Rheological Considerations of Pharmaceutical Formulations: Focus on Viscoelasticity.

Controlling rheological properties offers the opportunity to gain insight into the physical characteristics, structure, stability and drug release rate of formulations. To better understand the physical properties of hydrogels, not only rotational but also oscillatory experiments should be performed. Viscoelastic properties, including elastic and viscous properties, are measured using oscillatory rheology. The gel strength and elasticity of hydrogels are of great importance for pharmaceutical development as the application of viscoelastic preparations has considerably expanded in recent decades. Viscosupplementation, ophthalmic surgery and tissue engineering are just a few examples from the wide range of possible applications of viscoelastic hydrogels. Hyaluronic acid, alginate, gellan gum, pectin and chitosan are remarkable representatives of gelling agents that attract great attention applied in biomedical fields. This review provides a brief summary of rheological properties, highlighting the viscoelasticity of hydrogels with great potential in biomedicine.

Patterns of erythropoiesis-stimulating agent use for chemotherapy-induced anemia in lung cancer: results of a retrospective Hungarian real-life clinical data analysis.

OBJECTIVE: Lung cancer carries a relatively high risk of chemotherapy-induced anemia, one of the most frequent hematological complications. Previous data show a lack of optimal anemia correction in patients with chemotherapy-induced anemia. This paper analyzes real-life data considering the prevalence and severity of chemotherapy-induced anemia, together with the frequency and efficacy of erythropoietin treatment of anemia in Hungarian lung cancer patients. RESEARCH DESIGN AND METHODS: Data of 482 patients with histological or cytological confirmed lung cancer receiving chemotherapy were collected retrospectively between 1 January and 31 December, 2008. In all, 83 (17%) of them developed chemotherapy-induced moderate to severe anemia (44.6% male, 55.4% female; mean age 70 ± 8.6 years; NSCLC 67.5%, small cell lung cancer 32.5%). RESULTS: More than 50% of the patients suffering from moderate to severe chemotherapy-induced anemia (hemoglobin below 10 g/dl) did not receive erythropoietin treatment. Chemotherapy had to be postponed due to anemia in 32.26% of the patients receiving erythropoietin supplementation, while this was seen in 41.94% of the group without erythropoietin treatment (p < 0.05). In patients not receiving erythropoietin, the severity of anemia increased, while erythropoietin treated patients maintained acceptable hemoglobin levels after the end of the chemotherapy. CONCLUSIONS: The data draws attention to the fact that nowadays chemotherapy-induced anemia is not treated according to current guidelines in many lung cancer cases in Hungary.

Cisplatin-vinorelbine chemotherapy in non-small cell lung cancer is safe and well tolerated: results of a retrospective Hungarian clinical data analysis.

OBJECTIVE: The efficacy of cisplatin-vinorelbine chemotherapy (CT) in NSCLC is well established. In this retrospective data analysis, haematological safety and tolerability, furthermore the effects of cisplatin-vinorelbine combination on patients' quality of life (QoL) are examined by reviewing the clinical data of NSCLC patients in a retrospective manner. RESEARCH DESIGN/METHODS: All patients (n = 25) received the following regimen: cisplatin (80 mg/m(2) on day 1 by i.v. infusion) and vinorelbine (30 mg/m(2) on days 1 and 8 by i.v. infusion; 21-day cycles; patients received four cycles of CT). Haematological laboratory and QoL data on day 1 of all cycles were collected. Quality of life was assessed by reviewing the data of patients' charts considering physical limitation, fatigue, nausea, vomiting, diarrhoea, constipation, social activities, fever, appetite and weight loss. The absence of problems was scored as 0, moderate complaints as 1 and serious deterioration as 2. RESULTS: The QoL data showed no significant deterioration in the analysed symptoms of patients during the four cycles of cisplatin-vinorelbine CT (total QoL score was 3.0 +/- 1.4 points before treatment versus 3.6 +/- 0.5 on day 1 of the last cycle, p > 0.05). Haemoglobin values were 118.4 +/- 12.3 g/l before CT and 109.0 +/- 11.3 g/l on day 1 of last cycle of CT (p > 0.05). The mean number of platelets in the beginning and in the end was 256 +/- 123(*)10(12)/l and 217 +/- 119(*)10(12)/l, respectively (p < 0.05). White blood cell count was 8.36 +/- 3.21(*)10(9)/l, absolute granulocyte count 5.95 +/- 5.81(*)10(9)/l before the treatment, and these data were 4.50 +/- 1.96(*)10(9)/l and 2.15 +/- 1.21(*)10(9)/l, respectively, on day 1 of last cycle of CT (both p < 0.005). CONCLUSIONS: Cisplatin-vinorelbine CT is a safe and well-tolerated chemotherapeutic option of NSCLC.

