Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: Esophageal adenocarcinoma is associated with poor survival despite advances in systemic therapy. Readily available serum biomarkers may improve risk stratification; however, their combined role in biomarker-guided treatment decisions remains insufficiently investigated. Objectives: To evaluate the prognostic significance of combined baseline carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels and explore their utility for biomarker-based risk stratification in patients with esophageal adenocarcinoma receiving systemic chemotherapy. Methods: This retrospective real-world cohort study included 38 patients with histologically confirmed esophageal adenocarcinoma who received systemic chemotherapy at a tertiary referral center between January 2016 and December 2021. Patients were classified into three exploratory biomarker-defined risk groups according to baseline serum CEA and CA19-9 levels. Overall survival was evaluated using Kaplan–Meier analysis and Cox proportional hazards regression, while treatment outcomes were explored across biomarker-defined groups and chemotherapy regimens. Results: Elevated baseline CEA and CA19-9 levels were associated with shorter overall survival. Patients with simultaneous elevation of both biomarkers demonstrated the poorest survival outcomes (multivariable hazard ratio = 2.22). Differences in survival were observed across chemotherapy regimen groups within biomarker-defined categories; however, these comparisons were exploratory and may have been influenced by treatment-selection bias and unmeasured clinical factors. Patients with distal or gastroesophageal junction adenocarcinoma showed more favorable outcomes than those with cervical or thoracic tuxzmors. Conclusion: Combined assessment of baseline CEA and CA19-9 may provide a practical and inexpensive approach for biological risk stratification in esophageal adenocarcinoma. However, these findings do not establish that the biomarkers can guide chemotherapy selection. Prospective multicenter studies with independent validation are required to determine their prognostic and predictive value before biomarker-guided treatment selection can be recommended in routine clinical practice.

Abstract: Background: Toxic acute renal failure (ARF) involves severe oxidative stress. The Nrf2 pathway is a key antioxidant defense mechanism. Objectives: To investigate whether naloxone combined with hemoperfusion alleviates oxidative injury via Nrf2 activation in toxic ARF. Methods: In this single-center retrospective cohort study at Qiqihar Medical University Hospital, 67 patients were enrolled through medical record screening. The control group (n=39) received hemoperfusion alone; the observation group (n=28) received additional intravenous naloxone (0.8 mg bolus + 2.0 mg/24 h infusion for 7 days). Renal function and oxidative markers were assessed before treatment, at 24 h and day 7. Multivariate regression analysis was used to adjust for confounding factors. Separately, 30 rats were randomized into control, model and treatment groups (n=10 each). The treatment group received intraperitoneal naloxone (1.0 mg/kg) plus simulated hemoperfusion. Results: After adjusting for baseline imbalances, combined therapy was independently associated with significant reductions in Scr and BUN in patients (adjusted β = -8.52, 95% CI: -12.37 to -4.67, P < 0.001) and with significant improvements in renal function and histopathology in rats. Combined therapy decreased tubular injury markers (β2-MG, KIM-1, NGAL, L-FABP) in rats. Mechanistically, it was associated with activation of the Nrf2/HO-1/NQO1 pathway, enhanced SOD activity and reduced MDA levels. Improvements were time-dependent (24 h to day 7). Conclusions: Naloxone combined with hemoperfusion activates the Nrf2 pathway, attenuates oxidative stress and improves renal function in toxic acute renal failure.

Abstract: Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, joint swelling, pain, cartilage destruction and bone erosion. Qingteng Waifu San is an external sinomenine-containing preparation, but its site-specific transdermal response requires disease-relevant evaluation. Objectives: To compare Zusanli (ST36)-site and adjacent non-acupoint transdermal application of Qingteng Waifu San in an ovalbumin/complete Freund’s adjuvant-induced RA rabbit model and to evaluate formulation, neuropeptide, inflammatory, behavioural and histopathological outcomes. Methods: Forty-eight New Zealand white rabbits were allocated into six groups (n=8 each): normal control, vehicle-only transdermal control, acupuncture, acupoint injection, ST36-site transdermal Qingteng Waifu San and adjacent non-acupoint transdermal Qingteng Waifu San. Gel appearance, pH, viscosity, spreadability, sinomenine content and high-performance liquid chromatography (HPLC) fingerprint similarity were assessed. Substance P (SP), calcitonin gene-related peptide (CGRP), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1 beta (IL-1beta) were measured by enzyme-linked immunosorbent assay (ELISA). SP and CGRP messenger RNA (mRNA) were analysed by real-time polymerase chain reaction (PCR). Arthritis score, paw volume, mechanical withdrawal threshold and histopathological scores were assessed. Results: The vehicle-only group showed RA-related changes compared with normal controls. ST36-site Qingteng Waifu San reduced arthritis score, paw volume, serum cytokines and histopathological injury scores and improved mechanical withdrawal threshold compared with vehicle-only control. SP and CGRP levels were higher after ST36 application than after adjacent non-acupoint application, indicating site-dependent neurocutaneous modulation. Conclusion: ST36-site transdermal Qingteng Waifu San produced stronger neuropeptide modulation and more favourable RA-related outcome profiles than adjacent non-acupoint application.

