Pharmacology Research & Perspectives

BackgroundThe CXCR2 receptor pathway plays a major role in inflammatory and invasive angiogenesis in human disease. ObjectiveWe evaluated AZD5069, a selective CXCR2 antagonist, as an angiogenesis inhibitor in human cell culture. MethodsHuman Umbilical Venous Endothelial Cells (HUVECs), Human Aortic Endothelial Cells (HAECs), and Human Pulmonary Artery Endothelial Cells (HPAECs) were cultured with standard in vitro techniques. AZD5069 (0, 8, 16, 32, 64, 128, 256 M) was evaluated as an angiogenesis inhibitor with fluorescent-labeled 5-Ethynyl-2-deoxyuridine (EdU) uptake to quantify endothelial cell proliferation, scratch assay to quantify endothelial cell migration, and Geltrex assay to quantify endothelial cell tubule and hub formation. AZD5069 cytotoxicity was evaluated with in situ terminal deoxynucleotidyl transferase 2-Deoxyuridine triphosphate- 5 (dUTP) nick-end labeling (TUNEL) to quantify apoptosis and membrane-impermeable cyanine dye uptake to quantify necrotic cell death. ResultsAZD5069 significantly reduced HUVEC, HAEC, and HPAEC proliferation, migration, tubule count, total tubule length, and node count with a dose-response. AZD5069 did not cause apoptosis nor necrotic cell death. ConclusionsAZD5069 inhibited angiogenesis without cytotoxicity in human endothelial cell culture. The endothelial cell CXCR2 receptor pathway may be a novel target for anti-angiogenesis therapy. AZD5069 may have clinical utility in cardiovascular, oncologic, and inflammatory disease. Condensed AbstractThe CXCR2 receptor pathway plays a major role regulating angiogenesis in inflammation and cancer. The CXCR2 receptor pathway has been evaluated in humans as a target for therapy in inflammatory disease and cancer but not as a therapeutic approach to block pathologic angiogenesis. AZD5069 is a clinical stage, direct CXCR2 antagonist. In human endothelial cell culture, AZD5069 inhibited angiogenesis without causing apoptosis or necrotic cell death. The endothelial cell CXCR2 receptor pathway may be a novel target for anti-angiogenesis therapy. AZD5069 may have clinical utility as a novel angiogenesis blocker in human disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/731993v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1ac8fb4org.highwire.dtl.DTLVardef@ea89forg.highwire.dtl.DTLVardef@607f94org.highwire.dtl.DTLVardef@157cec4_HPS_FORMAT_FIGEXP M_FIG Visual Abstract: AZD5069, a selective CXCR2 antagonist, significantly reduced endothelial cell proliferation, migration, and vascular tubule formation without causing necrotic or apoptotic cell death. The endothelial cell CXCR2 receptor pathway may be a novel target for anti-angiogenesis therapy. AZD5069 may have clinical utility in human cardiovascular, oncologic, and inflammatory disease with pathologic, dysregulated, or excessive angiogenesis. C_FIG

ObjectivesTo evaluate supply-chain vulnerabilities affecting medications essential for treating sexually transmitted infection in the United States and identify disruption mechanisms that may predispose these therapies to shortages. MethodsWe conducted a qualitative, structured supply-chain vulnerability assessment of first-line medications for five priority sexually transmitted pathogens recommended by the Centers for Disease Control and Prevention and the World Health Organization: azithromycin, doxycycline, ceftriaxone, benzathine penicillin G, metronidazole, tinidazole, acyclovir, and cefixime. Using a predefined framework derived from pharmaceutical supply-chain disruption literature, we evaluated 13 disruption categories spanning raw material sourcing, active pharmaceutical ingredient production, manufacturing, distribution, market dynamics, information systems, and post-distribution loss mechanisms. Each category was assessed using four binary indicators and classified as relevant when at least two criteria were satisfied. ResultsMultiple disruption domains applied across the drug set. Recurrent vulnerabilities included geographically concentrated active pharmaceutical ingredient production, limited manufacturing redundancy in low-margin generic markets, manufacturing constraints affecting sterile injectable products, reliance on consolidated distribution networks, and susceptibility to demand surges and information-system disruptions. All eight drugs exhibited at least one regulatory or market signal consistent with potential supply vulnerability, including documented shortages, product discontinuations, or limited manufacturer participation. ConclusionsSupply-chain vulnerabilities were identified across multiple first-line sexually transmitted infection therapies, indicating that disruption risk is not confined to a single drug. There is a need for policy interventions to strengthen supply-chain resilience, including diversification of active pharmaceutical ingredient sourcing and distribution networks, as well as incentives for sustainable generic production.

