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Aim: To radiolabel dexketoprofen trometamol (DT) with [99mTc]Tc for developing inflammation imaging agent. Method: For this purpose, DT was radiolabeled using [99mTc]Tc, and radioactive thin layer chromatography (RTLC) was used in the quality control studies of [99mTc]Tc-DT. In addition, the effects of quality control factors (reducing agent, incubation time, pH value) on radiolabeling were studied. Finally, the stability study of [99mTc]Tc-DT was performed and the partition coefficient value of [99mTc]Tc-DT was calculated. Results: Based on the results, a new, simple, and fast direct technique was used for producing [99mTc]Tc-DT with over 92% labeling efficiency after 15 minutes of pH 9.0 incubation. 37 MBq [99mTc]Tc, 10 µg of stannous chloride dihydrate (reducing agent), and 250 µg of DT were utilized to produce the ideal radiolabeling conditions. According to the RTLC experiments, [99mTc]Tc-DT remained stable at room temperature for six hours. The [99mTc]Tc-DT logP has been determined to be -0.48 ± 0.02. Conclusions: Based on the acquired results, [99mTc]Tc-DT has the potential to be an imaging agent for inflammation. Further studies are in progress, such as biodistribution of [99mTc]Tc-DT.

Biowaiver based on the biopharmaceutics classification system (BCS) has been widely used in the global market for the approval of new generic drug products to avoid unnecessary in vivo bioequivalence (BE) studies. However, it is reported that three out of four formulations of dexketoprofen trometamol (DEX) tablets (BCS class I drug) failed the first BE study. The aim of this study was to determine whether the current biowaiver standard is reasonable for DEX. Thus, we successfully established a physiologically based pharmacokinetic (PBPK) model for DEX and examined the effects of dissolution, permeability, and gastric emptying time on DEX absorption under BCS-based biowaiver conditions using sensitivity analyses. Parameter sensitivity analysis showed that the dissolution rate in pH 1.2 media, permeability, and liquid gastric emptying time were sensitive parameters of C max . Therefore, gastric emptying variation was introduced into the PBPK model, and virtual BE studys were conducted on original research formulation and the formulation of the boundary dissolution rate (f2 = 50) prescribed by the biowaiver guideline. The virtual BE results showed dissolution rate changes within the biowaiver range will not cause high non-BE ratio, indicate waive of DEX generic drugs would not lead the risk of C max when generic products satisfy the requirements of biowaiver guideline. However, the effect of excipients on gastric emptying as a sensitive factor needs to be further studied when the rapid elimination of BCS class I drug is biowaived.

There is little evidence on the ecological effect and sustainability of antimicrobial stewardship programmes (ASPs) in primary-care settings. We aimed to determine whether a multimodal, educational ASP would be sustainable in the long-term and reduce the incidence of infections caused by extended-spectrum β-lactamase-producing Escherichia coli in the community by optimising antibiotic use. We did this quasi-experimental intervention study in 214 primary health centres of four primary health-care districts in Andalusia, Spain. Local multidisciplinary teams, comprised of general practitioners, paediatricians, primary-care pharmacists, and epidemiologists, were created in each district and implemented a multimodal, education-based ASP. The core activity of the programme consisted of regular one-to-one educational interviews between a reference interviewing physician and prescribing physicians from each centre on the appropriateness of their most recent (same or preceding day) antibiotic prescriptions based on a structured questionnaire. Appropriate prescribing was defined as compliance of all checklist items with the reference guidelines. An average of five educational interviews were scheduled per prescriber per study year. We did an interrupted time-series analysis to assess the effect of the intervention on quarterly antibiotic use (prescription and collection by the patient) and quality of prescriptions (as defined daily doses per 1000 inhabitants per day) and incidence per 1000 inhabitants of E coli producing extended-spectrum β-lactamase (ESBL) isolated from urine samples. The study was done between January, 2012, and December, 2017, in a pre-intervention period of 2012–13 and an intervention period of 2014–17. Throughout the study period, there were 1387 physicians (1116 general practicioners and 271 paediatricians) in the included health centres serving a mean population of 1 937 512 people (299 331 children and 1 638 181 adults). 24 150 educational interviews were done over the 4 years. Inappropriate antibiotic prescribing was identified in 1794 (36·5%) of 4917 educational interviews in 2014 compared with 1793 (26·9%) of 6665 in 2017 (p<0·0001). The intervention was associated with a sustained reduction in the use of ciprofloxacin (relative effect −15·9%, 95% CI −23·9 to −8·0) and cephalosporins (−22·6%, −35·9 to −9·2), and a sustained increase in the use of amoxicillin (22·2%, 6·4 to 38·0) and fosfomycin trometamol (6·1%, 2·6 to 9·6). The incidence density of ESBL-producing E coli decreased by −0·028 cases per 1000 inhabitants (95% CI −0·034 to −0·021) after the start of the programme, reversing the pre-intervention increase and leading to a relative reduction of −65·6% (−68·2 to −63·0) 4 years later. Our data suggest that implementation of a multimodal ASP in primary care that is based on individual educational interviews improves the use of antibiotics and results in a sustained significant reduction of infections by ESBL-producing E coli in the community. This information should encourage the implementation of ASPs in primary care. Instituto de Salud Carlos III, Spanish Government (PI14/01523).

