Search Results (82)

The assessment of surface water quality of the Danube River and Black Sea was performed taking into account the amounts determined for heavy metals (As, Cd, Cr, Cu, Hg, Mn, Ni, Pb, Zn), nutrients (compounds of N and P, chlorophyll a), emerging contaminants (CECs) (pharmaceutics and endocrine disruptors—19 quantified compounds, out of 30 targeted chemicals), heterotrophic bacteria and total coliforms, in thirty-two locations from the lower Danube sector (starting with km 375 up to the river mouths), the Danube Delta Biosphere Reserve (three Danube branches—Chilia, Sulina, and Sf. Gheorghe) and the Romanian coastal area of the Black Sea. The heavy metals levels were found in the following ranges: 3.0–6.5 μg/L As; 0.51–1.32 μg/L Cd; 21.6–61.2 μg/L Cr; 10.2–28.6 μg/L Cu; 196–351 μg/L Mn; 12.3–47.67 μg/L Ni; 5.2–15.5 μg/L Pb; 44–74 μg/L Zn; 0.01–0.08 μg/L Hg. The nutrient concentrations vary in the intervals: 0.04–0.45 mg/L N-NH₄; 0.01–0.06 mg/L N-NO₂; 0.07–1.9 mg/L N-NO₃; 1.0–3.2 mg/L N total; 0.01–0.05 mg/L P-PO₄; 0.02–0.27 mg/L P total, and 0.8–17.3 μg/L chlorophyll a. The concentrations of CECs from various classes (sulfamethoxazole, trimethoprim, ciprofloxacin, flumequine, amoxicillin, cefuroxime, dicloxacillin, carbamazepine, pravastatin, erythromycin, piroxicam, ketoprofen, diclofenac, naproxen, enilconazole (imazalil), clotrimazole, drospirenone, 17α-ethinylestradiol, and bisphenol A) were compared with values reported for European rivers and the Danube River water in various river sectors. The highest detection frequencies were registered for bisphenol A (100%), sulfamethoxazole (96%), carbamazepine and diclofenac (87%), trimethoprim (78%), pravastatin (46%), and imazalil (34%). Bisphenol A exhibited the largest concentrations (342 ng/L), followed by diclofenac (132 ng/L), carbamazepine (38 ng/L), and sulfamethoxazole (36 ng/L). For most of the contaminants, Black Sea coastal water showed lower concentrations than the Danube water and good ecological status for surface water. Correlations between CECs and total coliforms suggest insufficient treated wastewater effluents as a common contamination source and possible use of CECs as indirect fecal pollution indicator in aquatic systems. This is the first study carried out in the connected system Danube River–Danube Delta–Black Sea for a large palette of toxicants classes and microbial pollutants, which will serve as a baseline for future monitoring of water quality in the region. Full article

Background: The bioavailability of a drug depends, among other parameters, on solubility. One of the strategies used to enhance the solubility of sparingly soluble drugs is the use of excipients. Excipients can interact with the drug by increasing its solubility and/or stabilizing supersaturated solutions. Some of the most common excipients are cyclodextrins and hydrophilic polymers. Objectives: The effect of two cyclodextrins (captisol and cavasol) and three hydrophilic polymers (klucel, kollidon and plasdone S630) on the solubility of three ionizable drugs (benzthiazide, isoxicam, and piroxicam) is evaluated at biorelevant pH values, using two complementary techniques. Methods: The solubility enhancement was evaluated by the comparison of the solubility with and without the presence of excipients through the shake-flask and CheqSol methodology. Results: Captisol and cavasol slightly increase the concentration of the neutral species of the drugs in the solution before precipitation begins, although they do not enhance the supersaturation duration nor the thermodynamic solubility of the drugs. The increase in solubility in the presence of cyclodextrins is mainly caused by the ionization state of the drug. Hydrophilic polymers not only improve thermodynamic solubility but also the extent and the duration of the supersaturation. Some metastable forms are observed for benzthiazide and isoxicam in the presence of kollidon and plasdone S630. Conclusions: The shake-flask method enabled the evaluation of thermodynamic solubility both in the absence and presence of excipients. Meanwhile, the CheqSol method provided insights into the presence of supersaturated solutions. Different behavior is observed depending on the nature of the excipient. Full article