ABSTRACT Background: Self medication with analgesics and non steroidal anti inflammatory drugs (NSAIDs) is common in low- and middle income countries and may expose users to preventable adverse outcomes. Evidence from Guinea remains scarce. This study aimed to estimate the prevalence of self medication with analgesics and NSAIDs among pharmacy clients in urban Conakry, identify associated factors, and describe clinical risk situations. Methods: We conducted a pharmacy based analytical cross sectional study in 30 private pharmacies across Conakry, Guinea. A total of 1,032 participants seeking analgesics or NSAIDs were enrolled between November 3, 2012, and April 5, 2013. Self-medication was defined as acquisition or use without a valid medical prescription. Factors associated with self-medication were analysed using multivariable logistic regression. Results: Among 1,032 participants, 603 reported self medication (prevalence 58.4%). Previous unsupervised use was reported by 78.7%. The most frequently used medicines were paracetamol (56.9%, n=587), diclofenac (21.3%, n=220), ibuprofen (17.9%, n=185), and aspirin (3.9%, n=40). Overall, 68.0% (n=702) reported no knowledge of potential adverse effects. Clinical risk situations were frequent: gastrointestinal disorders (41.3%, n=426), hypertension (9.2%, n=95), and pregnancy exposure among reproductive age women (26.0%). In multivariable analysis, self medication was independently associated with previous analgesic/NSAID use (aOR = 2.8, 95% CI: 2.1 to 3.6), lack of knowledge of adverse effects (aOR = 1.9, 95% CI: 1.4 to 2.5), informal occupation (aOR = 1.6, 95% CI: 1.2 to 2.2), and age 18 to 59 years (aOR = 1.5, 95% CI: 1.1 to 2.1). Conclusions: In this pharmacy based study conducted in urban Conakry, self medication with analgesics and NSAIDs was common and frequently associated with limited awareness of potential adverse effects. These findings support the need for strengthened pharmaceutical regulation, pharmacist-led counselling, health literacy interventions, and improved access to primary care. Keywords: self medication; analgesics; NSAIDs; paracetamol; diclofenac; ibuprofen; pharmacy; Guinea; Conakry; drug safety; public health.

Introduction: Adverse drug withdrawal events (ADWEs) are a key safety concern with deprescribing but are infrequently reported in trials. Although pharmacovigilance systems have advanced our understanding of medication-related harms, it is unclear how extensively these systems have been used for ADWEs. Objectives: To examine the reporting patterns of ADWEs for all drugs recorded in United States and European pharmacovigilance databases between 2004 and 2023. Methods: A retrospective study was conducted using two pharmacovigilance databases, the publicly available FDA-FAERS dataset and EMA-EV Level 2A (individual-level) dataset. ADWE cases were identified using relevant MedDRA preferred terms. Data on patient characteristics, reporter type, drugs, indication, ADWE outcomes, dechallenge/rechallenge, seriousness criteria, time to onset, duration, and causality were summarised. Results: A total of 158,505 ADWE reports were analysed (FDA-FAERS: 145,514; EMA-EV: 12,987), with mean ages of 46.1 (FDA; 55.3% female) and 45.5 years (EMA; 57.1% female). The frequently reported drug classes were opioids (FDA: oxycodone, 29.8%; EMA: buprenorphine, 19%), antidepressants (FDA: duloxetine, 32%; EMA: venlafaxine, 25.9%) and gabapentinoids (FDA: pregabalin, 6.7%; EMA: pregabalin, 6.0%). The most common adverse outcomes were other serious medical conditions (FDA=63.9%; EMA=46.0%), hospitalisation (FDA=15.9%; EMA=28.3%), and disability (FDA=13.3%; EMA=6.2%) and these outcomes varied significantly based on sex and age group (p<0.05). Conclusions: This study provides novel evidence of reporting patterns and characteristics of ADWEs across drugs in pharmacovigilance data. These findings emphasise that adverse drug reaction reporting systems need to accommodate ADWEs (i.e., clarity on terminologies, dechallenge/rechallenge, causality assessment) to effectively capture ADWE-related data to support evidence-based deprescribing practices for better patient safety

3:(-)-trans-Cannabidiol ((-)-CBD) is a principal phytocannabinoid from Cannabis sativa. (-)-CBD has complex pharmacology but is a relatively weak inhibitor of CB1 and CB2 receptor signalling. Cannabidiol has two chiral centres and thus four stereoisomers. (+)-trans-CBD ((+)-CBD) has a higher affinity than (-)-CBD at CB1 and CB2, but its pharmacodynamic effects at these receptors are incompletely described. We examined the activity of (+)-CBD at human CB1 and CB2 receptors using a fluorescence-based assay of membrane potential in AtT20 cells stably expressing CB1 or CB2 receptors. (+)-CBD produced a rapid, concentration-dependent hyperpolarization in CB2-expressing cells (pEC50 6.63 {+/-} 0.08) with a maximal effect [~]90% of the response to CP55940. The CB2 response was blocked by pertussis toxin pretreatment and competitively inhibited by the CB2 antagonist AM630 (Schild slope 1.1 {+/-} 0.1). (+)-CBD was a low-efficacy, low-potency CB1 agonist and inhibited somatostatin-receptor effects at high concentrations (10-30 {micro}M). It had no effect on the membrane potential of AtT20 wild-type cells. In silico modelling of ligand interactions with CB2 indicated that (+)-CBD but not (-)-CBD formed an H-bond with Ser285, a residue crucial for agonist activation of CB2. Our data suggests (+)-CBD acted as a CB2 agonist via the orthosteric binding site on the receptor. Synthetic CBD, including (+)-CBD, has previously been administered in clinical trials, presumably without consideration of its potential CB2 agonist activity. Given the relative safety of (-)-CBD in people, (+)-CBD may be a useful drug to explore CB2-sensitive disease states, should it prove similarly safe.

