Cardiovascular drugs in environmental waters and wastewaters: method optimization and real sample analysis.

A sensitive method for determination of the eight most prescribed drugs used in combined cardiovascular therapy in Serbia was developed and optimized. The method was based on SPE followed by LC/ion trap-MS/MS with positive electrospray ionization. Parameters that affect the SPE were optimized, such as the eluent, sample pH, and sample volume. Good recoveries from groundwater (87.6-120.9%) as well as wastewater (84.5-106.6%) were achieved with this method, except in the case of atorvastatin (26.1 and 45.2%, respectively). The method was applied in the analysis of four river water samples collected in Serbia, as well as nine corresponding groundwater samples. Residues of the P-blockers metoprolol and bisoprolol as well as the anticoagulant clopidogrel were detected for the first time in river water. Groundwater samples did not contain drug residues. Influents and effluents of two wastewater treatment plants showed the predominant presence of metoprolol and enalapril. The removal rate of metoprolol was generally low, whereas enalapril was eliminated with the highest efficiency. Atorvastatin was detected in influents and completely removed in the treatment.

Biomedical Applications of Thermosensitive Hydrogels for Controlled/Modulated Piroxicam Delivery.

The objectives of this study are the synthesis of thermosensitive poly(N-isopropylacrylamide-co-2-hydroxypropyl methacrylate), p(NiPAm-HPMet), hydrogels and the analysis of a drug-delivery system based on piroxicam, as a model drug, and synthesized hydrogels. A high pressure liquid chromatography method has been used in order to determine both qualitative and quantitative amounts of unreacted monomers and crosslinkers from polymerized hydrogels. Swelling kinetics and the order of a swelling process of the hydrogels have been analyzed at 10 and 40 °C. The copolymers' thermal properties have been monitored by the differential scanning calorimetry (DSC) method. DSC termograms have shown that melting occurs in two temperature intervals (142.36-150.72 °C and 153.14-156.49 °C). A matrix system with incorporated piroxicam has been analyzed by using FTIR and SEM methods. Structural analysis has demonstrated that intermolecular non-covalent interactions have been built between side-groups of copolymer and loaded piroxicam. Morphology of p(NiPAm-HPMet) after drug incorporation indicates the piroxicam presence into the copolymer pores. Kinetic parameters of the piroxicam release from hydrogels at 37 °C and pH 7.4 indicate that the fluid transport mechanism corresponds to Fickian diffusion. As a result, formulation of thermosensitive p(NiPAm-HPMet) hydrogels with incorporated piroxicam could be of interest for further testing as a drug carrier for modulated and prolonged release, especially for topical administration.

Temperature-Sensitive Hydrogels as Carriers for Modulated Delivery of Acetaminophen.

The purposes of this study are the polymerization of temperature-sensitive copolymers based on N-isopropyl acrylamide and 10 mol % of 2-hydroxypropylmethacrylate, characterisations of their thermal, morphological and swelling properties, as well as the analysis of potential application in drug-delivery systems. Acetaminophen, the representative of non-steroidal anti-inflammatory drugs, was used as a model drug in this study. It is a common pain relief drug, which is also used for fever treatment. However, oral administration comes with certain health risks, mainly the overdose and frequent administration of up to four times a day. The goal of applying temperature-sensitive hydrogel is to enable extended administration once a day, depending on the body temperature. The swelling behavior of the obtained poly(N-isopropyl acrylamide-co-2-hydroxypropylmethacrylate) (p(NIPA/HPMA)) hydrogels and their temperature-sensitivity, kinetics and order of swelling processes at 18 and 38 °C were analyzed. The thermal properties of these hydrogels were observed by the DSC method, and the obtained thermograms showed both melting and glass transitions. The drug delivery system of p(NIPA/HPMA) hydrogels with loaded acetaminophen was analyzed using scanning electron microscopy and Fourier transform infrared spectroscopy methods. Structural analysis of FTIR spectra indicates that non-covalent intermolecular interactions of the type of hydrogen bonds were formed among functional groups of acetaminophen and side-chains of p(NIPA/HPMA) hydrogels. The surface structure of p(NIPA/HPMA) hydrogels after drug loading indicates the acetaminophen presence into the pores of the hydrogel network, and their loading efficiency was higher than 92%. Qualitative and quantitative analysis of acetaminophen, determined by the high-pressure liquid chromatography method, showed that about 90-99% of the loaded amount was released from p(NIPA/HPMA) hydrogels within 24 h. Kinetic parameters of the acetaminophen release under simulated gastrointestinal conditions were determined. Based on obtained results, the drug delivery system of temperature-sensitive p(NIPA/HPMA) hydrogels with loaded acetaminophen could be suitable for additional investigation for modulated drug administration, e.g., for extended drug administration.

Cancer incidence in a population living near a petrochemical facility and oil refinery.