Plant-based food supplements (FS) of doubtful traceability have now emerged as a new threat to human health. Food supplements adulterated with pharmaceutical ingredients are considered “medicines in disguise” by regulatory authorities, which is a sub-category of falsified medicines. In the context of illegal manufacture and trade, as well as in the absence of an official phyto- and/or pharmacovigilance system, emergency departments and poison control centers constitute a early warning system for detecting ingested suspect FS. In the present investigation, we set up efficient workflows for the systematic characterization of adulterated plant-based FS in the context of an original local early warning alert system (i.e., FalsiMedTrack) involving an emergency department, a poison center, and academic analytical chemistry laboratories. Fit-for-purpose cross-analytical methods were employed, including sophisticated methods such as liquid chromatography coupled to high-resolution mass spectrometry, nuclear magnetic resonance, X-ray powder diffraction, as well as the most accessible and affordable HPLC method with UV/DAD detection. The strategy was applied successfully to typical cases of suspect plant-based health products, i.e., sample incriminated in patients experiencing side effects and herbal products currently commercialized for their “amazing health benefits”. The samples contained active pharmaceutical ingredients, including diclofenac, piroxicam, dexamethasone 21-acetate, and sibutramine. We provided evidence of “medicines in disguise” presented as food supplements, which raises concerns about their quality and safety. Full article

The increase in life expectancy has led to a rise of musculoskeletal disorders. Calcium phosphate cements (CPCs), thanks to some amazing features such as the ability to harden in vivo, bioactivity, and resorbability, are promising candidates to treat these diseases, notwithstanding their poor mechanical properties. We aimed to synthesise pure and barium- or silicon-doped brushite-based CPCs loaded with piroxicam to study the effects of the substitution on physical-chemical and pharmaceutical properties before and after cement immersion in phosphate buffer for different time periods. Our results demonstrated that piroxicam became amorphous in the hardened cements. The dopants did not change the brushite structure or its lamellar morphology, while both Ba and Si additions improved the initial Young’s modulus compared to the pure cement, and the opposite trend was observed for compressive strength. Both the compressive strength and the elastic modulus decreased for the samples immersed in solution compared to the non-immersed samples, with stabilisation as the number of days increased. After 7 days, the whole drug amount was released, with a slower and constant kinetic for the Ba-doped cements compared to the pure and Si-doped ones. Full article

Background: This study demonstrates the application of the sequential design of experiments (DoE) approach within the quality by design (QbD) framework to optimize extrusion processes through screening, optimization, and robustness testing. Methods: An in-line UV–Vis process analytical technology (PAT) system was successfully employed to monitor critical quality attributes (CQAs) of piroxicam amorphous solid dispersion (ASD) extrusion products, specifically lightness (L*). Results: L* measurement proved highly effective for ensuring the quality and uniformity of ASDs, offering real-time insights into their physical appearance and process stability. Small variations in L* acted as early indicators of processing issues, such as phase separation or bubble formation, enabling timely intervention. This straightforward and rapid technique supports real-time process monitoring and control, allowing automated adjustments to maintain product consistency and quality. By adopting this strategy, manufacturers can minimize variability, reduce waste, and ensure adherence to quality target product profiles (QTPPs). Conclusions: Overall, this study highlights the value of in-line UV–Vis spectroscopy as a PAT tool in hot melt extrusion, enhancing CQA assessment and advancing the efficiency and reliability of ASD manufacturing. Full article

