New Ibuprofen Cystamine Salts With Improved Solubility and Anti-Inflammatory Effect.

Two novel ibuprofen cystamine salts (IBU-CYS 1 and IBU-CYS 2) are synthesized by coupling the anion of ibuprofen with cystamine dihydrochloride in 1 : 1 and 2 : 1 ratio to improve the solubility and bioavailability of ibuprofen. The salts are characterized by 1H NMR, FT-IR and UV-Vis spectroscopy, differential scanning calorimetry (DSC), thermogravimetry (TGA, DTA) and X-ray diffraction measurements. IBU-CYS 1 and IBU-CYS 2 show higher solubility (6.11 and 7.81 mg/mL) compared to ibuprofen (0.04 mg/mL) in water. IBU-CYS2 was encapsulated into 2-hydroxyethyl methacrylate: poly (ethylene glycol) acrylate hydrogels for enhanced delivery. The in vitro studies in PBS (pH 7.4) indicate that the salts are effective in relieving inflammatory responses induced by lipopolysaccharide in RAW264.7 macrophage cells (nitrite inhibition percentages of IBU-CYS 1, IBU-CYS 2 and ibuprofen: approximately 34.29, 27.03 and 31.50 respectively) while indicating no cytotoxicity. Therefore, these salts may be promising candidates for the development of effective formulations of this drug.

Prognostic Value of the Expression of Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR-1) in Chronic Lymphocytic Leukemia.

Background: The transmembrane receptor tyrosine kinase-like orphan receptor 1 (ROR1) has acted on the causation and sustentation of mature B-cell lymphomagenesis for chronic lymphocytic leukemia (CLL) cells. The study attempted to show whether there is a relationship between the level of ROR1 surface expression in CLL cells and disease findings. Materials and Methods: The level of ROR1 cell surface expression was determined in accordance with the flow cytometric analysis of CLL patients at the first diagnosis time.  Two groups were formed according to the high and low ROR1 levels. The cut-off point for the ROR1 level was calculated for advanced-stage disease using receiver operating characteristic (ROC) curves. A two-sided p-value <0,05 was considered statistically significant. Results: 108 CLL cases with a median age of 60 were enrolled. The median percentage of ROR1 cell surface marker positivity in the CD5/CD19 positive leukemic cell was 62%. The CLL cases with high ROR1 levels have thrombocytopenia (p=0.042), anemia (p=0.028), and high beta-2 microglobulin value ≥3 mg/dL (p=0.002) and the need for first-line treatment (p=0.043). Conclusion: The poor prognostic parameters such as splenomegaly, anemia, higher beta-2 microglobulin levels, intermediate/advanced RAI stage disease, and need for first-line treatment had associated high-level ROR 1 expression of our CLL patients. It needs to be investigated for its effect on predicting disease burden and aggressiveness with more comprehensive studies on ROR1 expression levels in CLL cases.

Knowledge, attitudes and behaviors of family physicians about childhood vaccinations that are not in the routine vaccination schedule: a cross-sectional study.