Abstract Background: Acute postoperative pain affects more than 80% of surgical patients, with orthopedic lower limb procedures consistently associated with severe pain intensity and high opioid requirements. Preemptive analgesia with oral agents has been proposed to attenuate central and peripheral sensitization prior to surgical incision. Tapentadol, a dual-mechanism -opioid receptor agonist and norepinephrine reuptake inhibitor, and pregabalin, a voltage-gated calcium channel modulator, represent pharmacologically distinct premedication options; however, direct comparative data in this surgical context are lacking. This pilot randomized controlled trial aimed to compare the analgesic efficacy and safety of 72-hour oral premedication with tapentadol versus pregabalin in patients undergoing elective lower limb surgery under neuraxial anesthesia. Methods: In this double-blind, parallel-group pilot trial, 46 patients scheduled for elective lower limb surgery under neuraxial anesthesia were randomized equally to receive tapentadol 50mg orally every 12 hours (Group A, n = 23) or pregabalin 75mg orally every 24 hours (Group B, n = 23), initiated 72 hours before surgical incision. The primary outcome was postoperative pain intensity assessed using the Numeric Rating Scale (NRS, 0-10) at post-anesthesia care unit (PACU) arrival (T0) and at 30 (T1), 60 (T2), 90 (T3), and 120 (T4) minutes thereafter. Secondary outcomes included Verbal Rating Scale (VRS) scores, rescue morphine consumption, and safety. The primary longitudinal analysis used a linear mixed model (LMM) with Group, Time, and Group x Time interaction as fixed effects and a random intercept per patient; between-group contrasts at each timepoint were derived from estimated marginal means with Holm correction. Effect sizes are reported as Cohen's d. Results: All 46 patients completed the study with no missing data. Both groups were pain-free at T0 (NRS=0). Pain scores diverged progressively from T1 onward, with the pregabalin group reporting consistently higher NRS values at every time point. The LMM revealed a significant main effect of Time (F4,181.6 = 23.61, p < 0.001) and a borderline-significant Group x Time interaction in the continuous-time sensitivity model (F1,187.6 = 3.79, p = 0.053). Post-hoc contrasts identified a statistically significant, large effect between-group difference at T3 (mean NRS difference -0.91, p = 0.006, Cohen's d = -0.96) and a medium-effect trend at T2 (d = -0.59, p = 0.089). Rescue analgesia was required by 4.3% of tapentadol patients versus 21.7% of pregabalin patients. Nausea and vomiting were equally present in both groups (17.4%). No hypersensitivity reactions were observed in either arm. Conclusions: Seventy-two-hour oral premedication with tapentadol 100mg/day provided superior postoperative analgesia compared with pregabalin 75 mg/day at the 90-minute PACU time point, with a large effect size and a fivefold reduction in rescue analgesia requirements. Both agents were well tolerated. These pilot data support the conduct of a fully powered, multicenter randomized controlled trial to confirm the analgesic superiority of tapentadol premedication in orthopedic lower limb surgery.

Background: Orthopedic surgeries are associated with significant intraoperative and postoperative pain, necessitating effective anesthesia strategies. Spinal anesthesia is commonly used for lower limb procedures due to its rapid onset and reliability; however, its limited duration may compromise prolonged surgical procedures and early postoperative pain control. Adjuvants such as dexamethasone have been explored to enhance and prolong the effects of local anesthetics. While evidence supports its efficacy, data from low-resource settings remain limited. Objective: To assess the effect of intrathecal dexamethasone as an adjuvant to bupivacaine on sensory block duration, time to first postoperative analgesia, and postoperative pain in patients undergoing lower limb orthopedic surgery at KCMC. Methodology: A randomized, double-blind controlled trial was conducted among 96 adult patients undergoing elective lower limb orthopedic surgery under spinal anesthesia. Participants were allocated using a computer-generated randomization sequence to receive either bupivacaine 15 mg with dexamethasone 4 mg (intervention group) or bupivacaine 15 mg with 1 ml normal saline (control group). Outcomes included sensory and motor block duration, time to first postoperative analgesia, and postoperative pain scores. Results: The dexamethasone group demonstrated a significantly prolonged sensory block duration (231 +/- 6 vs. 156 +/- 9 minutes; mean difference 75.11 minutes, 95% CI: 71.92-78.29; p < 0.001) and delayed time to first postoperative analgesia (252 +/- 7 vs. 181 +/- 7 minutes; mean difference 71.89 minutes, 95% CI: 68.91-74.86; p < 0.001). Motor block duration was also significantly longer (184 +/- 7 vs. 130 +/- 5 minutes; mean difference 53.42 minutes, 95% CI: 50.99-55.85; p < 0.001). Postoperative pain scores were significantly lower at 1 hour (mean difference -1.29 points, 95% CI: -1.52 to -1.05; p < 0.001) and at 2 hours (mean difference -1.97 points, 95% CI: -2.21 to -1.73; p < 0.001). Intraoperative opioid and benzodiazepine use were significantly reduced in the intervention group. Conclusion: The addition of intrathecal dexamethasone to bupivacaine significantly enhances sensory block duration, delays postoperative analgesia need, and improves early pain control. These findings support its use as a potentially practical adjuvant in resource-limited settings.