Pyrimidine derivatives exhibit a wide range of biological activities, including anti-inflammatory properties. The aim of this study was to investigate the effects of tested pyrimidine derivatives on the activity of cyclooxygenase isoenzymes (COX-1 and COX-2), antioxidant properties, and their ability to inhibit the growth of inflammatory cells. In vitro tests were conducted to assess the ability of pyrimidine derivatives L1–L4 to inhibit COX-1 and COX-2 activity using the TMPD oxidation assay (N,N,N′,N′-tetramethyl-p-phenylenediamine). The compounds’ ability to inhibit the growth of lipopolysaccharide (LPS)-stimulated THP-1 (human leukemia monocytic) monocyte cells and their impact on reactive oxygen species (ROS) levels in an inflammatory model were also evaluated. The binding properties of human serum albumin (HSA) were assessed using UV–Vis spectroscopy, circular dichroism (CD), and isothermal titration calorimetry (ITC). Among the tested pyrimidine derivatives, L1 and L2 showed high selectivity towards COX-2, outperforming piroxicam and achieving results comparable to meloxicam. In the sulforhodamine B (SRB) assay, L1 and L2 demonstrated dose-dependent inhibition of LPS-stimulated THP-1 cell growth. Additionally, ROS assays indicated that these compounds reduced free radical levels, confirming their antioxidant properties. Binding studies with albumin revealed that L1 and L2 formed stable complexes with HSA. These results suggest that these compounds could serve as a basis for further research into anti-inflammatory and anticancer drugs with reduced toxicity. Full article

Objectives: This systematic review was designed to summarize randomized controlled trials of intra-articular administration of non-steroidal anti-inflammatory drugs (NSAIDs) for temporomandibular disorders. Methods: Randomized controlled trials regarding intra-articular injections of non-steroidal anti-inflammatory drugs for temporomandibular disorders were included in the review. The final search was conducted on 16 June 2024 in the Bielefeld Academic Search Engine, PubMed, and Scopus databases. Results: Of the 173 identified studies, 6 were eligible for review. In trials comparing arthrocentesis alone to arthrocentesis with NSAIDs, slight differences in joint pain were noted. For tenoxicam, differences were under 1 point on a 0–10 scale after 4 weeks, with inconsistent results. Piroxicam showed no significant difference, and pain levels were minimal in both groups. For maximum mouth opening (MMO), tenoxicam showed no significant difference. Piroxicam increased MMO by nearly 5 mm, based on one small trial with bias concerns. Conclusions: Currently, there is no strong scientific evidence supporting the injection of NSAIDs into the temporomandibular joint to relieve pain or increase jaw movement. Preliminary reports on piroxicam with arthrocentesis and tenoxicam or diclofenac without rinsing justify further research. Full article

This rapid review summarizes the latest primary research in temporomandibular joint (TMJ) injection treatment. The final literature searches were conducted on 4 January 2024. Selection was performed systematically following predefined eligibility criteria. Randomized control trials concerning the treatment of TMJ disorders with intra-articular injections were included. Studies on more invasive interventions were excluded. Quality of life, joint pain and range of mandibular mobility were assessed. Ultimately, 12 studies covering a total of 603 patients qualified. They concerned: (1) arthrocentesis (AC) and the administration of, (2) injectable platelet-rich fibrin (I-PRF), (3) platelet-rich plasma (PRP), (4) hyaluronic acid (HA), (5) non-steroidal anti-inflammatory drugs (NSAIDs), and (6) hypertonic dextrose (HD) with a local anesthetic. The dominant approach was to perform arthrocentesis before administering the appropriate injection substance (I-PRF, PRP, HA, or NSAID). Two current studies on the intra-articular administration of NSAIDs, specifically tenoxicam and piroxicam, are noteworthy. A mixture of PRP and HA was injected in another two trials. These two innovative approaches may prove to be significant directions for further research on injection treatment of TMJs. Full article

The antifungal agent, ketoconazole, and the anti-inflammatory drug, piroxicam, were incorporated into matrices of xanthan or oleic acid-esterified xanthan (Xn) and polyurethane (PU), to develop topical drug delivery systems. Compared to matrices without bioactive compounds, which only showed a nominal compressive stress of 32.18 kPa (sample xanthan–polyurethane) at a strain of 71.26%, the compressive resilience of the biomaterials increased to nearly 50.04 kPa (sample xanthan–polyurethane–ketoconazole) at a strain of 71.34%. The compressive strength decreased to around 30.67 kPa upon encapsulating a second drug within the xanthan–polyurethane framework (sample xanthan–polyurethane–piroxicam/ketoconazole), while the peak sustainable strain increased to 87.21%. The Weibull model provided the most suitable fit for the drug release kinetics. Unlike the materials based on xanthan–polyurethane, those made with oleic acid-esterified xanthan–polyurethane released the active ingredients more slowly (the release rate constant showed lower values). All the materials demonstrated antimicrobial effectiveness. Furthermore, a higher volume of piroxicam was released from oleic acid-esterified xanthan–polyurethane–piroxicam (64%) as compared to xanthan–polyurethane–piroxicam (44%). Considering these results, materials that include polyurethane and either modified or unmodified xanthan showed promise as topical drug delivery systems for releasing piroxicam and ketoconazole. Full article

