Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: Dual antiplatelet therapy (DAPT) is essential for secondary prevention of coronary artery disease (CAD), but gastrointestinal (GI) intolerance often leads elderly patients to self-reduce the dose or discontinue medication. Objectives: To compare the effects of monthly alternating aspirin and clopidogrel versus continuous DAPT on GI symptoms, medication adherence and 6‑month major adverse cardiovascular events (MACE) in elderly community patients with stable CAD. Methods: This retrospective cohort study included 160 elderly patients with stable CAD, who were non-randomly assigned to alternating DAPT (n=80) or continuous DAPT (n=80) according to their documented antiplatelet regimens in clinical practice. GSRS, MMAS-8 and adverse events were evaluated at baseline and 6 months. Results: At 6 months, the observation group’s GSRS total score remained stable (15.14±4.52 to 15.84±4.89, +0.70, P>0.05), while the control group significantly worsened (15.18±4.48 to 19.59±5.67, +4.41, P<0.05); the between-group difference was significant (P<0.05). The MMAS-8 score was higher in the observation group (7.58±0.76 vs. 6.94±1.15, P<0.001), with higher adherence rates (72.50% vs. 51.25%, P=0.006). Total GI adverse events were lower in the observation group (6.25% vs. 18.75%, P=0.017), but GI bleeding did not differ significantly. MACE occurred in 3 cases (3.75%) in each group (P=1.000); however, statistical power was severely insufficient to infer cardiovascular non‑inferiority. Conclusion: Alternating monthly use of aspirin and clopidogrel during the 6-month observation period of this study did not show a significant increase in the risk of MACE. Under these conditions, this regimen attenuated the progressive worsening of gastrointestinal symptoms in elderly patients (scores remained stable rather than significantly worsening) and significantly improved medication adherence. Within this study's specific population (stable elderly CAD patients) and 6-month observation window, this strategy offers a promising alternative worthy of further investigation. Its long-term benefits and cardiovascular safety require confirmation by prospective large-scale trials.

Abstract: Background: Aneurysmal subarachnoid hemorrhage (aSAH) is frequently complicated by hemodynamic instability and impaired cerebral perfusion, which may require vasoactive support. However, the association between norepinephrine (NE) exposure and short-term mortality in aSAH remains uncertain. Objectives: To evaluate the association between NE infusion and 28-day all-cause mortality among patients with aSAH treated with endovascular embolization, while accounting for baseline severity and measured confounding. Methods: This single-center retrospective cohort study included consecutive patients with aSAH who underwent endovascular embolization at The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China, from January 1, 2022 to August 31, 2025. Patients were classified according to NE administration during the acute hospitalization. The primary outcome was 28-day all-cause mortality. Survival was compared using Kaplan-Meier curves and log-rank tests. Cox proportional hazards models were fitted in crude, adjusted and fully adjusted forms. Propensity score-based overlap weighting was applied as a sensitivity analysis to improve covariate balance; balance was evaluated using standardized mean differences (SMDs). Results: A total of 259 patients were included in this study, of whom 67 received norepinephrine. The 28-day mortality rate was higher in the NE group than in the non-NE group (47.8% vs. 15.7%, P<0.001). After full adjustment for laboratory and other relevant covariates, NE use remained associated with an increased risk of 28-day mortality (HR=2.892, 95% CI: 1.566-5.338, P<0.001). Consistent results were observed in the overlap-weighted (OW) analysis (HR=2.211, 95% CI: 1.218-4.015, P=0.009). No significant interactions were identified in the subgroup analyses.Conclusion: NE infusion was associated with higher 28-day mortality in patients with aSAH. Because NE use may also indicate severe hemodynamic instability, these findings should be interpreted as an association rather than proof of causality. Prospective studies with detailed dose-duration data are needed.

Abstract: Background: Gastric ulcer is a prevalent global health issue, often associated with oxidative stress and limited by the adverse effects of conventional therapies. Although Capparis aphylla (Roth) has been traditionally used in folk medicine to manage gastric disorders, its pharmacological activity and underlying mechanisms remain poorly explored. Objectives: This study aimed to evaluate the gastroprotective and antioxidant effects of Capparis aphylla stem bark extracts using an in-vivo ethanol-induced rat model, along with in silico molecular docking analysis. Methods: Sprague-Dawley rats were administered crude hydro-methanolic extract (CAC), aqueous (CAA), or butanolic (CAB) fractions at doses of 100-400 mg/kg for 14 consecutive days. Gastric ulcers were induced using absolute ethanol (90% v/v, 5 mL/kg), followed by daily exposure to 80% ethanol to maintain gastric injury. Ranitidine (50 mg/kg) served as the reference drug. Evaluations included the ulcer index (UI), percentage protection, gastric juice pH, total acidity, and oxidative stress markers (SOD, CAT, GSH, MDA, and nitrite). Phytochemicals identified via GC-MS were subjected to molecular docking against EP3, H₂ and AT1R receptors. Results: The butanolic fraction (CAB) at 400 mg/kg exhibited the highest gastroprotective effect (90% inhibition), surpassing ranitidine (44.1%). Treatment groups showed significant restoration of antioxidant enzymes (SOD, CAT and GSH) and marked reductions in MDA and nitrite levels (p < 0.001). Among the 17 identified compounds, 9-octadecenoic acid methyl ester demonstrated the strongest binding affinity (−7.9 kcal/mol) toward the EP3 receptor. Histopathological findings further confirmed restoration of gastric mucosal integrity, particularly in the CAB-treated group. Conclusion: Capparis aphylla exhibits potent anti-ulcer activity through a synergistic mechanism involving suppression of oxidative stress and modulation of gastric acid secretion. These findings provide scientific validation for its traditional use and highlight its promising gastroprotective potential.