Background: Post-dural puncture headache (PDPH) affects up to 11.2% of patients after neuraxial anesthesia. The sphenopalatine ganglion block (SPGB) is a promising minimally invasive intervention, but high-quality randomized trial data are limited. We conducted a pilot randomized controlled trial to assess feasibility and inform a future definitive trial. Methods: Twenty-six patients with PDPH following accidental dural puncture with 17G Tuohy needles were randomized to conservative management (bed rest, hydration) or SPGB (bilateral intranasal 2% lidocaine). Primary outcomes were feasibility (recruitment, retention, protocol adherence). Secondary outcomes included pain intensity (Numeric Rating Scale, NRS 0-10) at 30 minutes, 12 hours, and 24 hours; rescue analgesia requirements; mobilization time; and adverse events. Results: Feasibility was confirmed: 100% recruitment of target sample, 100% retention, 100% protocol adherence. At 30 minutes, all SPGB patients reported complete pain resolution (NRS=0) versus median NRS 3 (IQR 2) in controls (p<0.001), though this finding is limited by lack of blinding and baseline assessment. No SPGB patients required rescue analgesia or experienced adverse events. Conservative group patients had prolonged hospitalization (46%). Sample size calculation for a definitive trial (90% power, =0.05) yields 120 participants (60/group). Conclusions: A definitive RCT comparing SPGB to conservative management for PDPH is feasible. Preliminary efficacy data suggest rapid analgesia with SPGB, but rigorous confirmation in a sham-controlled trial is required. Trial registration: ClinicalTrials.gov -NCT07494383 (retrospectively registered). Keywords: Post-dural puncture headache, sphenopalatine ganglion block, pilot study, feasibility, regional anesthesia, randomized controlled trial

BackgroundNeuropathic pain is a major source of disability and distress with few pharmacological options for treatment. Opioid drugs can be effective, but high doses are needed, leading to unwanted effects. BMS-986122 is a positive allosteric modulator of the mu opioid receptor that potentiates acute opioid antinociception without increasing opioid-induced constipation, reward, or respiratory depression. Therefore, we asked if BMS-986122 could increase the effects of low-dose opioid analgesics in chronic neuropathic pain. MethodsWe employed the spared nerve injury and tibial neuroma models in rats and assessed the tactile hypersensitivity of the hind paw and site of neuroma, respectively. ResultsAdministration of low doses of (R)-methadone, morphine, or buprenorphine slightly reduced the tactile hypersensitivity of the hind paw the in spared nerve injury model. Pretreatment with BMS-986122 significantly enhanced the reversal of hypersensitivity, reaching the effect of high-dose gabapentin, a standard of care in neuropathic pain. Pretreatment with BMS-986122 similarly increased the anti-allodynic effects of low dose (R)-methadone on neuroma pain. A similar effect of (R)-methadone in the absence of BMS-986122 was only observed at a dose where respiratory distress was seen. ConclusionsThese findings show that allosteric modulators of the mu opioid receptor such as BMS-986122 can enhance opioid activity that could translate to a safe and effective treatment for chronic neuropathic pain.

ABSTRACT Background: Post-traumatic elbow stiffness is a recognised complication following orthopaedic trauma surgery, occurring in 10-15% of trauma patients sustaining injuries. Pain remains the primary barrier to physiotherapy compliance, with surgical arthrolysis carrying recurrence rates of up to 34%. The supraclavicular brachial plexus block, referred to as the 'spinal of the arm', provides anaesthesia and analgesia to the entire upper limb below the shoulder. A structured non-surgical approach combining continuous catheter analgesia with timed rehabilitation was identified as an unmet need in this patient group. Methods: A single-centre retrospective observational study was conducted on data of patients treated for post-surgical upper limb stiffness between January 2022 and April 2026. Of 30 patients identified, 28 with elbow involvement formed the primary analysis group following exclusion of 2 patients with isolated wrist stiffness and complex regional pain syndrome. Ultrasound- guided supraclavicular brachial plexus catheters were inserted using the Contiplex system. Patients received 0.5% Bupivacaine (10-15ml) for initial blockade, followed by daily top-up doses of 0.2% Ropivacaine(20ml) given 30 minutes prior to structured physiotherapy and CPM sessions for up to 5 days. The primary outcome was change in arc of elbow motion in degrees, measured by the attending orthopaedic consultant using standard goniometry. Results: Complete pre- and post- intervention data were available for all 28 patients. Mean pre-intervention arc of elbow motion was 39.1{degrees}(SD+/-23.2{degrees}), improving to 104.2{degrees}(SD+/- 30.0{degrees}) post-intervention. Mean improvement was 65.1{degrees}(SD+/- 30.6{degrees} ); 95% CI 53.8{degrees} to 76.4{degrees} ; range 10{degrees}-140{degrees} ; paired t-test t=-11.27, p<0.0001). Mean catheter duration was 5.2 days (SD+/- 1.3). Five patients (17.9%) experienced mechanical catheter complications- 3 dislodgements, 1 kinking and 1 block failure- with no episodes of Local Anaesthetic Systemic toxicity, infection or neurological deficit. Conclusion: Continuous supraclavicular brachial plexus catheter analgesia represents a promising, minimally invasive rehabilitation tool for post-surgical elbow stiffness - achieving statistically and clinically meaningful Range of Motion (ROM) improvement through targeted regional analgesia, without the need for surgical intervention. These findings support prospective evaluation of this protocol as a primary non-surgical rehabilitation strategy.