In this paper, a self-assembly method was used to prepare gold nanorod composites, and a seed-growth method was used to adjust the amount of AgNO₃ solution, enabling the preparation of gold nanorods with different aspect ratios. AuNRs@SiO₂ nanocomposite particles were then prepared by using the Stöber method to coat the gold nanorod surface with silica. Transmission electron microscopy showed that the maximum aspect ratio of the gold nanorods was 4.53, which was achieved using 2 mL of 10 mM AgNO₃ solution. The Raman-scattering intensity of the gold nanorods was studied using rhodamine 6G, thiram, melamine, and piroxicam, and detection limits of 10⁻⁸ M, 10⁻⁵ M, and 10⁻³ M were, respectively, achieved. As a substrate, these gold nanorods showed good repeatability and reproducibility, and trace detection was successfully achieved. A transmission electron microscopy analysis shows that the SiO₂ shell became thicker with increasing tetraethyl orthosilicate addition. Using AuNRs@SiO₂ as the base and R6G, thiram, and piroxicam as the probes, measurable detection limits of 10⁻⁹ M, 10⁻⁶ M, and 10⁻⁵ M were achieved, and this composite also showed excellent repeatability and reproducibility. Full article

Non-steroidal anti-inflammatory piroxicam (PRX) is a poorly water-soluble drug that provides relief in different arthritides. Reducing the particle size of PRX increases its bioavailability. For pediatric, geriatric, and dysphagic patients, oral dispersible systems ease administration. Moreover, fast disintegration followed by drug release and absorption through the oral mucosa can induce rapid systemic effects. We aimed to produce an orodispersible lyophilizate (OL) consisting of nanosized PRX. PRX was solved in ethyl acetate and then sonicated into a poloxamer-188 solution to perform spray-ultrasound-assisted solvent diffusion-based nanoprecipitation. The solid form was formulated via freeze drying in blister sockets. Mannitol and sodium alginate were applied as excipients. Dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA) were used to determine the particle size. The morphology was characterized by scanning electron microscopy (SEM). To establish the crystallinity, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) were used. A disintegration and in vitro dissolution test were performed. DLS and NTA presented a nanosized PRX diameter. The SEM pictures showed a porous structure. PRX became amorphous according to the XRPD and DSC curves. The disintegration time was less than 1 min and the dissolution profile improved. The final product was an innovative anti-inflammatory drug delivery system. Full article

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed drugs to treat pain or fever. However, oral administration of NSAIDs is frequently associated with adverse effects due to their inhibitory effect on the constitutively expressed cyclooxygenase enzyme 1 (COX-1) in, for instance, the gastrointestinal tract. A systemic delivery, such as a buccal delivery, of NSAIDs would be beneficial and additionally has the advantage of a non-invasive administration route, especially favourable for children or the elderly. To investigate the transport of NSAIDs across the buccal mucosa and determine their potential for buccal therapeutic usage, celecoxib, diclofenac, ibuprofen and piroxicam were tested using an established oral mucosa Transwell^® model based on human cell line TR146. Carboxyfluorescein and diazepam were applied as internal paracellular and transcellular marker molecule, respectively. Calculated permeability coefficients revealed a transport ranking of ibuprofen > piroxicam > diclofenac > celecoxib. Transporter protein inhibitor verapamil increased the permeability for ibuprofen, piroxicam and celecoxib, whereas probenecid increased the permeability for all tested NSAIDs. Furthermore, influence of local inflammation of the buccal mucosa on the transport of NSAIDs was mimicked by treating cells with a cytokine mixture of TNF-α, IL-1ß and IFN-γ followed by transport studies with ibuprofen (+ probenecid). Cellular response to pro-inflammatory stimuli was confirmed by upregulation of cytokine targets at the mRNA level, increased secreted cytokine levels and a significant decrease in the paracellular barrier. Permeability of ibuprofen was increased across cell layers treated with cytokines, while addition of probenecid increased permeability of ibuprofen in controls, but not across cell layers treated with cytokines. In summary, the suitability of the in vitro oral mucosa model to measure NSAID transport rankings was demonstrated, and the involvement of transporter proteins was confirmed; an inflammation model was established, and increased NSAID transport upon inflammation was measured. Full article

