Assessment of Monitoring and Management Practices of Antipsychotic-Induced Hyperprolactinemia at a Medical City in Riyadh, Saudi Arabia: A Retrospective Cohort Study.

BACKGROUND: Hyperprolactinemia is a commonly underestimated adverse effect of antipsychotic medications. There are still no consensus guidelines for the optimal monitoring and treatment strategies. OBJECTIVE: The aim of the study was to assess the monitoring and treatment practices of antipsychotic-induced hyperprolactinemia, in addition to the prevalence and risk factors associated with it. METHODS: A retrospective cohort observational study was conducted among patients attending the psychiatric clinics at an academic tertiary hospital in Riyadh, Saudi Arabia, from May 2020 until May 2021, by reviewing each patient's medical record for up to five years. RESULTS: Among the 662 patients, 35 patients (5.3%) and 242 patients (36.6%) had their serum prolactin levels monitored (at baseline and at follow-up, respectively). The prevalence of hyperprolactinemia was observed in 212 patients (32%). Only 76 patients (36%) were symptomatic. Female gender, younger age, and bipolar disorder had a significantly higher risk of developing hyperprolactinemia. 60% of the confirmed cases received treatment, of which 76 (60%) were adherent to treatment guidelines. The most common treatment strategies implemented were dose reduction (42.5%) and aripiprazole augmentation (29.1%). CONCLUSION: It is imperative to conduct a baseline check of prolactin levels before commencing any antipsychotic therapy. Similarly, routine prolactin level monitoring is recommended regardless of symptoms in patients treated with antipsychotics with a possible prolactin-raising effect. Adherence to evidence-based treatment guidelines can improve patient quality of life and therapeutic compliance.

Does sequential examination under anaesthesia provide a reliable method to determine a management plan for unstable lateral compression pelvic ring injuries? a prospective study.

PURPOSE: To assess the reliability of sequential examination under anaesthesia (EUA) to determine pelvic instability and to evaluate radiological and functional outcomes in unstable lateral compression (LC) injuries. METHODS: A prospective case series study was conducted from 2020 to 2022 at a university hospital on 43 cases with LC injuries that met the inclusion criteria. Sequential EUA was carried out in three steps. Posterior-only fixation or anterior-posterior fixation was done according to the algorithm. Each patient was followed up for at least 12 months, both radiologically and functionally. RESULTS: Forty cases proved unstable and were fixed. None showed secondary displacement in the anterior-posterior fixation group. However, five cases (19.2%) of the posterior-only fixation group showed secondary displacement with a mean of 5.9 mm. Four cases of them had tetra-ramic injuries. There is a high tendency for secondary displacement at 14.5 mm or more preoperative displacement of the rami. Patients with secondary displacement showed comparable functional outcome scores to patients without secondary displacement. Posterior-only fixation showed shorter operative time, lesser radiological exposure, blood loss and iatrogenic nerve injury than anterior-posterior fixation. CONCLUSION: EUA is a reliable method to determine pelvic instability and management plan for LC fractures with unilateral anterior ring injury. Anterior-posterior fixation is needed if there is a tetra-ramic fracture or initial anterior ring displacement of 14.5 mm or more, irrespective of EUA.

Transvenous lead extraction, factors affecting procedural difficulty.

BACKGROUND: A complex transvenous lead extraction (TLE) procedure could be associated with lower success and higher complication rates in inexperienced hands. In this study, we aim to assess the factors that determine procedural difficulty in TLE. METHODS: We retrospectively studied 200 consecutive patients undergoing TLE in a single referral centre from June 2020 to December 2021. Lead extraction difficulty was assessed by the success of simple manual traction with or without a locking stylet, the need for advanced extraction tools and the number of tools required to extract the lead. Logistic and linear regression analyses were used to determine the factors independently affecting these 3 parameters. RESULTS: 363 leads were extracted from 200 patients (79% males, mean age 66.85 years). The indication for TLE was device-related infection in 51.5%. Multivariate analysis revealed the lead indwelling time to be the only factor affecting the 3 parameters of difficulty. Passive fixation leads and dual coil leads increased procedural difficulty by affecting 2 parameters each. Factors that affected one parameter included infected leads, coronary sinus leads, older age of the patient and a history of valvular heart disease, all associated with a simpler procedure. Right ventricular leads were associated with a more complex one. CONCLUSION: The most important factor that increased TLE procedural difficulty was a longer lead indwelling time, followed by passive fixation and dual-coil leads. Other contributing factors were the presence of infection, coronary sinus leads, older patients, a history of valvular heart disease and right ventricular leads.