Effective postoperative pain control is essential following laparoscopic cholecystectomy, yet the analgesic value of a standardised 150 mg preoperative dose of pregabalin has not been clearly established. This systematic review and meta-analysis synthesised evidence from seven randomised controlled trials published between 2008 and 2025 to evaluate the efficacy and safety of pregabalin when administered before surgery. Four trials reported 24-hour postoperative pain scores, and pooled analysis demonstrated that pregabalin significantly reduced pain compared with control (SMD = 0.80 lower; 95% CI, 1.42 to 0.18 lower; p = 0.01), although statistical heterogeneity was high (I-squared = 81%). Pregabalin also produced notable reductions in opioid consumption, including fentanyl (SMD = 1.24 lower; p = 0.002) and tramadol (SMD = 4.21 lower; p = 0.002), again with considerable variability across studies. Sedation was slightly increased but did not reach statistical significance, and there were no significant differences in postoperative nausea, vomiting, or headache. Sensitivity analyses supported the stability of these findings. Overall, the results indicate that a single 150 mg preoperative dose of pregabalin meaningfully reduces postoperative pain and opioid requirements following laparoscopic cholecystectomy while maintaining an acceptable safety profile, supporting its use as part of a multimodal analgesic strategy.

Background & Aims: Activation of apoptosis signal-regulating kinase 1 (ASK1), a ubiquitous redox-sensitive kinase, results in inflammation, apoptosis, and fibrosis, key common pathways in human liver disease. SRT-015 is a novel, small molecule inhibitor of ASK1. This study evaluated the in vitro efficacy of SRT-015, compared it to other ASK1 inhibitors, and determined the in vivo efficacy of SRT-015 across multiple acute and chronic liver disease models. Methods: In vitro studies determined the kinase potency and selectivity of SRT-015, and cellular studies were used to demonstrate direct mechanisms of action. The cardiac hERG channel inhibition was assessed and PK determined in rodents and nonhuman primates. In vivo studies evaluated SRT-015 efficacy in rodent models of drug-induced hepatotoxicity (acetaminophen (APAP) overdose), alcohol-associated liver disease (ALD), metabolic-disease associated steatohepatitis (MASH) and cholestatic disease (bile duct ligation, BDL). Results: SRT-015, was demonstrated a selective ASK1 kinase, and SRT-015 treatment directly inhibited fibrosis, apoptosis and inflammation in activated human fibroblasts, hepatocytes and PBMCs, respectively without safety signals or hERG inhibition. Other ASK1 inhibitors had safety concerns or limited functional activity. Liver and kidney selective PK were observed for SRT-015 in all species evaluated. In vivo, SRT-015 treatment was efficacious in the acute mouse APAP overdose and ALD model significantly (P<0.05) decreasing serum ALT. Using a therapeutic diet-induced obesity (DIO)-MASH model with biopsy-verified fibrosis, SRT-015 treatment significantly (P<0.05) inhibited DIO-induced liver enzymes, hepatomegaly, fibrosis, inflammation, and apoptosis independent of body weight loss whereas treatment with selonsertib was ineffective. In a rat cholestatic model, SRT-015 treatment significantly (P<0.05) decreased fibrosis and stellate cell activation. Conclusions: These findings support SRT-015 as a potential therapeutic for human liver diseases of any etiology.

BACKGROUND: Caudal block is widely employed in pediatric lower abdominal surgeries and adult anorectal surgical by its simplicity of operation, reliable efficacy, and high safety. Previous studies have found that the dose of ropivacaine for Caudal block in adults exhibits gender differences. However, it remains unclear whether such differences in the median effective concentration (EC50) of ropivacaine also exist in the elderly population . METHODS: This is a double-blind, prospective study, We enrolled patients aged 60-80 years with ASA physical status I-? who were scheduled for anorectal surgery under caudal anesthesia, and allocated them to 2 study groups according to their gender. Each participant received a single injection of 20mL ropivacaine. Using Dixons up-and-down sequential allocation, the initial concentration of ropivacaine was set at 0.35% and the subsequent concentrations were determined by the analgesic response of the previous patients to the pinprick testing. The concentration change was 0.025%. The EC50 of ropivacaine in each group was determined using the the up-and-down method and probit regression. The primary outcome was the EC50 (95% confidence interval [CI]) of the 2 groups. Data on the surgical time, analgesic duration, and adverse events during surgery were also recorded. RESULTS: This study included a total of 40 elderly patients (20 male and 20 female). The EC50 of ropivacaine for caudal block in elderly male patients was 0.263% (95% CI: 0.179%-0.311%), while that in elderly female patients was 0.281% (95% CI: 0.161%-0.353%). The EC50 of ropivacaine for caudal block in elderly female patients was approximately 6.4% higher than that in elderly male patients. CONCLUSIONS: There is a significant gender difference in the EC50 of ropivacaine for caudal block among the elderly, with elderly female requiring a higher EC50 than male.

BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) and weak opioids such as tramadol are cornerstones of multimodal analgesia, particu-larly in settings with limited access to potent opioids. However, cross-class equianalgesic data comparing these agents remain scarce. This pilot ran-domised controlled trial aimed to explore the analgesic equivalence of ke-torolac, diclofenac, and tramadol administered as premedication in patients undergoing minimally invasive surgery. MethodsIn this double-blind, parallel-group pilot trial, 30 patients scheduled for elective minimally invasive surgery (28 laparoscopic cholecys-tectomies, 2 laparoscopic abdominal wall repairs) under balanced general anaesthesia were randomised to receive intravenous tramadol 150 mg, ke-torolac 60 mg, or diclofenac 150 mg 45 minutes before skin incision. The primary outcome was pain intensity measured using the Numerical Rating Scale (NRS, 0-10) at recovery room arrival (T0) and at 30 (T1), 60 (T2), and 90 (T3) minutes thereafter. Secondary outcomes included Verbal Rating Scale (VRS) scores, rescue morphine consumption, and safety. Between-group comparisons were performed using Kruskal-Wallis tests with Dunn post-hoc corrections; within-group trajectories were analysed using Fried-man tests. Effect sizes were estimated with epsilon-squared and Kendalls W. ResultsAll 30 patients completed the study. At T0 and T1, NRS scores were higher in the ketorolac group (median 1.5 and 3, respectively) compared with tramadol and diclofenac (both median 0 at T0; T1: tramadol 1, diclofenac 2; p < 0.05 for both). However, by T2 and T3, all three groups converged to a median NRS of 2 (p > 0.05 for between-group differences). Rescue analgesia requirements at T1 were 0/10 (tramadol), 3/10 (ketorolac), and 2/10 (diclofenac), with no statistically significant differences (p = 0.19). No hypersensitivity reactions occurred. Within-group analyses showed con-sistent pain trajectories, with Kendalls W ranging from 0.31 (ketorolac) to 0.64 (tramadol). ConclusionsIn this pilot study, equianalgesic doses of tramadol, ke-torolac, and diclofenac provided comparable postoperative pain control over 90 minutes following minimally invasive surgery. All agents were well toler-ated. These findings support the feasibility of a larger definitive trial and offer clinically useful guidance for analgesic selection in resource-limited settings. Trial registrationClinicalTrials.gov - NCT07500454 (retrospectively registered). HighlightsO_LIDouble-blind pilot RCT compared equianalgesic doses of tramadol, ke-torolac, and diclofenac. C_LIO_LIAll three groups converged to median NRS 2 by 60 minutes postoper-atively. C_LIO_LIEarly higher pain in the ketorolac group was partly attributed to age imbalance ({rho}=0.49, p=0.006). C_LIO_LINo hypersensitivity reactions occurred in any group. C_LIO_LIDefinitive trial requires 27 patients per group (90 total with 10% attri-tion). C_LI

Mocravimod (KRP203) is a selective sphingosine 1-phosphate (S1P) receptor modulator currently in development for patients with haematological malignancies undergoing allogenic haematopoietic cell transplantation (HCT). This first-in-human, randomised, double-blind, placebo-controlled, single ascending oral dose study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of mocravimod in 136 healthy adult participants (EudraCT No. 2006-006814-13). Participants received single doses ranging from 0.01 to 40 mg or placebo, with a cohort dedicated to studying food-effect at 3 mg. Mocravimod demonstrated slow absorption (mean Tmax 6-11 hrs), extensive distribution, and a long terminal half-life (91-132 hrs). Exposure increased dose-proportionally for doses [&ge;]2 mg. The most common adverse events were headache, dizziness, and fatigue, all graded as mild or moderate; no serious adverse events or deaths occurred. Mocravimod-phosphate induced robust, dose-dependent reductions in lymphocyte counts, with significant decreases at doses [&ge;]2 mg and recovery to baseline observed in all but the highest dose groups. Cardiac effects included transient bradycardia and benign second-degree atrioventricular (AV) block at higher doses, without clinically significant arrhythmias. Food intake had minimal impact on PK. No clinically meaningful changes in pulmonary function or laboratory safety signals were detected. These results indicate that single oral doses of mocravimod up to 40 mg are safe and well tolerated in healthy adults, with predictable PK and expected PD effects. The findings support further clinical development of mocravimod as a targeted immunomodulator in settings such as allogeneic HCT for haematological malignancies.