AIM: In our country, there are childhood vaccinations that are not included in the routine vaccination schedule and that families have to buy and have for a fee. In addition to income level, family physicians' recommendations also play a major role in getting these vaccines.Our study was planned to determine the level of knowledge, attitudes and behaviors of family physicians about rotavirus, HPV and meningococcal vaccines, which are not included in the routine vaccination scheme of the Ministry of Health. MATERIALS AND METHODS: Our cross-sectional and descriptive study was carried out between May and July 2019. The population of our study consists of approximately 30 000 family physicians working as Family Physicians in Turkey. When the sample size is calculated with 5% margin of error and 95% confidence interval, it turns out to be 381. A 15-question questionnaire prepared by scanning the literature and including socio-demographic characteristics was presented to the participants. The Likert scale, which includes 12 questions about rotavirus, meningococcus, HPV and vaccines developed for these microorganisms, was administered to physicians either face-to-face or via the internet. In our study, the statistical significance level was accepted as P < 0.05, and the SPSS statistical package program was used in the calculations. RESULTS: 81 Research Assistants, 62 Family Medicine Specialists and 234 Family Physicians participated in our study, and the participants were determined by simple random sampling method. The mean age of the participating physicians was 37.96 ± 9.3 (min: 25 and max: 68). 50.9% of the physicians were women, 79.8% were married, 85.1% were in the city center, and 62.1% were practicing family medicine as general practitioners. 74.82% of the participating physicians recommend rotavirus and 56.2% HPV vaccines to their patients. 10.6% (40 people) of the physicians participating in our study did not recommend any of the rotavirus, HPV, meningococcal, influenza and adult pertussis vaccines to their patients. In the evaluation of the reason for this, 58.7% (27 people) of physicians who did not recommend special vaccines state that they did not recommend vaccines because they are not included in the routine vaccination schedule of the Ministry of Health. Another important reason was that the vaccines are paid (30.4%, 14 people). To the question of having sufficient information about special vaccines that are not included in the routine vaccination schedule, 26% of the participants stated that they have sufficient knowledge, and 56.5% stated that they have partial knowledge. The Likert knowledge questions total score of those who recommended at least one vaccine to their patients was significantly higher than those who did not recommend it at all. Likert knowledge questions total score of those who had at least one vaccination was significantly higher than those who never had it (P = 0.001). CONCLUSION: In general, as the level of knowledge about private vaccines decreases, the rates of self-vaccination, recommending it to their patients, and asking it to be included in the national vaccine schedule decrease. For this reason, increasing the knowledge of physicians about vaccines not included in the national vaccination schedule will contribute to the dissemination of vaccines, thus increasing immunity and reducing mortality and morbidity.

Phosphonic acid-functionalized poly(amido amine) macromers for biomedical applications.

Novel phosphonic acid-functionalized poly(amido amine) (PAA) macromers are synthesized through aza-Michael addition of 2-aminoethyl phosphonic acid or its mixture with 5-amino-1-pentanol at different ratios onto N,N'-methylene bis(acrylamide) to control the amount of phosphonic acid functionality. The macromers were homo- and copolymerized with 2-hydroxyethyl methacrylate at different ratios to obtain hydrogels with various hydrophilicities. The hydrogels' swelling, biodegradation and mineralization properties were evaluated. The swelling and degradation rates of the gels can be tuned by the chemical structure of PAA macromer precursors as well as pH and CaCl2 pre-treatment. The hydrogels show composition-dependent mineralization in SBF and 5xSBF, as evidenced from Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDX) analyses. The degradation products of the hydrogels have no effect on U-2 OS, Saos-2 and NIH 3T3 cells, suggesting their cytocompatibility. Overall, these materials have potential to be used as nontoxic degradable biomaterials.

Stimuli-responsive poly(hydroxyethyl methacrylate) hydrogels from carboxylic acid-functionalized crosslinkers.

Tailoring hydrogel properties by modifications of the crosslinker structure is a good method for the design of hydrogels with a wide range of properties. In this study, two novel carboxylic acid-functionalized dimethacrylate crosslinkers (1a and 2a) are synthesized by the reaction of poly(ethylene glycol) or 2-hydroxyethyl disulfide with tert-butyl α-bromomethacrylate followed by cleavage of tert-butyl groups using trifluoroacetic acid. Their copolymerization reactivity with 2-hydroxyethyl methacrylate (HEMA) investigated by photopolymerization studies performed on photo-differential scanning calorimetry shows higher reactivity of 2a compared to 1a. These crosslinkers are then used at different ratios for fabrication of pH- and redox-responsive poly(2-hydroxyethyl methacrylate)-based hydrogels. The swelling behavior of the hydrogels is found to be dependent on the structure of the crosslinker, degree of crosslinking, pH, and CaCl2 concentration. The redox-responsive behavior is demonstrated by degradation of the hydrogel upon exposure to 1,4-dithiothreitol. The dye Rhodamine 6G and the drug resorcinol are used as models to demonstrate the pH and redox dependent release of loaded compounds from the hydrogels. The electrostatic interactions between the carboxylate groups and the positively charged R6G are found to govern the release profile in DTT and counteract the diffusion of dye molecules and significant amount of release (79% in 120 hr) occurs only at highly acidic conditions. The degradation mediated release in DTT is observed better in case of resorcinol (around 88% in 5 hr). Overall, these hydrogels can be regarded as good candidates for several applications, such as matrices for controlled release, tissue repair, and regeneration.

Phosphonate-functionalized poly(ß-amino ester) macromers as potential biomaterials.