Effectiveness of antiemetic in reducing chemotherapy-induced nausea and vomiting in adult patients; An oncology center experience.

INTRODUCTION: Chemotherapy-induced nausea and vomiting (CINV) are two serious adverse effect of cancer chemotherapy. The objectives of this study are to assess patient satisfaction with antiemetics prescribed, incidence of nausea and vomiting in cancer patients, and the effectiveness of antiemetic regimens in reducing CINV. METHODS: This is a prospective observational cross-sectional patient survey study, conducted between January and July 2021 in the oncology center at King Saud University Medical City, Riyadh, Saudi Arabia. A suitable, data entry form was designed to collect data including patient demographics, cancer type, antiemetics prescribed, chemotherapy regimen, and incidence of CINV. RESULTS: The sample comprised 283 cancer patients with a mean age of 47.7 (±14.6) years. Colorectal and breast cancer (n = 67; 23.6%, for each) were the two most common diagnoses. Among the patients who received chemotherapy, most patients (n = 144; 50.8%) received chemotherapy that was classified as highly emetogenic, and 139 (49%) received moderately emetogenic chemotherapy. Antiemetics were given to control CINV before chemotherapy administration (as prophylaxis) were either combination therapy (170 patients (60.0%) received four classes of antiemetics, 72 (25.4%) received three classes; and 31 (10.9%) received two classes) or monotherapy (six patients (2.1%) received one drug). Four patients (1.4%) did not receive any antiemetic medication. Antiemetics given to control CINV after chemotherapy administration (for delayed CINV) were also either in combination (151 patients (53.3%) received three classes of antiemetics and 94 (33.2%) received two classes) or as monotherapy, where 27 patients (9.5%) received one medication. Eleven patients (3.8%) did not receive any antiemetic. The incidence rates for acute and delayed nausea after chemotherapy treatment were 32.1% and 30.7%, respectively; and those for acute and delayed vomiting were 13.4% and 10.2%, respectively. Acute nausea was much more frequent than vomiting. CONCLUSION: The incidence of CINV was relatively high, and patients who received chemotherapy continued to experience nausea and vomiting despite receiving antiemetic treatment. This demonstrates that antiemetic regimens used are not effective in preventing CINV.

New Sulfamethoxazole Derivatives as Selective Carbonic Anhydrase IX and XII Inhibitors: Design, Synthesis, Cytotoxic Activity and Molecular Modeling.

In this study new sulphamethoxazole derivatives (S1-S4, S6-S12, and S14-S22) were designed and synthesized and their structures were fully characterized and validated using NMR, mass, and IR spectroscopy, as well as elemental analyses. All new derivatives (S1-S22) were assayed against human carbonic anhydrase (hCAs IX and XII) for their inhibitory activities. hCAs IX and XII were chosen due to the fact that CAIX expression is recognized as a hypoxia marker with a poor prognosis in breast cancer. When compared to Dorzolamide HCl as a standard reference, derivatives S2, S3, S8, S9, and S15 had the most effective inhibition with low IC50 values. The active compounds were further evaluated against hCAs I and II inhibitory activity and compounds S8, S9 and S15 showed the least inhibitory effect compared to the reference standard, acetazolamide, indicating that their effect in normal cells is the lowest. Cell viability tests for the selected compounds were carried out on MCF7 (normoxia and hypoxia) and on the normal breast cell line (MCF10a) with Staurosporine as a standard. The results showed that compound S15 had a highly potent cytotoxic effect. Furthermore, cell cycle analysis results showed that compound S15 triggered cell cycle arrest and apoptosis in G1/S of MCF7 cancer cells. Finally, molecular docking was performed to point out the possible explanation for the vital structural features and key-interactions exerted by our ligands with hCAs IX and XII that might share additional designs and highlight possible leads for a hopeful anticancer agent. Consequently, sulphamethoxazole Derivative S15 could be the potential lead for emerging selective cytotoxic compounds directing h CAs IX and XII.