Hot melt extrusion (HME) offers a high-throughput process to manufacture amorphous solid dispersions. A variety of experimental and model-based approaches exist to predict API solubility in polymer melts, but these methods are typically aimed at determining the thermodynamic solubility and do not take into account kinetics of dissolution or the associated degradation of the API during thermal processing, both of which are critical considerations in generating a successful amorphous solid dispersion by HME. This work aims to develop a material-sparing approach for screening manufacturability of a given pharmaceutical API by HME using physically relevant time, temperature, and shear. Piroxicam, ritonavir, and phenytoin were used as model APIs with PVP VA64 as the dispersion polymer. We present a screening flowchart, aided by a simple custom device, that allows rapid formulation screening to predict both achievable API loadings and expected degradation from an HME process. This method has good correlation to processing with a micro compounder, a common HME screening industry standard, but only requires 200 mg of API or less. Full article

Lipid and/or polymer-based drug conjugates can potentially minimize side effects by increasing drug accumulation at target sites and thus augment patient compliance. Formulation factors can present a potent influence on the characteristics of the obtained systems. The selection of an appropriate solvent with satisfactory rheological properties, miscibility, and biocompatibility is essential to optimize drug release. This work presents a computational study of the effect of the basic formulation factors on the characteristics of the obtained in situ-forming particulates (IFPs) encapsulating a model drug using a 2¹.3¹ full factorial experimental design. The emulsion method was employed for the preparation of lipid and/or polymer-based IFPs. The IFP release profiles and parameters were computed. Additionally, a desirability study was carried out to choose the optimum formulation for further morphological examination, rheological study, and PBPK physiological modeling. Results revealed that the type of particulate forming agent (lipid/polymer) and the incorporation of structure additives like Brij 52 and Eudragit RL can effectively augment the release profile as well as the burst of the drug. The optimized formulation exhibited a pseudoplastic rheological behavior and yielded uniformly spherical-shaped dense particulates with a PS of 573.92 ± 23.5 nm upon injection. Physiological modeling simulation revealed the pioneer pharmacokinetic properties of the optimized formulation compared to the observed data. These results assure the importance of controlling the formulation factors during drug development, the potentiality of the optimized IFPs for the intramuscular delivery of piroxicam, and the reliability of PBPK physiological modeling in predicting the biological performance of new formulations with effective cost management. Full article

It was recently shown that targeting extracellular vimentin (eVim) is safe and effective in preclinical models. Here, we report the safety and efficacy in client-owned dogs with spontaneous bladder cancer of CVx1, an iBoost technology-based vaccine targeting eVim in combination with COX-2 inhibition. This was a single-arm prospective phase 1/2 study with CVx1 in 20 client-owned dogs with spontaneous UC which involved four subcutaneous vaccinations with CVx1 at 2-week intervals for induction of antibody titers, followed by maintenance vaccinations at 2-month intervals. Additionally, daily cyclooxygenase (COX)-2 inhibition with meloxicam was given. The response was assessed by antibody titers, physical condition, abdominal ultrasound and thorax X-ray. The primary endpoints were the development of antibody titers, as well as overall survival compared to a historical control group receiving carboplatin and COX-2 inhibition with piroxicam. Kaplan–Meier survival analysis was performed. All dogs developed antibodies against eVim. Titers were adequately maintained for the duration of this study. A median overall survival of 374 days was observed, which was 196 days for the historical control group (p < 0.01). Short-term grade 1–2 toxicity at the injection site and some related systemic symptoms peri-vaccination were observed. No toxicity was observed related to the induced antibody response. A limitation of this study is the single-arm prospective setting. CVx1 plus meloxicam consistently induced efficient antibody titers, was well tolerated and showed prolonged survival. The results obtained merit further development for human clinical care. Full article