There is growing concern that pollution from petrochemical and oil refinery installations in Pancevo (Serbia) has increased the incidence of various diseases including cancer. The aim of our study was to investigate cancer incidence in Pancevo and to compare it with the region of central Serbia. Cancer incidence data were obtained from the corresponding Serbian Cancer Registries. Systematic local monitoring of benzene, toluene and methyl mercaptane in the atmosphere within Pancevo's industrial area indicated that the average monthly and yearly concentrations often exceeded permitted levels proposed by EU standards (5 microgm(-3)). Cancer incidence was lower in Pancevo than in central Serbia (the standardised incidence for all types of cancers in Pancevo was 218.3 and in central Serbia it was 241.7 per 100,000 inhabitants). The available data do not allow us to correlate air pollution in Pancevo with increased cancer incidence.

A QSAR study of acute toxicity of N-substituted fluoroacetamides to rats.

Acute toxicity in vivo toward rats, of nineteen N-alkyl and N-cycloalkyl fluorocetamides [F-CH(2)-C(O)-NH-R] was correlated with their structure-dependent properties. Used descriptors are: molecular weights (M(w)) and heat of formation (DeltaH(f)) of compounds; molar refractivity (CMR), lipophilicity (ClogP), Broto lipol values, virtual logP, molecular lipophilic potential (MLP), Van der Waals surfaces (VdW SAS) and hydropathicity surface (ILM) of whole molecules; Taft steric parameters (E(s)); E(s) values with Hancock corrections (E(s)(CH)) and Verloop sterimol (B(5)) and (L) parameters of alkyl and cycloalkyl residues; superdelocalizabilities and electron densities on the [NH-C(O)-CH(2)-F] fragment. Strong quantitative structure-activity relationships were assessed. Obtained correlation suggested that lipophilicity, shape and bulkiness of the alkyl and cycloalkyl substituents, particular nearest vicinity of the amide nitrogen, as well charges on the amide moiety are the main factors that influence on the acute toxicity of studied compounds toward rats. Mechanism of toxic action was proposed.

Computational and spectroscopic data correlation study of N,N'-bisarylmalonamides (Part II).

To complement a previous UV study, we present a quantitative evaluation of substituent effects on spectroscopic data ((1)H and (13)C NMR chemical shifts as well as FT-IR absorption frequency) applied to N,N'-bisarylmalonamides, using simple and extended Hammett equations as well as the Swain-Lupton equation. Furthermore, the DFT CAM-B3LYP/6-311+G(d,p) method was applied to study the impact of different solvents on the geometry of the molecules and their spectral data. Additionally, experimental data are correlated with theoretical results; excellent linear dependence was obtained. The overall results presented in this paper show that N,N'-bisarylmalonamides are prominent candidates for model molecules.

Artificial neural networks in the modeling and optimization of aspirin extended release tablets with Eudragit L 100 as matrix substance.

The purpose of the present study was to model the effects of the concentration of Eudragit L 100 and compression pressure as the most important process and formulation variables on the in vitro release profile of aspirin from matrix tablets formulated with Eudragit L 100 as matrix substance and to optimize the formulation by artificial neural network. As model formulations, 10 kinds of aspirin matrix tablets were prepared. The amount of Eudragit L 100 and the compression pressure were selected as causal factors. In vitro dissolution time profiles at 4 different sampling times were chosen as responses. A set of release parameters and causal factors were used as tutorial data for the generalized regression neural network (GRNN) and analyzed using a computer. Observed results of drug release studies indicate that drug release rates vary widely between investigated formulations, with a range of 5 hours to more than 10 hours to complete dissolution. The GRNN model was optimized. The root mean square value for the trained network was 1.12%, which indicated that the optimal GRNN model was reached. Applying the generalized distance function method, the optimal tablet formulation predicted by GRNN was with 5% of Eudragit L 100 and tablet hardness 60N. Calculated difference (f1 2.465) and similarity (f2 85.61) factors indicate that there is no difference between predicted and experimentally observed drug release profiles for the optimal formulation. This work illustrates the potential for an artificial neural network, GRNN, to assist in development of extended release dosage forms.

Spectroscopic and quantum mechanical investigation of N,N'-bisarylmalonamides: solvent and structural effects.

The UV absorption spectra of ten N,N'-bisarylmalonamides have been recorded in the range 200-400 nm in a set of selected solvents. The solute-solvent interactions have been analyzed on the basis of the linear solvation energy relationship (LSER) concept proposed by Kamlet and Taft. The effects of substituents on the absorption spectra have been interpreted by correlating absorption frequencies with Hammett substituent constants. Furthermore, the experimental findings have been interpreted using the DFT CAM-B3LYP/6-311+G(d,p) method. Electronic energies have been calculated using the same method in combination with the implicit solvation model (conductor-like polarizable continuum model, CPCM) as well as with the explicit addition of two molecules of solvent.