effects of polyacrylic acid polymers (Ultrez 10, Ultrez 20, Carbopol 980, and Carbopol 940) on the viscosity and the in vitro permeation of phenolic compounds from the gel prepared from natural horse chestnut seed extract. Experiments were performed in the presence and in the absence of peppermint oil (Mentha piperita). Our results showed that peppermint oil decreased the viscosity of the gels and permeation of phenolic compounds from all gel samples. Results show that the highest content of phenolic compounds (1.758 μg cm^-2) permeated in vitro from gel based on Carbopol Ultrez 20 without peppermint oil added (p < 0.05 vs. other tested polymers).

PDE4B was previously shown to be a dominant PDE4 subtype of neutrophils. However, its physiological role in the neutrophil function has not been evaluated. In this study, the inhibitory effects of a phosphodiesterase 4B (PDE4B)- selective inhibitor (compound A) and subtype non-selective PDE4 inhibitors (roflumilast and cilomilast) were evaluated in human peripheral blood cells. Compound A, roflumilast and cilomilast in a similar manner inhibited TNF-α production by LPS-stimulated human mononuclear cells. However, the inhibitory effect of compound A on IL-8 or LTB4-induced chemotactic response of neutrophils was modest even at the highest concentration (10 μmol L^-1), whereas roflumilast and cilomilast inhibited IL-8 or LTB₄-induced neutrophil chemotaxis. Our results suggest that PDE4B does not play an important role during the chemotactic response of human neutrophils.

The aim of this study was to evaluate the release of rosmarinic acid (RA) from the experimental topical formulations with the Melissa officinalis L. extract and to evaluate its penetration through undamaged human skin ex vivo. The results of the in vitro release study showed that higher amounts of RA were released from the emulsion vehicle when lemon balm extract was added in its dry form. An inverse correlation was detected between the released amount of RA and the consistency index of the formulation. Different penetration of RA into the skin may be influenced by the characteristics of the vehicle as well as by the form of the extract. The results of penetration assessment showed that the intensity of RA penetration was influenced by its lipophilic properties: RA was accumulating in the epidermis, while the dermis served as a barrier, impeding its deeper penetration.

Thermal properties of N-carbamoyl benzotriazole derivatives and N,N’,N’’-tribenzyloxyisocyanuric acid were investigated using thermogravimetric analysis and differential scanning calorimetry. The results revealed a difference between structural analogs of N-carbamoyl benzotriazole derivatives. They seem to be in agreement with the previously proposed formation of N,N’,N’’-tribenzyloxyisocyanuric acid from 1-(N-benzyloxycarbamoyl) benzotriazole, via an intermediary N-benzyloxyisocyanate acid, during heating. Substantially different thermal properties were observed for structural analogues, 1-(N-methoxycarbamoyl) benzotriazole and 1-(N-ethoxycarbamoyl) benzotriazole. In contrast to N-benzyloxyisocyanate, no corresponding reactions were observed for their decomposition products, i.e., methoxyisocyanate and ethoxyisocyanate.