Molecular interactions in imatinib-DPPC liposomes.

Imatinib (Gleevec) is a novel chemotherapeutic agent against Bcr-Abl protein tyrozine kinase, playing a crucial role in the therapy of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). Our study aimed at designing a liposomal imatinib formulation and investigating molecular interactions between lipid and imatinib, within the liposomal membrane. Multilamellar (MLV) and small unilamellar (SUV) vesicles were prepared from alpha-L-dipalmitoyl-phosphatidylcholine (DPPC). The effect of imatinib on the DPPC membrane was studied by electron paramagnetic resonance (EPR) spectroscopy and differential scanning calorimetry (DSC), at pH 5.2 and 9.0, where imatinib is in monocationic and neutral form, respectively. Our results indicate that imatinib interacts mainly with the DPPC head groups, leading to a slight increase in the mobility of the polar headgroups in case of MLVs. Contrary to that, imatinib causes a significant decrease in the fluidity of SUVs, which can be the result of a pH-dependent fusion/fission effect. The size distribution and morphology of liposomes were checked by dynamic light scattering and freeze-fracture electron microscopy. Our results direct attention to investigate the interactions of imatinib with artificial/biological membranes.

[Investigation of the effects of drugs and UV radiation on biological and artificial membranes]. / Gyógyszermolekulák es UV-fény hatásának vizsgálata biológiai- es modellmembránokon.

Investigation of the effects exerted by different physical and chemical agents on biological and model-membranes is of prominent importance. Recently, a general trend can be observed in the formulation of drugs: incorporation of the drugs into liposomes. Knowledge of the molecular interactions between the transporting lipids and the incorporated agents is therefore very important. Nowadays, the increased environmental UV radiation requires investigation of the effects of the UV radiation exerted on biological membranes. Beside of modeling biological effects, studies on the effects of the UV radiation on model membranes can result in new knowledge on the stability of the liposomes containing phototoxic drugs. During my study, three different methods (EPR spectroscopy, DSC and light scattering measurements) have been applied to investigate the molecular interactions between drugs and the lipid molecules. Derivatives of the morphine as well as the (fluoro)quinolones mainly interact with the headgroups of the lipid molecules resulting in an increase of the molecular ordering of the lipids. My observation that drugs with protonable/deprotonable groups can modify the membrane-fluidity due to specific, local interactions with the lipid/stearic acid molecules of a membrane depending on the pH as well, call attention to choose optimal pH-interval for such drug formulations. Investigating the UVA effect on human fibroblast cell line I concluded that a decrease in the membrane fluidity due to UVA radiation can be detected only at doses higher, than 150 kJ/m2, and close to the lipid head groups.

Effect of UVA radiation on membrane fluidity and radical decay in human fibroblasts as detected by spin labeled stearic acids.

The ultraviolet A (UVA) radiation component of sunlight (320-400 nm) has been shown to be a source of oxidative stress to cells via generation of reactive oxygen species. We report here some consequences of the UVA irradiation on cell membranes detected by electron paramagnetic resonance (EPR) spectroscopy. Paramagnetic nitroxide derivatives of stearic acid bearing the monitoring group at different depths in the hydrocarbon chain were incorporated into human fibroblasts membranes to analyze two main characteristics: kinetics of the nitroxide reduction and membrane fluidity. These two characteristics were compared for control and UVA-irradiated (0-250 kJ/m(2)) cells. The term relative redox capacity (RRC) was introduced to characterize and to compare free radical reduction measured by EPR with some well-known viability/clonogenicity tests. Our results showed that UVA-irradiation produces a more rigid membrane structure, especially at higher doses. Furthermore, we found that trends agree in survival measured by neutral red (NR), trypan blue (TB), and clonogenic efficiency compared with RRC values measured by EPR for low and medium exposure doses. Above 100 kJ/m(2), differences between these tests were observed. Antioxidant effect was modeled by alpha-tocopherol-acetate treatment of the cells before UVA irradiation. While NR, TB and clonogenicity tests showed protection at the highest UVA doses (>100 kJ/m(2)), results obtained with EPR measurements, both membrane fluidity and kinetics, or using MTT test did not exhibit this protective effect.