A Comprehensive Overview of Globally Approved JAK Inhibitors.

Janus kinase (JAK) is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2. The JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer conditions. Targeting the JAK family kinases with small-molecule inhibitors has proved to be effective in the treatment of different types of diseases. In the current review, eleven of the JAK inhibitors that received approval for clinical use have been discussed. These drugs are abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib. The aim of the current review was to provide an integrated overview of the chemical and pharmacological data of the globally approved JAK inhibitors. The synthetic routes of the eleven drugs were described. In addition, their inhibitory activities against different kinases and their pharmacological uses have also been explained. Moreover, their crystal structures with different kinases were summarized, with a primary focus on their binding modes and interactions. The proposed metabolic pathways and metabolites of these drugs were also illustrated. To sum up, the data in the current review could help in the design of new JAK inhibitors with potential therapeutic benefits in inflammatory and autoimmune diseases.

New 1,2,4-oxadiazole/pyrrolidine hybrids as topoisomerase IV and DNA gyrase inhibitors with promising antibacterial activity.

A series of hybridized pyrrolidine compounds with a 1,2,4-oxadiazole moiety were synthesized to develop effective molecules against the enzymes DNA gyrase and topoisomerase IV (Topo IV). Compounds 8-20 were developed based on a previously disclosed series of compounds from our lab, but with small structural modifications in the hopes of increasing the compounds' biological activity. In comparison to novobiocin, with IC50 = 170 nM, the findings of the DNA gyrase inhibitory assay revealed that compounds 16 and 17 were the most potent of all synthesized derivatives, with IC50 values of 180 and 210 nM, respectively. Compound 17 had the strongest inhibitory effect against Escherichia coli Topo IV of all the synthesized compounds, with an IC50 value of 13 µM, which was comparable to novobiocin (IC50 = 11 µM). Therefore, hybrids 16 and 17 appeared to be potential dual-target inhibitors. In the minimal inhibitory concentration (MIC) assays, compound 17 outperformed ciprofloxacin against E. coli, with an MIC of 55 ng/ml, compared to 60 ng/ml for ciprofloxacin. Finally, the docking study, along with the in vitro experiments, supports our promising approach to effectively develop potent leads for further optimization as dual DNA gyrase and Topo IV inhibitors.

The use of Verbrugge forceps for reduction of the posterior column element in displaced acetabular fractures: clinical and radiological evaluation.

PURPOSE: Different reduction techniques and tools are described to facilitate anatomical reduction of acetabular fractures. However, maintenance of reduction, plate placement, and fracture fixation remain a challenge owing to the large surface area occupied by the available reduction tools. This study aims at radiological and functional assessment of the effectiveness of a novel reduction technique for the posterior column element in displaced acetabular fractures. METHODS: A prospective study was conducted for evaluation of a novel reduction technique; the use of the conventional large holding Verbrugge forceps for reduction of posterior column and transverse, with or without posterior wall, fractures. Intra-operative safety and reduction time were evaluated. The immediate postoperative quality of reduction was assessed using Matta radiographic criteria. The functional outcome was evaluated at the latest follow-up visit using the modified Merle d'Aubigne and Postel (MDP) score. RESULTS: Thirty patients with a mean follow-up of 18.1 months were included. Fifteen had transverse/posterior wall, ten had transverse, and five had posterior column fractures. All fractures were displaced ≥ 2 mm on anteroposterior and/or Judet views of the pelvis without traction. The average operative time was 100.4 min with 12.5 min reduction time. No intra-operative complications were encountered. Twenty-three patients (76.6%) had anatomical while seven (23.3%) had imperfect reduction. The functional outcome score was excellent in three patients, good in 18, fair in four, and poor in five patients at the latest follow-up. CONCLUSION: The use of the conventional large Verbrugge bone-holding forceps for the reduction of the posterior column element in displaced acetabular fractures using the Kocher-Langenbeck approach is a safe, effective, time-saving, and technically undemanding procedure.