Biodegradability, hemocompatibility, resistance to protein adsorption, and strong interactions with hydroxyapatite (HAP)-based tissues such as dentin, enamel, and bone are important properties of phosphorus-containing biomaterials. Here, novel phosphonate-functionalized poly(ß-amino ester) (PBAE) macromers are synthesized through aza-Michael addition of various diacrylates [1,6-hexanediol diacrylate (HDDA), poly(ethylene glycol) diacrylate (PEGDA, Mn = 575), 1,4-butanediol diacrylate (BDDA), 1,6-hexanediol ethoxylate diacrylate (HDEDA) and triethylene glycol diacrylate (TEGDA)] and a phosphonate-containing primary amine (diethyl 2-aminoethylphosphonate, A1) efficiently without any catalyst; where replacement of A1 with propyl amine (PA) served as control. The macromers, whose molecular weight is ca. 1000-4000 Da as confirmed by both GPC and 1 H-NMR spectroscopy, are photopolymerized to give biodegradable gels. The degradation behavior and cell interaction of these gels are studied. The degradation rates of the gels can be varied by choice of starting acrylates and the acrylate:amine ratio. Furthermore, the gels showed slightly higher degradability than PA-based analogs (controls). Except TEGDA and PEGDA-based ones, all phosphonate-functionalized PBAE gels supported the attachment of larger number of SaOS-2 cells than nonphosphonated ones and the best film was found to be the one based on HDEDA-A1 with balanced hydrophilicity. Degradation products of these films have no significant cytotoxicity except HDDA-PA. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1390-1399, 2018.

Bisphosphonic Acid-Functionalized Cross-Linkers to Tailor Hydrogel Properties for Biomedical Applications.

Two bisphosphonic acid-functionalized cross-linkers (one novel) with different spacer chain characteristics were synthesized and incorporated into hydrogels by copolymerization with 2-hydroxyethyl methacrylate at different ratios to control the hydrogels' swelling, mechanical properties, and ability to support mineralization for biomedical applications. The cross-linkers were synthesized by reaction of 2-isocyanatoethyl methacrylate and bisphosphonated diamines followed by selective dealkylation of the bisphosphonate ester groups. The hydrogels provide in vitro growth of carbonated apatite, morphology affected by the cross-linker structure. The hydrogels exhibit a high Young's modulus E (up to 400 kPa) and can sustain up to 10.2 ± 0.1 MPa compressive stresses. E and hence the cross-link density significantly increases upon mineralization reflecting the formation of many bisphosphonate BP-Ca2+ bonds acting as additional cross-links. Cyclic mechanical tests reveal self-recoverability of hydrogels because of reversible nature of BP-Ca2+ bonds. The results suggest that these cross-linkers can add calcium-binding abilities to hydrogels synthesized from any monomer and improve their mechanical, swelling, and mineralization properties and hence are potentially useful materials for biomedical applications.

Bisphosphonate-functionalized poly(ß-amino ester) network polymers.

Three novel bisphosphonate-functionalized secondary diamines are synthesized and incorporated into poly(ß-amino ester)s (PBAEs) to investigate the effects of bisphosphonates on biodegradation and toxicity of PBAE polymer networks. These three novel amines, BPA1, BPA2, and BPA3, were prepared from the reactions of 1,4-butanediamine, 1,6-hexanediamine, or 4,9-dioxa-1,12-dodecanediamine with tetraethyl vinylidene bisphosphonate, respectively. The PBAE macromers were obtained from the aza-Michael addition reaction of these amines to 1,6-hexane diol diacrylate (HDDA) and poly(ethylene glycol) diacrylate (PEGDA, Mn = 575) and photopolymerized to produce biodegradable gels. These gels with different chemistries exhibited similar degradation behavior with mass loss of 53-73% within 24 h, indicating that degradation is mostly governed by the bisphosphonate group. Based on the in vitro cytotoxicity evaluation against NIH 3T3 mouse embryonic fibroblast cells, the degradation products do not exhibit significant toxicity in most cases. It was also shown that PBAE macromers can be used as cross-linkers for the synthesis of 2-hydroxyethyl methacrylate hydrogels, conferring small and customizable degradation rates upon them. The materials reported have potential to be used as nontoxic degradable biomaterials. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1412-1421, 2017.