Abstract: Background: Breast cancer is still the most common cause of cancer death all over the world and invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are its two predominant histological subtypes. Ki-67, a marker of cell proliferation and E-cadherin, an essential epithelial cell–cell adhesion molecule, are common prognostic biomarkers that have proven predictive values of response to taxane-based chemotherapy; however, the significance of their gene expression in predicting benefit from taxane therapy across various IDC and ILC subtypes in combination with targeted agents is still less defined. Objectives: This study was conducted to assess the predictive value of Ki-67 and E-cadherin expression for treatment response, progression-free survival (PFS), and overall survival (OS), whereas docetaxel- or paclitaxel-based chemotherapy with trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive cases is used among patients with both IDC and ILC. Methods: The study comprised 200 stage I–III breast cancer patients including 100 IDC and 100 ILC. Tumors were classified into low (30%) based on Ki-67 and E-cadherin expression status, which was evaluated by immunohistochemistry (IHC). All patients received one of the standard taxane-containing chemotherapy regimens with or without trastuzumab for HER2-positive tumors. Eligibility for treatment was not dependent on biomarker status. Tumor responses were determined according to the RECIST criteria and OS was calculated by Kaplan–Meier estimates as well as multivariate Cox regression analysis. Results: Low-dose-treated tumors with low Ki-67 showed significantly higher percent tumor volume reduction (45%) than high Ki-67 tumors (15%; p < 0.01). The rates of complete response (CR) or partial response (PR) were significantly higher in the presence than in the absence of E-cadherin (35% vs 20%; p = 0.04). Patients with a low Ki-67 index had a median PFS of 18 months compared to ≥high Ki-67 group (9 months; p < 0.001). In HER2-positive patients, median PFS was also longer in comparison with HER2-negative controls (22 vs 15 months; p = 0.03). Conclusion: Ki-67 and E-cadherin expression for the prognosis of response as well as survival in patients with IDC and ILC undergoing taxane-based chemotherapy can be independently stratified. These results imply that combining proliferation and adhesion markers may contribute to personalized treatment decision-making beyond their prognostic implications.

Abstract: Background: Overexpression of ATP-binding cassette subfamily B member 1 (ABCB1) is a major driver of docetaxel resistance in prostate cancer. Thus, identifying effective agents that specifically target ABCB1 is essential for overcoming chemoresistance. Objectives: This study aimed to determine whether reserpine, a lipophilic indole alkaloid derived from Rauwolfia, could reverse docetaxel resistance in prostate cancer by modulating ABCB1. Methods: Network pharmacology analysis was used to identify potential targets of Rauwolfia-derived compounds. Molecular docking, cellular thermal shift assay and molecular dynamics simulation were performed to evaluate the interaction between reserpine and ABCB1. Cytotoxicity and reversal assays were conducted in docetaxel-resistant prostate cancer cells and ABCB1-overexpressing cells. Colony formation, 3D spheroid, doxorubicin accumulation/efflux, ATPase, apoptosis and cell-cycle assays were used to investigate the functional effects and underlying mechanism. Results: Reserpine was identified as a candidate Rauwolfia-derived compound associated with ABCB1. Computational and target-engagement analyses supported direct interaction between reserpine and ABCB1. At minimally cytotoxic concentrations, reserpine significantly restored docetaxel sensitivity in DU145-DTX, LNCaP-DTX and HEK293-ABCB1 cells, while showing little effect in parental control cells. Reserpine did not alter ABCB1 expression or subcellular localization, but increased intracellular accumulation of doxorubicin, inhibited drug efflux and stimulated ABCB1 ATPase activity. In addition, reserpine enhanced docetaxel-induced apoptosis and G₂/M arrest in resistant prostate cancer cells. Conclusion: Our Reserpine was identified as a promising natural small molecule capable of overcoming ABCB1-dependent docetaxel resistance, warranting further evaluation for prostate cancer therapy.