Effect of amlodipine versus bisoprolol in hypertensive patients on maintenance hemodialysis: A randomized controlled trial.

BACKGROUND: Left ventricular hypertrophy and asymmetric dimethylarginine (ADMA) are surrogate markers of cardiovascular disease (CVD) in the dialysis population. This study aimed to evaluate the effect of a calcium channel blocker-based antihypertensive regimen compared to a beta-blocker-based antihypertensive regimen on left ventricular mass index (LVMI) and ADMA levels in hypertensive patients on hemodialysis (HD). METHODS: This was a parallel-design, open-label, single-center randomized controlled trial on 46 hypertensive patients on maintenance HD, with no history of CVD. Patients were randomly assigned to receive amlodipine 10 mg/d (n = 23) or bisoprolol 10 mg/d (n = 23). Office-based blood pressure (BP) was targeted to ≤ 140/ 90 mm Hg. The outcome was the change in LVMI and ADMA from baseline to 6 months. RESULTS: Baseline demographic and clinical characteristics did not vary between groups. After 6 months of treatment, amlodipine-based therapy induced a greater reduction in LVMI from baseline than bisoprolol-based treatment (35 ±â€Š34.2 vs 9.8 ±â€Š35.9 gm/m2; P = .017). A similar reduction in the mean BP occurred with treatment in both groups. ADMA concentration decreased significantly from baseline in the amlodipine group (0.75 ±â€Š0.73 to 0.65 ±â€Š0.67 nmol/mL; P = .001), but increased nonsignificantly in the bisoprolol group (0.64 ±â€Š0.61 to 0.78 ±â€Š0.64 nmol/mL; P = .052). CONCLUSION: This study showed that compared to a bisoprolol-based regimen, an amlodipine-based antihypertensive regimen resulted in a significantly greater reduction in LVMI and ADMA levels from baseline in hypertensive patients on HD despite similar BP reduction in both groups. These findings support the re-evaluation of amlodipine as a potential first-line antihypertensive treatment in patients on HD without previous CVD. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT04085562, registered September 2019.

Discovery of novel oxazole-based macrocycles as anti-coronaviral agents targeting SARS-CoV-2 main protease.

We have discovered a family of synthetic oxazole-based macrocycles to be active against SARS-CoV-2. The synthesis, pharmacological properties, and docking studies of the compounds are reported in this study. The structure of the new macrocycles was confirmed by NMR spectroscopy and mass spectrometry. Compounds 13, 14, and 15a-c were evaluated for their anti-SARS-CoV-2 activity on SARS-COV-2 (NRC-03-nhCoV) virus in Vero-E6 cells. Isopropyl triester 13 and triacid 14 demonstrated superior inhibitory activities against SARS-CoV-2 compared to carboxamides 15a-c. MTT cytotoxicity assays showed that the CC50 (50% cytotoxicity concentration) of 13, 14, and 15a-c ranged from 159.1 to 741.8 µM and their safety indices ranged from 2.50 to 39.1. Study of the viral inhibition via different mechanisms of action (viral adsorption, replication, or virucidal property) showed that 14 had mild virucidal (60%) and inhibitory effects on virus adsorption (66%) at 20 µM concentrations. Compound 13 displayed several inhibitory effects at three levels, but the potency of its action is primarily virucidal. The inhibitory activity of compounds 13, 14, and 15a-c against the enzyme SARS-CoV-2 Mpro was evaluated. Isopropyl triester 13 had a significant inhibition activity against SARS-CoV-2 Mpro with an IC50 of 2.58 µM. Large substituents on the macrocyclic template significantly reduced the inhibitory effects of the compounds. Study of the docking of the compounds in the SARS CoV-2-Mpro active site showed that the most potent macrocycles 13 and 14 exhibited the best fit and highest affinity for the active site binding pocket. Taken together, the present study shows that the new macrocyclic compounds constitute a new family of SARS CoV-2-Mpro inhibitors that are worth being further optimized and developed.