BackgroundThe discontinuation of Fasiglifam (TAK-875), a GPR40/FFAR1 full agonist, during Phase 3 clinical trials due to hepatotoxicity led to widespread abandonment of GPR40 as a viable therapeutic target for type 2 diabetes mellitus (T2DM). However, mechanistic evidence suggests that Fasiglifams hepatotoxicity arises from mitochondrial liability driven by high lipophilicity (aLogP = 5.31), rather than from on-target GPR40 signaling. We hypothesized that target-level failure was incorrectly inferred from compound-level safety concerns, and that superior candidates exist within publicly available databases. MethodsWe queried ChEMBL Release 36 (28 GB SQLite, 74 tables) for all compounds with documented GPR40/FFAR1 activity (UniProt: O14842). Compounds were filtered by EC50 [&le;] 10 nM in nM units with standard relation "=". Drug-likeness was assessed using Lipinskis Rule of Five (Ro5), aLogP, molecular weight (MW), hydrogen bond donors/acceptors (HBD/HBA), and polar surface area (PSA). A parallel analysis of Therapeutic Target Database (TTD v10.1.01, 4,298 targets) provided clinical context. A real-world evidence (RWE) patient stratification framework was constructed using EMR data from tens of millions of patients with >10 years of longitudinal follow-up. ResultsOf 2,637 GPR40-active compounds in ChEMBL 36, 526 (19.9%) demonstrated EC50 < 100 nM and 102 (3.9%) demonstrated EC50 < 10 nM. Eight compounds met stringent drug-likeness criteria (Ro5 violations = 0, aLogP < 5.0, EC50 [&le;] 1 nM). The lead compound (CHEMBL4859651) exhibited EC50 = 0.04 nM (8.75-fold more potent than Fasiglifam), MW = 297 Da (43% lower), and aLogP = 4.30 (19% lower), with zero Ro5 violations. Mean MW of the eight candidates was 317 {+/-} 28 Da versus 524 Da for Fasiglifam. A parallel GCK analysis identified a protein-protein interaction target (CHEMBL3885579, GCK-GKRP interface) harboring 40 exclusive compounds as an orthogonal strategy for partial GCK activation. ConclusionsSystematic cheminformatic analysis reveals that compounds with substantially superior activity and drug-likeness profiles relative to Fasiglifam exist within ChEMBL 36. Fasiglifams hepatotoxicity is attributable to compound-specific physicochemical properties, not GPR40-mediated toxicity. RWE patient stratification may further mitigate hepatotoxicity risk for next-generation GPR40 agonists. These findings argue for systematic reappraisal of GPR40 as a viable therapeutic target for T2DM.

Introduction: Progressive multiple sclerosis (MS), including primary progressive MS (PPMS) and non-active secondary progressive MS (nSPMS), remains an unmet need, as few treatments target innate immune pathways. Masitinib (AB1010) is a selective tyrosine kinase inhibitor that targets c-Kit and colony-stimulating factor 1 receptor pathways. This mechanism disrupts mast cell-microglia interactions, key innate immune effectors in progressive MS pathogenesis, reducing neuroinflammation and neuronal damage. In the phase 3 AB07002 trial, masitinib (4.5 mg/kg/d) over 96 weeks met its primary endpoint. Comparable signals in PPMS and nSPMS indicated masitinib benefited both phenotypes. Secondary analyses showed that masitinib lowered the progression to wheelchair dependence (EDSS [&ge;]7, 12 weeks) and reduced the 12-week confirmed EDSS progression risk by 37% versus placebo, although the results were underpowered for these endpoints. Methods: This study aimed to confirm that oral masitinib achieves central nervous system (CNS) concentrations sufficient to modulate CSF1R and wild-type c-Kit, thereby underpinning its neuroprotective potential. Male Sprague Dawley rats (n=12, ~200 g) were administered a single oral dose (30 mg/kg). Plasma and brain samples were collected at 2, 4, 8, and 24 hours post-dose (n=3 per time point). Masitinib (AB1010) and its metabolite (AB3280) were quantified in plasma and brain homogenates using LC-MS/MS. Results: Masitinib reached a brain Cmax of 223.5 ng/mL (~450 nM), exceeding IC50 values for CSF1R and wild-type c-KIT by ~5-fold and 2-fold, respectively, indicating effective CNS target engagement. The active metabolite AB3280 also achieved brain Cmax levels with full inhibitory activity. Masitinib demonstrated consistent CNS penetration supported by a proportional plasma-to-brain exposure relationship. Conclusion: The favorable CNS penetration and safety profile of masitinib, alongside its unique mast cell inhibition, position it as a compelling candidate for progressive MS treatment, either as monotherapy or in combination with other agents. This multifaceted immunomodulatory approach addresses critical unmet needs in progressive MS and supports further clinical development.

Background: Sphingosine 1-phosphate receptor (S1PR) modulators can cause transient, dose-related negative chronotropic effects. Mocravimod is an oral S1PR modulator that is developed as a maintenance therapy in allogenic haematopoietic cell transplantation (allo-HCT). This phase I study evaluated whether two dose-titration regimens attenuate early bradycardia when initiating mocravimod while preserving pharmacokinetic (PK) and pharmacodynamic (PD) activity. Patients and methods: In this randomized, double-blind, placebo-controlled, parallel-group study, healthy adults received once-daily oral mocravimod using either dose titration (DT) regimen DT1 (0.3-2.0 mg with 4-day stepwise escalation) or regimen DT2 (0.5 mg to Day 14, 1.2 mg Days 15-18, then 2 mg), a fixed 2 mg regimen, or placebo for 21 days. The primary endpoint was the number of bradycardia episodes on treatment initiation and dose-escalation days derived from 24-hour Holter monitoring; PK of mocravimod and mocravimod-phosphate (whole blood) and PD effects (absolute lymphocyte count [ALC]) were assessed. Results: Fifty-six participants were randomized and 53 completed the study. Both titration regimens resulted in fewer bradycardia episodes than fixed initiation at 2 mg during the first week of treatment. Differences between titration and fixed dosing were no longer evident after Day 9, consistent with tolerance development. PK profiles were consistent with prior phase I data. By Day 21, DT1 achieved exposures close to the fixed 2 mg regimen, whereas DT2 yielded lower exposures, reflecting slower escalation. Peripheral lymphopenia developed in all active treatment groups and was comparable between regimens by Day 21, returning toward baseline by study end. Safety was similar between titration regimens and placebo, with similar distribution and incidence of adverse events. No serious adverse events occurred. Conclusion: Two practical titration regimens mitigated the early negative chronotropic effect observed with fixed-dose initiation of mocravimod at 2 mg once daily. Importantly, titration preserved the expected PK and PD profile, supporting dose escalation as an effective initiation strategy to improve early cardiac tolerability.

