Pharmaceuticals2016, 9(3), 34; doi:10.3390/ph9030034 (registering DOI) - published 24 June 2016 Show/Hide Abstract
Abstract: The performance of compressed tablet drug delivery systems made using polymeric materials depend on multiple factors, such as surface properties like contact angle, surface free energy and water absorption rate, besides the release mechanisms driven by the kind of polymer used. Hence, it should be possible to establish a relationship between the surface properties and the drug release kinetics. Compressed tablets with different proportions of poly(maleic acid-alt-octadecene) potassium salt (0%, 10%, 20%, 30% and 40%) were prepared. Blends of a model drug (ampicillin trihydrate) and the polymer material were analyzed by DSC. The surface properties of the tablets were determined by the sessile drop method, while the surface energy was determined using the semi-empirical Young-Dupre, Neumann and OWRK models. The release profiles were determined simulating in vitro conditions (buffer solutions pH 1.2 and pH 7.4 with ionic strength of 1.5 M at 37 °C (310.15 K)). A kinetic analysis of the dissolution profiles using different models (zero order, first order, Higuchi and Korsmeyer-Peppas) was realized. The results showed a significant effect of the proportion of polymer in both the surface properties of the tablets and the dissolution release, indicating a relationship between the kinetic and thermodynamic properties.
Pharmaceuticals2016, 9(2), 33; doi:10.3390/ph9020033 - published 16 June 2016 Show/Hide Abstract
Abstract: Tumor heterogeneity has been compared with Darwinian evolution and survival of the fittest. The evolutionary ecosystem of tumors consisting of heterogeneous tumor cell populations represents a considerable challenge to tumor therapy, since all genetically and phenotypically different subpopulations have to be efficiently killed by therapy. Otherwise, even small surviving subpopulations may cause repopulation and refractory tumors. Single-cell sequencing allows for a better understanding of the genomic principles of tumor heterogeneity and represents the basis for more successful tumor treatments. The isolation and sequencing of single tumor cells still represents a considerable technical challenge and consists of three major steps: (1) single cell isolation (e.g., by laser-capture microdissection), fluorescence-activated cell sorting, micromanipulation, whole genome amplification (e.g., with the help of Phi29 DNA polymerase), and transcriptome-wide next generation sequencing technologies (e.g., 454 pyrosequencing, Illumina sequencing, and other systems). Data demonstrating the feasibility of single-cell sequencing for monitoring the emergence of drug-resistant cell clones in patient samples are discussed herein. It is envisioned that single-cell sequencing will be a valuable asset to assist the design of regimens for personalized tumor therapies based on tumor subpopulation-specific genetic alterations in individual patients.
Pharmaceuticals2016, 9(2), 32; doi:10.3390/ph9020032 - published 13 June 2016 Show/Hide Abstract
Abstract: Novel esters of γ-aminobutyric acid (GABA) with monocyclic terpenes were synthesized via Steglich esterification and characterized by 1H-NMR, IR and mass spectral studies. Their anticonvulsant, analgesic and anti-inflammatory activities were evaluated by a PTZ-induced convulsion model, AITC-induced hyperalgesia and AITC-induced paw edema, respectively. All studied esters, as well as their parent terpenes, were found to produce antinociceptive effects in the AITC-induced model and attenuate acute pain more than the reference drug benzocaine after their topical application. GABA esters of l-menthol and thymol were also shown to exceed the reference drug ibuprofen in their ability to decrease the inflammatory state induced by intraplantar injection of the TRPA1 activator AITC. The present findings indicate that GABA esters of carvacrol and guaiacol are not a classical prodrug and possess their own pharmacological activity. Prolonged antiseizure action of the ester based on the amino acid and guaiacol (200 mg/kg) was revealed at 24 h after oral administration. Furthermore, orally co-administered gidazepam (1 mg/kg) and GABA esters of l-menthol, thymol and carvacrol produce synergistic seizure prevention effects.