Corneal cross-linking (CXL) using riboflavin and ultraviolet A (UVA) light has become a useful treatment option for not only corneal ectasias, such as keratoconus, but also a number of other corneal diseases. Riboflavin is a photoactivated chromophore that plays an integral role in facilitating collagen crosslinking. Modifications to its formulation and administration have been proposed to overcome shortcomings of the original epithelium-off Dresden CXL protocol and increase its applicability across various clinical scenarios. Hypoosmolar riboflavin formulations have been used to artificially thicken thin corneas prior to cross-linking to mitigate safety concerns regarding the corneal endothelium, whereas hyperosmolar formulations have been used to reduce corneal oedema when treating bullous keratopathy. Transepithelial protocols incorporate supplementary topical medications such as tetracaine, benzalkonium chloride, ethylenediaminetetraacetic acid and trometamol to disrupt the corneal epithelium and improve corneal penetration of riboflavin. Further assistive techniques include use of iontophoresis and other wearable adjuncts to facilitate epithelium-on riboflavin administration. Recent advances include, Photoactivated Chromophore for Keratitis-Corneal Cross-linking (PACK-CXL) for treatment of infectious keratitis, customised protocols (CurV) utilising riboflavin coupled with customised UVA shapes to induce targeted stiffening have further induced interest in the field. This review aims to examine the latest advances in riboflavin and UVA administration, and their efficacy and safety in treating a range of corneal diseases. With such diverse riboflavin delivery options, CXL is well primed to complement the armamentarium of therapeutic options available for the treatment of a variety of corneal diseases.

PurposeTo evaluate preoperative asymptomatic bacteriuria (ASB) treatment to reduce early-periprosthetic joint infections (early-PJIs) after hip hemiarthroplasty (HHA) for fracture.MethodsOpen-label, multicenter RCT comparing fosfomycin-trometamol versus no intervention with a parallel follow-up cohort without ASB. Primary outcome: early-PJI after HHA.ResultsFive hundred ninety-four patients enrolled (mean age 84.3); 152(25%) with ASB (77 treated with fosfomycin-trometamol/75 controls) and 442(75%) without. Despite the study closed without the intended sample size, ASB was not predictive of early-PJI (OR: 1.06 [95%CI: 0.33–3.38]), and its treatment did not modify early-PJI incidence (OR: 1.03 [95%CI: 0.15–7.10]).ConclusionsNeither preoperative ASB nor its treatment appears to be risk factors of early-PJI after HHA. ClinicalTrials.gov Identifier: Eudra CT 2016-001108-47

The present Phase I study investigated, for the first time, fosfomycin pharmacokinetics in humans after two 3 g doses of fosfomycin trometamol administered 27 h apart, according to the dose regimen recommended for the prophylactic indication for transrectal prostate biopsy in adult men. Plasma, urine and seminal plasma concentrations were measured after one and two consecutive doses in 24 healthy men, representative of the target population of the prophylactic indication. Prostate and seminal vesicle concentrations were estimated based on seminal plasma concentrations using a one-step regression method. The exposure to fosfomycin was very similar in rate (Cmax, tmax) after one and two doses. The AUC showed a minimal increment. On average, the apparent volume of distribution was high (>100 L), and the mean clearance had an intermediate value. The total amount and dose fraction of fosfomycin excreted in urine showed a small increment after two doses. The renal clearance was about 5 L/h. The fosfomycin concentration in the prostate and seminal vesicles showed that the antibiotic increased on average after two consecutive doses. This result confirmed the ability of fosfomycin to distribute into the prostate and into seminal vesicles after one single dose and that a two consecutive dose regimen increases the antibiotic availability inside these peripheral tissues.