Background: Mocravimod is an oral sphingosine-1-phosphate (S1P) receptor modulator. This Phase 1 multiple-ascending-dose study evaluated its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy volunteers. Methods: In this double-blind, randomized, placebo-controlled, parallel-group trial, 60 healthy male volunteers were enrolled in five cohorts. Mocravimod was administered once daily at 0.3, 0.6, 1.2, or 3.0 mg for 14 days, or at 2.0 mg for 28 days. Safety assessments included adverse events (AEs), laboratory tests, vital signs, electrocardiography, and Holter monitoring. PK of mocravimod and its active metabolite, mocravimod-phosphate, and PD effects on absolute lymphocyte count (ALC) and leukocyte subsets were assessed. Results: Fifty-nine of 60 participants completed the study. One participant in the 3.0 mg cohort discontinued treatment because of asymptomatic transaminase elevation. No deaths or serious AEs occurred. AEs were mostly mild or moderate, transient, and showed no clear dose relationship. Mocravimod produced dose-dependent reductions in ALC from 0.6 mg onward, with maximum geometric mean reductions of 65%, 74%, 83%, and 77% at 0.6, 1.2, 2.0, and 3.0 mg, respectively. ALC values recovered to above the lower limit of normal during follow-up in all cohorts. Holter monitoring showed an initial placebo-corrected reduction in heart rate of approximately 10-15 beats/min at doses of 1.2-3.0 mg, which attenuated with continued dosing. One participant in the 3.0 mg cohort had a recurrent daytime second-degree atrioventricular block (Mobitz I/Wenckebach), reported as a mild non-dose-limiting AE. No QT prolongation was observed. Exposure to mocravimod and mocravimod-phosphate increased approximately dose-proportionally. Steady state was reached by Day 14 (Day 28 in the 2.0 mg cohort), accumulation was approximately five- to sevenfold, terminal half-lives were approximately 100-40 hours for both analytes, and parent-to-metabolite exposure ratios were close to 1. Conclusions: Once-daily mocravimod up to 3.0 mg for 14 days and 2.0 mg for 28 days was generally well tolerated and showed predictable S1P-modulator class effects on lymphocyte counts and heart rate, with PK properties supporting once-daily dosing and further clinical development.

BackgroundCocaine produces cardiovascular toxicity through intense sympathetic stimulation and direct myocardial injury, generating presentations ranging from hypertension and tachycardia to coronary vasospasm, arrhythmia, and myocardial depression. {beta}-blockers are foundational therapies in acute coronary syndromes, yet their use after cocaine exposure remains controversial due to concerns about unopposed -adrenergic stimulation. MethodsA systematic review was conducted in accordance with PRISMA guidelines. PubMed and Google Scholar (2000-2026) were searched for observational studies of adults ([&ge;]18 years) presenting to acute care with recent cocaine use that compared outcomes between {beta}-blocker recipients and non-recipients. Eligible studies reported in-hospital mortality, myocardial infarction/troponin rise, clinically significant arrhythmia, or haemodynamic instability. Risk of bias was assessed using the Newcastle-Ottawa Scale, and certainty of evidence using GRADE. ResultsFour retrospective ED cohorts (n = 1,140) met inclusion criteria; 503 patients received at least one {beta}-blocker dose. Across studies, {beta}-blocker use was not associated with increased in-hospital mortality or malignant arrhythmias. Myocardial infarction was heterogeneous and sensitive to definition and timing. Haemodynamic data showed no hypertensive surge and modest systolic blood pressure reductions. Risk of bias was moderate, and certainty of evidence very low to low. ConclusionsIn typical ED presentations of recent cocaine use, {beta}-blocker administration does not appear to increase mortality, myocardial infarction, or malignant arrhythmias, and available haemodynamic data do not support a reproducible unopposed- response. However, mechanistic and preclinical evidence suggests potential harm in severe intoxication or myocardial depression. A selective, phenotype-guided approach is warranted, and prospective mechanistic studies are needed. Key PointsO_LIBeta-blockers did not increase deaths, heart attacks, or dangerous heart rhythms in adults who came to the emergency department after recent cocaine use. C_LIO_LIBlood pressure generally decreased after beta-blocker treatment, and no consistent "unopposed alpha" reaction was seen in typical presentations. C_LIO_LICaution is still needed in severe intoxication or cases with heart muscle weakness, but for most emergency presentations, beta-blockers appear safe when used appropriately. C_LI