Pharmaceuticals2016, 9(2), 31; doi:10.3390/ph9020031 - published 6 June 2016 Show/Hide Abstract
Abstract: Objectives: Fibrosis is involved in many chronic diseases. It affects the functionality of vital organs, such as liver, lung, heart and kidney. Two novel imaging agents for positron emission tomography (PET) imaging of fibrosis have previously pre-clinically demonstrated promising target binding and organ distribution characteristics. However, the relevant disease monitoring in the clinical setup would require multiple repetitive examinations per year. Thus, it is of paramount importance to investigate the absorbed doses and total effective doses and thus, the potential maximum number of examinations per year. Methods: Two cyclic peptide (c[CPGRVMHGLHLGDDEGPC]) analogues coupled via an ethylene glycol linker (EG2) to either 2-(4,7-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7-triazonan-1-yl)acetic acid (NO2A-Col) or 4-(4,7-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7-triazacyclononan-1-yl)-5-(tert-butoxy)-5-oxopentanoic acid (NODAGA-Col) were labelled with 68Ga. The resulting agents, [68Ga]Ga-NO2A-Col and [68Ga]Ga-NODAGA-Col, were administered in the tail vein of male and female Sprague–Dawley rats (N = 24). An ex vivo organ distribution study was performed at the 5-, 10-, 20-, 40-, 60- and 120-min time points. The resulting data were extrapolated for the estimation of human organ and total body absorbed and total effective doses using Organ Level Internal Dose Assessment Code software (OLINDA/EXM 1.1) assuming a similar organ distribution pattern between the species. Time-integrated radioactivity in each organ was calculated by trapezoidal integration followed by a single-exponential fit to the data points extrapolated to infinity. The resulting values were used for the residence time calculation. Results: Ex vivo organ distribution data revealed fast blood clearance and washout from most of the organs. Although the highest organ absorbed dose was found for kidneys (0.1 mGy/MBq), this organ was not the dose-limiting one and would allow for the administration of over 1460 MBq per year for both [68Ga]Ga-NO2A-Col and [68Ga]Ga-NODAGA-Col. The total effective dose was the limiting parameter with 0.0155/0.0156 (female/male) mSv/MBq and 0.0164/0.0158 (female/male) mSv/MBq, respectively, for [68Ga]Ga-NO2A-Col and [68Ga]Ga-NODAGA-Col. This corresponded to the total amount of radioactivity that could be administered per year of 643 and 621 MBq before reaching the annual limit of 10 mSv. Thus, up to six examinations would be possible. The residence time and organ absorbed doses in liver and spleen were higher for [68Ga]Ga-NODAGA-Col as compared to [68Ga]Ga-NO2A-Col. Conclusion: The limiting parameter for the administered dose was the total effective dose that would allow for at least six examinations per year that might be sufficient for adequate disease monitoring in longitudinal studies and a routine clinical setup.
Pharmaceuticals2016, 9(2), 30; doi:10.3390/ph9020030 - published 25 May 2016 Show/Hide Abstract
Abstract: Staphylococcus aureus (SA) colonizes the vast majority of patients with atopic dermatitis (AD). Its resistance to antibiotics and ability to form biofilms are the main origins of therapeutic complications. Endogenous antimicrobial peptides (AMPs) exhibit strong activity against SA, including antibiotic resistant strains as well as bacteria existing in biofilm form. The purpose of the present work was to determine the antistaphylococcal activity of two amphibian peptides against SA isolated from patients with AD. The AMPs demonstrated permanent activity towards strains exposed to sublethal concentrations of the compounds and significantly stronger antibiofilm activity in comparison to that of conventional antimicrobials. The results suggest the potential application of amphibian AMPs as promising antistaphylococcal agents for the management of skin infections.
Pharmaceuticals2016, 9(2), 27; doi:10.3390/ph9020027 - published 19 May 2016 Show/Hide Abstract
Abstract: Substituted thiadiazines exert a reliable therapeutic effect in treating stress, and a schematic description of their ability to influence all aspects of a stress response has been depicted. This study was conducted to pharmacologically evaluate compound L-17, a substituted thiadiazine, (2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide) for possible anti-psychotic/antidepressant activity. Compound L-17 was synthesized by cyclocondensation of α-bromoacetophenone with the original morpholine-4-carbothionic acid hydrazide. Pharmacologic evaluations were conducted using methods described by E.F. Lavretskaya (1985), and in accordance with published guidelines for studying drugs for neuroleptic activity. Compound L-17 was evaluated for various possible mechanisms of action, including its effects on cholinergic system agonists/antagonists, dopaminergic neurotransmission, the adrenergic system, and 5-HT3 serotonin receptors. One or more of these mechanisms may be responsible for the beneficial effects shown by thiadiazine compounds in experiments conducted to evaluate their activity in models of acute stress and acute myocardial infarction.