Novel 1,5-diaryl pyrazole-3-carboxamides as selective COX-2/sEH inhibitors with analgesic, anti-inflammatory, and lower cardiotoxicity effects.

COX-2 selective drugs have been withdrawn from the market due to cardiovascular side effects, just a few years after their discovery. As a result, a new series of 1,5-diaryl pyrazole carboxamides 19-31 was synthesized as selective COX-2/sEH inhibitors with analgesic, anti-inflammatory, and lower cardiotoxic properties. The target compounds were synthesized and tested in vitro against COX-1, COX-2, and sEH enzymes. Compounds 20, 22 and 29 exhibited the most substantial COX-2 inhibitory activity (IC50 values: 0.82-1.12 µM) and had SIs of 13, 18, and 16, respectively, (c.f. celecoxib; SI = 8). Moreover, compounds 20, 22, and 29 were the most potent dual COX-2/sEH inhibitors, with IC50 values of 0.95, 0.80, and 0.85 nM against sEH, respectively, and were more potent than the standard AUDA (IC50 = 1.2 nM). Furthermore, in vivo studies revealed that these compounds were the most active as analgesic/anti-inflammatory derivatives with a good cardioprotective profile against cardiac biomarkers and inflammatory cytokines. Finally, the most active dual inhibitors were docked inside COX-2/sEH active sites to explain their binding modes.

Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Tri-Aryl Imidazole-Benzene Sulfonamide Hybrids as Promising Selective Carbonic Anhydrase IX and XII Inhibitors.

A novel series of tri-aryl imidazole derivatives 5a-n carrying benzene sulfonamide moiety has been designed for their selective inhibitory against hCA IX and XII activity. Six compounds were found to be potent and selective CA IX inhibitors with the order of 5g > 5b > 5d > 5e > 5g > 5n (Ki = 0.3-1.3 µM, and selectivity ratio for hCA IX over hCA XII = 5-12) relative to acetazolamide (Ki = 0.03 µM, and selectivity ratio for hCA IX over hCA XII = 0.20). The previous sixth inhibitors have been further investigated for their anti-proliferative activity against four different cancer cell lines using MTT assay. Compounds 5g and 5b demonstrated higher antiproliferative activity than other tested compounds (with GI50 = 2.3 and 2.8 M, respectively) in comparison to doxorubicin (GI50 = 1.1 M). Docking studies of these two compounds adopted orientation and binding interactions with a higher liability to enter the active side pocket CA-IX selectively similar to that of ligand 9FK. Molecular modelling simulation showed good agreement with the acquired biological evaluation.

Design, synthesis, and biological evaluation of novel EGFR inhibitors containing 5-chloro-3-hydroxymethyl-indole-2-carboxamide scaffold with apoptotic antiproliferative activity.

New EGFR inhibitor series of fifteen 5-chloro-3-hydroxymethyl-indole-2-carboxamide derivatives has been designed, synthesized, and tested for antiproliferative activity against a panel of cancer cell lines. The results showed that p-substituted phenethyl derivatives 10, 11, 13, 15 and 17-19 showed superior antiproliferative activity compared to their m-substituted counterparts 12, 14, 16 and 20. Compounds 15, 16, 19 and 20 displayed promising EGFR inhibitory activity as well as an increase in caspase 3 levels. Compounds 15 and 19 increased caspase-8 and 9 levels, as well as inducing Bax and decreasing Bcl-2 protein levels. Compound 19 demonstrated cell cycle arrest at pre-G1 and G2/M phases. The results of the docking study into the active site of EGFR revealed strong fitting of the new compounds with higher binding affinities compared to erlotinib.

Wasp Venom Biochemical Components and Their Potential in Biological Applications and Nanotechnological Interventions.