Abstract: Background: Intravenous lidocaine reduces propofol requirements and procedure-related adverse events. Objectives: The study aimed to test whether intravenous lidocaine would reduce the effect-site concentration of propofol required to achieve loss of consciousness and decrease propofol consumption during total intravenous anesthesia in gynecological laparoscopy. Methods: This was a prospective, randomized, double-blind, placebo-controlled trial. Sixty patients were randomly allocated to receive either intravenous lidocaine (1.5 mg•kg-¹ bolus) followed by continuous infusion or an equal volume of saline. Propofol was administered via target-controlled infusion starting at an effect-site concentration of 3.5 μg/mL. The concentration was then adjusted in steps of 0.5 μg/mLaccording to Dixon’s up-and-down sequential method: decreased if loss of consciousness was achieved, or increased if not. Loss of consciousness was defined as loss of response to verbal commands. The median effective concentration (EC50) of propofol for inducing loss of consciousness was calculated using the Dixon’s up-and-down method. General anesthesia was maintained with propofol and remifentanil, guided by state entropy (target 40-60) and surgical pleth index (target 20-50). Drug consumption was normalized to anesthesia duration and body weight. Results: The estimated EC50 of propofol for inducing loss of consciousness was significantly lower in the lidocaine group than in the saline group (3.32 μg/mL, 95% Confidence Interval (CI): 3.04-3.59 vs. 3.89 μg/mL, 95% CI: 3.50-4.28). Under the study protocol, the lidocaine group also required less propofol (8.62 mg•kg-1•h-1, 95% CI: 8.10-9.15 vs. 9.89 mg•kg-1•h-1, 95% CI: 9.05-10.73) and less remifentanil (0.23 μg•kg-1•min-1, 95% CI: 0.21-0.24 vs. 0.27 μg•kg-1•min-1, 95% CI: 0.24-0.30) compared with the saline group. Conclusion: Intravenous lidocaine reduced the propofol EC50 for Loss of Consciousness (LOC) and decreased intraoperative propofol and remifentanil consumptions in patients undergoing gynecological laparoscopy. These findings suggest a propofol- and opioid-sparing effect of intravenous lidocaine in this setting, although confirmation in larger multicenter trials is needed.

Abstract: Background: Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune demyelinating diseases of the central nervous system. The role of microRNA-34b (miR-34b) in NMOSD pathogenesis remains unclear. This study investigates the expression and functional mechanism of miR-34b in NMOSD, specifically its regulation of the TIA-1-stress granule pathway. Objectives: To determine the expression level of miR-34b in NMOSD tissues and cell lines and to elucidate whether miR-34b suppresses cell proliferation and promotes apoptosis by directly targeting the TIA-1-stress granule pathway. Methods: Real-time PCR was used to detect miR-34b expression in 25 NMOSD tissue specimens obtained from a hospital laboratory (13 early-stage, 12 chronic-stage) and 10 normal control tissues, as well as in RGC-5 cells. RGC-5 cells were transfected with miR-34b mimics, inhibitors or negative controls. Cell proliferation was assessed by MTT assay and cell cycle distribution and apoptosis was analyzed by flow cytometry (PI staining and Annexin V-FITC/PI double staining, respectively). The direct binding between miR-34b and the 3'-UTR of TIA-1 mRNA was validated using a dual-luciferase reporter assay. Protein expression levels of TIA-1, SG, HuR, CDK2 and BCL-2 were measured by Western blot. A rescue experiment was performed by co-transfecting miR-34b mimics with a TIA-1 overexpression plasmid. Results: miR-34b was lower in NMOSD vs controls (0.32 ± 0.08 vs. 1.00 ± 0.12, P<0.01), especially in the chronic stage. miR-34b mimics inhibited proliferation, induced G0/G1 arrest (68.5% vs. 52.1%, P<0.01) and increased apoptosis (22.6% vs. 8.3%, P<0.001). miR-34b inhibitor had opposite effects. miR-34b directly bound TIA-1 3'-UTR and downregulated TIA-1, SG, HuR. TIA-1 overexpression partially reversed miR-34b effects. Conclusions: miR-34b is downregulated in NMOSD. Overexpression of miR-34b suppresses proliferation and promotes apoptosis by targeting the TIA-1-stress granule pathway. Restoring miR-34b may be a therapeutic strategy for NMOSD.