•Vaccine excipient-positive BAT associates with delayed hypersensitivity manifestations.•DMG-PEG 2000 reactivity is frequent in patients with anti-SARS-CoV-2 vaccine hypersensitivity.•DMG-PEG 2000 reactivity associates with vaccination. Basophil activation test (BAT) can tackle multiple mechanisms underlying acute and delayed hypersensitivity to drugs and vaccines and might complement conventional allergy diagnostics but its role in anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-related hypersensitivity is ill-defined. Therefore, 89 patients with possible hypersensitivity (56 % with delayed mucocutaneous manifestations) to anti-SARS-CoV-2 vaccines were tested with BAT for Macrogol 3350, DMG-PEG 2000, PEG 20000, polysorbate-80 and trometamol and compared to 156 subjects undergoing pre-vaccine BAT. A positive BAT was associated with delayed reaction onset (p = 0.010) and resolution (p = 0.011). BAT was more frequently positive to DMG-PEG 2000 than to other excipients in both groups (p < 0.001). DMG-PEG 2000 reactivity was less frequent in vaccine-naïve (6 %) than vaccinated subjects (35 %, p < 0.001) and associated with mRNA-1273 vaccination. DMG-PEG 2000 BAT might therefore have a diagnostic role in subjects with delayed hypersensitivity reactions. Natural immunity might be a key player in basophil activation.

COVID-19 has been a growing global concern in the past four years. Several syndromes associated with this multi-organ viral infection have been observed since the outbreak. According to estimates, 10–15% of people with SARS-CoV- infection may have post-COVID-19 syndrome. Even months after infection, common residual signs and symptoms include myalgia, exhaustion, shortness of breath, rapid heartbeat, stroke, and memory and cognitive impairment which can negatively affect survivors’ quality of life and may consequently lead to their death. Therefore, it is necessary to think about potential therapy options for dealing with both short and long-term impacts. Paracetamol (a common analgesic and antipyretic) and Dexketoprofen Trometamol (a non-steroidal anti-inflammatory drug) are used together to relieve post-COVID symptoms like myalgia (muscle pain) and headache. Additionally, to prevent thrombotic events, Rivaroxaban is recommended for 35 days following discharge. Thus an eco-friendly HPLC-DAD technique was developed for simultaneous quantification of Paracetamol, Dexketoprofen Trometamol, and Rivaroxaban which are co-administered for treatment of post-COVID-19 syndrome. The suggested method was found to be linear in the concentration ranges of 3.00–45.00 µg/mL, 0.5–50.00 µg/mL, and 0.15–20.00 µg/mL, and a limit of detection down to 0.531 µg/mL, 0.095 µg/mL and 0.047 µg/mL for Paracetamol, Dexketoprofen Trometamol and Rivaroxaban, respectively. This method was effectively used to quantify the studied drugs in their bulk powder and spiked human plasma with high percentage recoveries (96.55–99.46%). The suggested approach was validated per International Conference on Harmonization (ICH) requirements and found to be within the acceptable ranges. The method was developed using Green Analytical Chemistry (GAC) principles, with the solvents used and run time having a significant effect on the method’s greenness. “Non-toxic” ethanol served as the organic modifier in the mobile phase, moreover, the total run time was 12 min making it suitable for the routine analysis of the mentioned drugs in plasma samples. To get a full image of the method’s greenness profile; two most recent greenness assessment tools, the Green Analytical Procedure Index (GAPI), and the Analytical GREEnness metric (AGREE), were employed, with White Analytical Chemistry (WAC) principles proving its environmental safety.

In this study, we aimed to compare the analgesic efficacy of intravenous dexketoprofen trometamol, fentanyl, and paracetamol in patients presenting to the emergency department with renal colic. Data obtained from the emergency departments of Gaziantep University's Hospital for Research and Practice along with two other state hospitals in Gaziantep, Turkey between January 2016 and January 2017 was used for this study. A total of three hundred patients (n=300), who presented to the ER with complaints most common to renal colic whose diagnoses were subsequently confirmed with Computerized Tomography were included in the study. Patients’ pain scores were recorded using the Visual Analogue Scale, at admission (immediately before drug administration), then at the 15th, and 30th minutes. SPSS 22.0 software package was used for analysis. p<0.05 was considered significant. At the 15th minute comparison, the efficacies of the three groups of drugs were not superior to one other, but at the 30th minute, dexketoprofen trometamol was statistically more effective than paracetamol and fentanyl. There was no statistically significant difference between fentanyl and paracetamol. The need for additional analgesia in the group receiving dexketoprofen trometamol was found to be lower. Dexketoprofen trometamol was statistically superior to the other two agents in achieving full analgesia at the end of the thirty-minute period. Fentanyl was found to be statistically significant in achieving moderate analgesia. As a Non-steroidal antiinflammatory drug dexketoprofen trometamol is superior to paracetamol and fentanyl in achieving analgesia and reducing the need for additional drugs for the treatment of renal colic.