Wasps, members of the order Hymenoptera, are distributed in different parts of the world, including Brazil, Thailand, Japan, Korea, and Argentina. The lifestyles of the wasps are solitary and social. Social wasps use venom as a defensive measure to protect their colonies, whereas solitary wasps use their venom to capture prey. Chemically, wasp venom possesses a wide variety of enzymes, proteins, peptides, volatile compounds, and bioactive constituents, which include phospholipase A2, antigen 5, mastoparan, and decoralin. The bioactive constituents have anticancer, antimicrobial, and anti-inflammatory effects. However, the limited quantities of wasp venom and the scarcity of advanced strategies for the synthesis of wasp venom's bioactive compounds remain a challenge facing the effective usage of wasp venom. Solid-phase peptide synthesis is currently used to prepare wasp venom peptides and their analogs such as mastoparan, anoplin, decoralin, polybia-CP, and polydim-I. The goal of the current review is to highlight the medicinal value of the wasp venom compounds, as well as limitations and possibilities. Wasp venom could be a potential and novel natural source to develop innovative pharmaceuticals and new agents for drug discovery.

Prediction of troponin I and N-terminal pro-brain natriuretic peptide levels in acute carbon monoxide poisoning using advanced electrocardiogram analysis, Alexandria, Egypt.

The study aimed at assessing the diagnostic ability of advanced electrocardiogram (ECG) analysis to predict the levels of NT-proBNP and Troponin I. ECG and the blood NT-proBNP and Troponin I were taken from 50 acutely carbon monoxide poisoned patients and 21 control subjects matched with age and sex. The severity of the studied cases was classified into mild, moderate, and severe using clinical classification. ECG parameters (RR interval, corrected QT (QTc) interval, P wave dispersion (Pwd)), and cardiac biomarkers (NT-proBNP and Troponin I) were significantly higher in cases than in control (p= 0.015, 0.008, 0.002, <0.001, and <0.001 respectively). Cut-off values resulted from combined ROC curves analysis can predict blood Troponin I more than 0.05 ng/ml and NT-proBNP more than 125 pg/ ml (with 88% and 84% accuracy respectively). In addition, two regression equations were developed using all studied ECG parameters to predict Troponin I and NT-proBNP (with 68% and 43% accuracy respectively). RR average, PR average, QRS average, QTd, QTc, and Pwd could be used to predict Troponin I and NT-proBNP levels with good accuracy in carbon monoxide poisoning patients.

Modified Ludloff's medial approach for management of Pipkin's type I femoral head fracture.

INTRODUCTION: Numerous approaches were described for the management of Pipkin's type I fracture with no consensus on the "standard of care". The strategic thinking of the ideal access is through the medial approach. MATERIAL AND METHODS: Using Ferguson intermuscular interval, prospective study was done (January 2014-2019) to evaluate radiological and functional outcomes using HHS and Thompson-Epstein criteria. Fracture patterns were subclassified: anterior and posterior-inferior (AI/PI) requiring different reduction positions. RESULTS: Twenty-one patients (mean FU = 24.3 months (range, 12-48)) were divided into 14 (67.7%) AI and seven PI. Excision was performed in five (23.8%) (AI = 3 (14.3%) and PI = 2) and ORIF in 16 (AI = 11 (52.4%) and PI = 5). At the last follow-up, two (9.5%) were graded as excellent, 11 (52.4%) as good, three (14.3%) as fair, and five as poor. CONCLUSION: Modified Ludloff's approach provides safe easy direct access to fracture allowing easy excision or direct anatomical reduction, perpendicular compression, and rigid fixation with minimal complications.

Structure-based design, synthesis, and biological evaluation of novel piperine-resveratrol hybrids as antiproliferative agents targeting SIRT-2.

A series of novel piperine-resveratrol hybrids 5a-h was designed, synthesized, and structurally elucidated by IR, and 1H, 13C, and 19F NMR. Antiproliferative activities of 5a-h were evaluated by NCI against sixty cancer cell lines. Compound 5b, possessing resveratrol pharmacophoric phenolic moieties, showed a complete cell death against leukemia HL-60 (TB) and Breast cancer MDA-MB-468 with growth inhibition percentage of -0.49 and -2.83, respectively. In addition, 5b recorded significant activity against the other cancer cell lines with growth inhibition percentage between 80 to 95. New 5a-h hybrids were evaluated for their inhibitory activities against Sirt-1 and Sirt-2 as molecular targets for their antiproliferative action. Results showed that compounds 5a-h were more potent inhibitors of Sirt-2 than Sirt-1 at 5 µm and 50 µm. Compound 5b showed the strongest inhibition of Sirt-2 (78 ± 3% and 26 ± 3% inhibition at 50 µM and 5 µM, respectively). Investigation of intermolecular interaction via Hirschfeld surface analysis indicates that these close contacts are mainly ascribed to the O-H⋯O hydrogen bonding. To get insights into the Sirt-2 inhibitory mechanism, a docking study was performed where 5b was found to fit nicely inside both extended C-pocket and selectivity pocket and could compete with the substrate acyl-Lys. Another possible binding pattern showed that 5b could act by partial occlusion of the NAD+ C-pocket. Collectively, these findings would contribute significantly to better understanding the Sirt-2 inhibitory mechanism in order to develop a new generation of refined and selective Sirt-2 inhibitors.

Symphyseal plate with trans-symphyseal cross-screws for fixation of tile-type B1 pelvic ring injuries: radiological and functional evaluation.

INTRODUCTION: Failure to neutralize the different physiological forces acting on the inferior as well as the superior regions of the pubic symphysis, the long healing time, is blamed for the repeated failures of conventional superior symphyseal plating. MATERIAL AND METHODS: A three years prospective case series study between January 2017 and December 2019 was done, to evaluate the radiological and the functional outcomes, using Matta/Tornetta and Majeed criteria respectively, of the combination of trans-symphyseal cross-screws configuration and superior symphyseal plate in Tile-type B1 pelvic injuries. RESULTS: Thirty patients, 18 with anteroposterior compression type II and 12 with type III, with a mean follow-up of 20 months ±5 were included. Radiologically, 26 (86.6%) cases showed an excellent, one (3.3%) good and three (10%) fair outcome. Clinically, excellent outcome in 26 (86.6%) cases, good in two (6.6%) cases, and fair in two (6.6%). Intra-operative drill bit breakage occurred in three (10%) cases and was the only reported technical complication. Significant re-displacement was reported in three (10%) cases. CONCLUSION: The open trans-symphyseal cross-screws for fixation of the superior symphyseal plate is a simple, efficient, and safe technique with the biomechanical advantages of an extra-fixation point to the inferior symphysis together with a long and a strong bony anchorage.

Discovery of novel urea-diarylpyrazole hybrids as dual COX-2/sEH inhibitors with improved anti-inflammatory activity and highly reduced cardiovascular risks.

Herein we describe our efforts to develop novel anti-inflammatory/analgesic agents devoid of known cardiovascular drawbacks. In doing so, two 1,5-diarylpyrazole series of urea linked (9a-f) and amide linked (11a-f) compounds were synthesized and evaluated in vitro as dual COX-2/sEH inhibitors using recombinant enzyme assays. The in vivo anti-inflammatory and analgesic activities were then examined using reported animal models. Compounds 9b and 9c showed the highest inhibitory activities against both COX-2 and sEH (IC50 of COX-2 = 1.85 and 1.24 µM; sEH = 0.55 and 0.40 nM, respectively), besides showing the best activity as anti-inflammatory agents. Interestingly, the cardiovascular profile of the two compounds 9b and 9c was evaluated through measuring some biochemical parameters such as prostacyclin (PGI2), lactate dehydrogenase (LDH), troponin-1 (Tn-1), tumor necrosis factor- α (TNF-α), creatine kinase-M (CK-M) and reduced glutathione (GSH) in addition to a histo-pathological study to investigate the changes in the heart muscle. The results confirmed that compounds 9b and 9c have a more favorable cardio-profile than celecoxib with much less cardiovascular risks associated with the common selective COX-2 inhibitors. Finally, the current work provided a promising approach that can be optimized to serve as a lead project to overcome the cardiovascular toxicity related to the traditional selective COX-2 inhibitors.